Identifying the role of Phytomolecules in&nbsp; the management of liver diseases by modulating NRF2 pathway: A Scoping Review Protocol

Ajay Mili; Priyobrat Rajkhowa; Krishnadas Nandakumar; Richard Lobo

doi:10.12688/f1000research.150635.2

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Study Protocol

Revised

Identifying the role of Phytomolecules in the management of liver diseases by modulating NRF2 pathway: A Scoping Review Protocol

[version 2; peer review: 2 approved]

Ajay Mili¹, Priyobrat Rajkhowa², Krishnadas Nandakumar³, Richard Lobo ¹

PUBLISHED 08 Jul 2024

Author details Author details

¹ Pharmacognosy, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
² Health Policy, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
³ Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India

Ajay Mili
Roles: Conceptualization, Data Curation, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing

Priyobrat Rajkhowa
Roles: Data Curation, Investigation, Methodology, Writing – Review & Editing

Krishnadas Nandakumar
Roles: Data Curation, Supervision, Writing – Review & Editing

Richard Lobo
Roles: Data Curation, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Manipal Academy of Higher Education gateway.

Abstract

Background

The Liver is a vital organ in the human body, which plays a crucial role in various physiological processes. Oxidative stress is a critical factor in the pathogenesis and progression of various liver diseases, contributing to cellular damage and dysfunction. The Liver is particularly vulnerable to the harmful effects of reactive oxygen species when the balance between their production and the body’s antioxidant defense mechanisms is disrupted. The nuclear factor erythroid 2-related factor 2 (NRF2) pathway has emerged as a promising therapeutic target for liver diseases due to its pivotal role in cellular defense against oxidative stress and inflammation. Plants have always been a source of drugs which has been used to treat various pharmacological disorders and most of its activity is due to its potential as an antioxidant. However, the specific mechanisms by which they interact with the NRF2 pathway and confer protection against liver diseases remain inadequately elucidated. Therefore, this scoping review aims to identify and analyze the existing literature pertaining to the relationship between Phytomolecules, which can modulate NRF2 and protect against liver diseases.

Methods

The proposed scoping review will follow the steps given by “Arksey and O’Malley and Levac et al”. Electronic databases (PubMed/MEDLINE, Embase, etc.) will be searched for recent relevant studies. A predefined criterion for the inclusion and exclusion of studies will be independently adopted by two reviewers. The review will be presented as per the “Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Review (PRISMA-ScR)” guidelines.

Conclusion

The scoping review finding is expected to help understanding the role of Phytomolecules in preventing liver diseases by modulating the NRF2 pathway. Ultimately, this review will serve as a foundational step toward developing targeted interventions to improve liver health outcomes and reduce the global burden of liver diseases.

Keywords

NRF2 pathway, Liver diseases, Phytomolecules, Oxidative stress

Corresponding author: Richard Lobo

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2024 Mili A et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Mili A, Rajkhowa P, Nandakumar K and Lobo R. Identifying the role of Phytomolecules in the management of liver diseases by modulating NRF2 pathway: A Scoping Review Protocol [version 2; peer review: 2 approved]. F1000Research 2024, 13:522 (https://doi.org/10.12688/f1000research.150635.2) First published: 22 May 2024, 13:522 (https://doi.org/10.12688/f1000research.150635.1) Latest published: 08 Jul 2024, 13:522 (https://doi.org/10.12688/f1000research.150635.2)

Revised Amendments from Version 1

In the Search Strategy section, we have incorporated grey literature to ensure a comprehensive review. The process for resolving disagreements between reviewers has been updated to reflect improved handling methods. Table 3 now includes non-English literature as part of the inclusion criteria, broadening the scope of our review. In the Collating, Summarizing, and Reporting the Results section, we have integrated thematic synthesis, a qualitative data analysis method, to provide a more in-depth analysis of the collected data.

See the authors' detailed response to the review by Tamer A. Addissouky

Introduction

Liver diseases represent a significant global health challenge, including a variety diseases including viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), drug-induced liver injury (DILI), and liver cirrhosis.¹^,² The liver, a pivotal metabolic organ, plays an important role in physiological processes including detoxification, metabolic regulation, protein biosynthesis, bile secretion, and immunomodulation. Intracellular reactive oxygen species (ROS) are produced internally, for instance during mitochondrial oxidative phosphorylation, or can emerge through interactions with external agents such as xenobiotic substances. For maintain the ROS levels, Liver has various antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase (SOD). Any imbalance in the working of the antioxidant enzymes can lead to oxidative stress and it is one of the key factors in the progression and onset of liver diseases.³^,⁴

The Nuclear factor erythroid 2-related factor 2 (NRF2) pathway has emerged as a promising target for managing liver diseases. NRF2, a transcription factor, is integral to cellular defense mechanisms against oxidative stress and inflammation. Upon activation, NRF2 facilitates the expression of various genes involved in antioxidant and detoxification processes, thereby increasing the synthesis of antioxidant enzymes and proteins that mitigate the negative impacts of ROS and pro-inflammatory mediators. Growing evidence implicates NRF2 pathway dysregulation in liver disease pathogenesis and progression. Both experimental and clinical investigations have explored NRF2 modulation to mitigate liver damage, attenuate inflammation, and enhance hepatocyte viability.⁵^,⁶ Consequently, identifying compounds capable of activating the NRF2 pathway holds potential for advancing liver disease management strategies.

Phytomolecules, also known as phytochemicals or secondary metabolites, have recently been gaining a distinguished status as a potential source of drugs for treating various diseases. Phytomolecules have various pharmacological activities, such as antioxidant,⁷^,⁸ anti-inflammatory,⁷ anticancer,⁹^,¹⁰ Cardioprotective,¹¹^,¹² Neuroprotective,¹³^,¹⁴ Hepatoprotective,¹⁵^,¹⁶ through their potential as an antioxidant and the potential to alter the signaling pathways.

It is essential to note that the precise role of Phytomolecules as modulators of the NRF2 pathway in managing liver diseases remains uncertain or ambiguous. Consequently, this scoping review is being undertaken to address this knowledge gap. By amalgamating existing literature on the role of Phytomolecules as modulators of the NRF2 pathway in managing liver diseases through the adoption of scoping review methodology, this study distinguishes itself and contributes novel evidence to the field.

Protocol

Methods

The protocol for the scoping review has been formulated by utilizing the frameworks proposed by “Arksey and O’Malley and Levac et al.”.¹⁷ This review will adhere to the guidelines outlined in the Preferred Reporting Item for Scoping Reviews (PRISMA-ScR). For ensuring proper reporting, the “Preferred Reporting Items for Scoping Reviews (PRISMA-ScR)” will be adopted.¹⁸

Review question

The review question was framed through systematic brainstorming and iteratively refining ideas by the team. A literature search on Phytomolecules, NRF2 and Liver disease was done, leading to our research question.

1. What are the different types of Phytomolecules that contribute to the modulation of the NRF2 pathway for protection against Liver disease?

Eligibility criteria

JBI manual for evidence synthesis 2020 format will be adopted for the development of research question PCC (Population, Concept, Context) (Table 1).¹⁹ The study’s primary goal is to methodically identify and map the existing literature on the role of Phytomolecules in managing liver diseases through the modulation of the NRF2 pathway.

Table 1. PCC framework.

Population (P)	The population of interest refers to the individuals or animals (rats or mice) being studied. In this case, the population would include individuals or animals with liver diseases. Liver diseases encompass a range of conditions, such as liver fibrosis, cirrhosis, hepatitis, non-alcoholic fatty liver disease (NAFLD), and others.
Concept (C)	The scoping review will explore the Phytomolecules and their role in modulating the NRF2 pathway. Also, management of liver diseases through the use of Phytomolecules.
Context (C)	The context of human and animal studies is chosen to establish the relevance of NRF2 in a controlled experimental setting.

Search strategy

A literature search will be done in the electronic database, including Scopus, Web of science, CINAHL, PubMed, and EMBASE, to identify recent relevant literature published from 2015 to 2024. The keywords which will be used for searching are listed in Table 2. The search will focus exclusively on articles written in English. We’ll conduct a comprehensive exploration of potentially relevant articles by scrutinizing the reference lists of the included papers and any available grey literature. Rayyan, an online platform, will be utilized to manage the collected data.²⁰

Table 2. Search terms.

Population: Liver disease	Concept 1: NRF2 pathway	Concept 2: Natural compounds
Non-alcoholic fatty Liver Non-alcoholic steatohepatitis Alcoholic fatty liver disease Alagille syndrome Biliary Atresia Cirrhosis Hemochromatosis Hepatitis Primary Biliary Cholangitis Cirrhosis Primary Sclerosing Cholangitis Porphyria Wilson Disease Drug induced liver injury Chemical induced liver injury	NRF2 Nuclear factor erythroid 2-related factor 2 Nuclear factor erythroid-derived 2-like 2 NFE2L2	Natural compound* Natural product* Extract* Natural molecule* Plant based compound* Phytomolecule* Phytocompound Botanical compound* Phytochemical* Herbal compound* Phytonutrient* Secondary metabolite*

* Wildcard character of Boolean search to include alternative form of word.

Scoping reviews are broad by nature, so searching, screening, and selecting studies can uncover new terms, ideas, and even sources of information that weren’t initially considered. The search strategy can be modified throughout the review process to keep up with these findings.

Study selection

All identified citations will be collected and uploaded into Rayyan, with duplicates being removed post-search. Two reviewers (AM & PR) will screen all retrieved titles and abstracts and assess the papers for eligibility based on predefined inclusion criteria. In cases where the reviewers are uncertain about a study's eligibility, a third reviewer (RL) or an independent opinion may be sought. The authors will reach a consensus on potentially relevant research through collective screening, and the full text of these studies will be retrieved for further review by agreement.

Included studies will undergo data charting and be reported by adhering to the PRISMA 2020 diagram.²¹ All studies meeting the inclusion and exclusion criteria, regardless of quality, will be incorporated (Table 3).

Table 3. Inclusion and exclusion criteria.

Inclusion criteria	Exclusion criteria
Studies investigating the role of nuclear factor erythroid 2-related factor 2 (NRF2) modulation in the management, prevention, or treatment of liver diseases.	Studies that do not specifically address the role of NRF2 in the management of liver diseases should be excluded.
Both experimental and observational studies, including randomized controlled trials, cohort studies, case-control studies, cross-sectional studies, case series and animal studies to be considered.	Any reviews, commentaries, Conference abstract presentations to be excluded.
Studies published in any language will be included. Non-English articles will be translated using online tools; if accurate translation is not possible, the study will be excluded, and this limitation will be duly noted in the limitations section.

Data charting

The process of data charting will be executed utilizing a predetermined format designed for this purpose. Two reviewers will independently chart data for each paper included in the review using Microsoft excel. In the case of any disagreement, the opinion of an additional or the third reviewer will be sought. This systematic procedure will assist in identifying gaps in the research area. The data extraction will include i) Study title, ii) Authors, iii) Publication year, iv) Study design, v) Study objectives, vi) Findings, vii) Study subjects, viii) Liver diseases studied, ix) Type of phytomolecules, x) Phytomolecule source, xi) NRF2 pathway modulation, xii) Outcome measures, xiii) Conclusion, and xiv) Recommendations.

The data extraction protocol will be iteratively refined as data is obtained from each included source of evidence. Any adjustments made will be meticulously documented within the scoping review. As a pragmatic measure, there will be no direct outreach to included study authors to solicit missing or supplementary data.

Collating, summarizing, and reporting the results

The study findings will be synthesized using a combination of narrative (qualitative analysis) and tabular formats to present the generated evidence. Qualitative and quantitative evidence from the developed data charting table will help in mapping the accessible literature and reporting studies that depict the key findings pertaining to the roles of Phytomolecules as NRF2 modulator in the management of liver diseases. The process will involve identifying knowledge gaps or areas necessitating further research. Additionally, consider disseminating the findings through publication in a peer-reviewed journal or presentation at relevant conferences.

Discussion

Throughout history, humans have utilized plants as a source of beneficial molecules, including Phytomolecules. Therefore, the present scoping review seeks to identify and document the Phytomolecules that can protect against liver disease by modulating the NRF2 pathway. The review’s findings will help provide a comprehensive overview of the Plant, its potential Phytomolecules, class of Phytomolecules, and the type of liver disease that can be treated or managed by Phytomolecules by NRF2 modulation. By providing early insights into a drug’s potential and guiding its development, they significantly increase the chances of success while ensuring ethical considerations and regulatory compliance, paving the way for developing safe and effective treatments.

The limitations of this review are that it excludes non-English databases in the literature search as it can cause practical implications, and neither will assess the quality of studies methodology.

Dissemination

Findings will be disseminated in a scientific journal.

Study status

The literature search is ongoing.

Ethical considerations

As there are no human participants involved, there will be no requirement for ethical approval. Patients and/or the public were not involved in the design of this protocol.

Authors contribution

Ajay Mili: Conceptualization, Methodology, Investigation, Data Curation, Writing- Original draft preparation, Writing-Reviewing and Editing. Priyobrat Rajkhowa: Methodology, Investigation, Data Curation, Writing-Reviewing and Editing. Krishnadas Nandakumar: Supervision, Data Curation, Writing-Reviewing and Editing. Richard Lobo: Supervision, Data Curation, Writing-Reviewing and Editing.

Data availability

Underlying data

No data are associated with this article.

Reporting guidelines

Open Science Framework: “PRISMA-ScR-Fillable-Checklist_10Sept2019”, https://doi.org/10.17605/OSF.IO/C3P8K.

Acknowledgment

Author Ajay Mili and Priyobrat Rajkhowa are thankful to the Manipal Academy of Higher Education (MAHE) for providing Dr.T.M.A. Pai Doctoral Fellowship. The authors also acknowledge with thanks the Manipal College of Pharmaceutical Sciences (MCOPS), Prasanna School of Public Health (PSPH), and the Manipal Academy of Higher Education (MAHE) for providing facilities for this work.

References

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Version 2

VERSION 2 PUBLISHED 22 May 2024

Author details Author details

Ajay Mili
Roles: Conceptualization, Data Curation, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing

Priyobrat Rajkhowa
Roles: Data Curation, Investigation, Methodology, Writing – Review & Editing

Krishnadas Nandakumar
Roles: Data Curation, Supervision, Writing – Review & Editing

Richard Lobo
Roles: Data Curation, Supervision, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (2)

version 2

Revised

Published: 08 Jul 2024, 13:522

https://doi.org/10.12688/f1000research.150635.2

version 1

Published: 22 May 2024, 13:522

https://doi.org/10.12688/f1000research.150635.1

© 2024 Mili A et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Mili A, Rajkhowa P, Nandakumar K and Lobo R. Identifying the role of Phytomolecules in the management of liver diseases by modulating NRF2 pathway: A Scoping Review Protocol [version 2; peer review: 2 approved]. F1000Research 2024, 13:522 (https://doi.org/10.12688/f1000research.150635.2)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Open Peer Review

Version 2

VERSION 2

PUBLISHED 08 Jul 2024

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Reviewer Report 22 Apr 2025

Anju Dhiman, Department of Pharmaceutical Sciences, Maharshi Dayanand University Rohtak, Rohtak, Haryana, India

Approved

https://doi.org/10.5256/f1000research.168761.r313388

The article titled "Identifying the role of Phyto-molecules in the management of liver disease by modulating NRF2 pathway: A Scoping Review Protocol" outlines a comprehensive review protocol aimed at exploring the therapeutic potential of phyto-molecules in liver disease management. Specifically, it focuses on the role of the NRF2 pathway, which is known for its protective effects against oxidative stress and inflammation in liver diseases. The review protocol aims to systematically examine existing evidence on how various plant-derived compounds can modulate the NRF2 pathway and contribute to liver health. Given the increasing interest in natural products as alternative or adjunctive treatments for liver diseases, this article is highly relevant for advancing research in this field.

Major Points:

Clarity and Structure of the Protocol:

The protocol is well-organized, with clear sections outlining the objectives, methodology, and expected outcomes. The systematic approach to reviewing the literature on phyto-molecules and NRF2 is commendable, as it provides a structured framework for the review process.

Importance of NRF2 in Liver Disease:

The focus on NRF2 as a target for liver disease therapy is highly relevant and timely. Given the central role of NRF2 in cellular defense mechanisms, its modulation through phyto-molecules offers promising therapeutic potential, especially in liver diseases that involve oxidative stress and inflammation.

Selection of Phyto-molecules:

The inclusion of a wide variety of plant-derived compounds provides a comprehensive perspective on the topic. The article addresses both commonly studied and lesser-known phyto-molecules, which will help broaden the scope of the review and offer new insights into liver disease management.

Methodology:

The methodology proposed for this scoping review is sound, and the inclusion/exclusion criteria are well-defined. The systematic search strategy ensures that the review will be thorough, and the article gives sufficient detail on how relevant studies will be selected and analyzed.

Minor Points:

Justification for Choosing Phyto-molecules:

While the protocol highlights the importance of phyto-molecules, a brief section discussing the rationale for focusing on these compounds over synthetic drugs could provide additional context. Phyto-molecules' potential advantages, such as fewer side effects, might strengthen the relevance of this study.

Future Implications and Applications:

The article could benefit from a brief discussion of the potential clinical implications of the findings. For instance, how the results could influence future drug development, clinical practices, or patient outcomes in liver disease management would provide a clearer picture of the long-term impact of the research.

Language and Terminology:

The language used in the article is generally clear, but some technical terms (e.g., "NRF2 pathway modulation") might be explained in simpler terms for a broader audience, particularly for non-experts in the field of molecular biology.

Conclusion: In conclusion, the article presents a promising scoping review protocol that addresses an important and relevant topic. The study's approach to examining phyto-molecules in the context of the NRF2 pathway for liver disease management is well thought out, and the methodology appears rigorous. I believe this review will contribute significantly to the current body of knowledge in the field.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Phytomedicines

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report 12 Jul 2024

Tamer A. Addissouky, Menoufia University, Shebeen El-Kom, Menofia Governorate, Egypt

Approved

https://doi.org/10.5256/f1000research.168761.r300409

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PUBLISHED 22 May 2024

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Reviewer Report 14 Jun 2024

Tamer A. Addissouky, Menoufia University, Shebeen El-Kom, Menofia Governorate, Egypt

Approved with Reservations

https://doi.org/10.5256/f1000research.165225.r288724

Positive points:
- The research question is clearly defined using the PCC framework which provides context and scope for the review.
- An extensive search strategy is described using relevant databases and search terms to capture all available literature.
- Clear inclusion/exclusion criteria are defined to filter relevant studies in a systematic manner.
- A team-based approach is outlined for the different stages of title/abstract screening, full-text review, and data extraction to ensure objectivity.
- Data will be charted using a standardized format and then summarised both narratively and quantitatively to synthesise evidence.
- Findings will be disseminated through publication, adding value.

Negative points:
- Quality assessment of studies is not mentioned which is important to evaluate strength of evidence.
- No mention of handling any disagreement between reviewers during study selection.
- Only English literature will be included which can introduce language bias.
- No plans to search grey literature sources which may contain some relevant data.
- No qualitative analysis is proposed which could provide contextual insights beyond numbers.

Recommendations:
- Develop and apply a quality assessment tool to appraise rigour of primary studies.
- Detail a clear process for resolving any disagreements between reviewers.
- Consider translating the abstracts of relevant non-English studies to broaden scope.
- Include searches of dissertations, conference abstracts and trials registries.
- Use qualitative data analysis methods like thematic synthesis for narrative findings.
- Engage stakeholders to obtain their perspectives and ensure findings are meaningful.
- Pilot test all tools and processes on a sample of studies to address any issues early.

In summary, this protocol outlines a rigorous systematic approach. Enhancing the quality assessment process, broadening the scope and applying qualitative synthesis would strengthen the review.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: biomedical

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response 08 Jul 2024

Richard Lobo, Pharmacognosy, Manipal Academy of Higher Education, Manipal, 576104, India

08 Jul 2024

Author Response
Dear Reviewer,
Thank you for your detailed and constructive feedback on our scoping review protocol. We appreciate your insights and suggestions, which will undoubtedly strengthen the rigor and comprehensiveness of ... Continue reading
Dear Reviewer,
Thank you for your detailed and constructive feedback on our scoping review protocol. We appreciate your insights and suggestions, which will undoubtedly strengthen the rigor and comprehensiveness of our study. Below are our responses and actions based on your specific points:

Acknowledgment: We acknowledge your positive feedback on several aspects of our protocol:

The research question is clearly defined using the PCC framework, providing a robust context and scope.

An extensive search strategy is outlined, utilizing relevant databases and search terms to comprehensively capture available literature.

Clear inclusion/exclusion criteria are defined to systematically filter relevant studies.

A team-based approach is planned for screening, review stages, and data extraction to ensure objectivity.

Data will be charted using a standardized format and synthesized both narratively and quantitatively.

Findings will be disseminated through publication, adding value to the existing literature.

Responses to Specific Questions:

Quality Assessment of Studies: We acknowledge your concern regarding the quality assessment of individual studies in our scoping review. Please note that our review is focused on mapping the breadth of literature rather than conducting a formal quality assessment. The methodology follows the Arksey, H., & O’Malley, L. (2005) framework, which does not include the adoption of a quality assessment for studies. We aim to adhere to this established methodology. Furthermore, this scoping review serves as a preliminary step toward a systematic review. Upon completion of the scoping review, we plan to conduct a systematic review where we will incorporate a quality assessment tool to evaluate the included studies.

Handling Disagreements Between Reviewers: We acknowledge your concern regarding the handling of disagreements between reviewers. This aspect is addressed in the study selection section of the methods section. We have now comprehensively detailed the process for handling disagreements between reviewers.

Language Bias: We acknowledge your comment regarding the inclusion of studies published in various languages. We will attempt to include studies published in any language in the scoping review. However, the translation of these studies will rely on online translation tools. If we are unable to accurately translate certain articles, they will be excluded from the review. This limitation will be duly acknowledged in the limitations section of the manuscript. We have mentioned our approach to including any language of studies in the scoping review in the manuscript in Table 3.

Grey Literature: We acknowledge the importance of including grey literature sources to capture additional relevant data. We have mentioned our approach to including grey literature in the manuscript in the search strategy section of the methods section.

Qualitative Analysis: We appreciate your emphasis on the importance of qualitative analysis. While we initially proposed only narrative analysis, we recognize the value of incorporating additional qualitative data analysis methods, such as thematic synthesis, to provide deeper contextual insights. We have addressed this in the “Collating, summarizing, and reporting the results” section of the manuscript.

Response to recommendations:

Develop and apply a quality assessment tool to appraise the rigor of primary studies: We wish to clarify that our scoping review does not include a formal quality assessment of individual studies, as per the methodology outlined by Arksey and O’Malley (2005), which does not prescribe such an assessment. Implementing changes to this methodology at this stage poses challenges.

Detail a clear process for resolving any disagreements between reviewers: We have embraced this recommendation and detailed a clear process for resolving disagreements between reviewers in the manuscript.

Consider translating abstracts of relevant non-English studies to broaden scope: Regarding language bias, we have accepted the recommendation to consider translating abstracts of relevant non-English studies using online tools. If translation accuracy cannot be ensured, studies will be excluded as outlined in the manuscript.

Include searches of dissertations, conference abstracts, and trials registries: We have accepted to include searches of grey literature sources such as dissertations, conference abstracts, and trial registries, as also specified in the manuscript.

Consider qualitative data analysis methods like thematic synthesis: We have embraced the suggestion to incorporate qualitative data analysis methods like thematic synthesis, which has been highlighted in the manuscript.

Engage stakeholders to ensure findings are meaningful: Upon completion of our study, we plan to consult various stakeholders to ensure that our findings are meaningful and impactful.

Pilot test all tools and processes on a sample of studies to address any issues early: Recognizing its importance, we have conducted pilot testing on our tools, including the data extraction chart, to address any potential issues early in the process.

We are committed to enhancing the transparency, rigor, and inclusivity of our scoping review methodology based on your valuable feedback. Please do not hesitate to reach out if you have any further questions or suggestions.
Dear Reviewer,
Thank you for your detailed and constructive feedback on our scoping review protocol. We appreciate your insights and suggestions, which will undoubtedly strengthen the rigor and comprehensiveness of our study. Below are our responses and actions based on your specific points:

Acknowledgment: We acknowledge your positive feedback on several aspects of our protocol:

The research question is clearly defined using the PCC framework, providing a robust context and scope.

An extensive search strategy is outlined, utilizing relevant databases and search terms to comprehensively capture available literature.

Clear inclusion/exclusion criteria are defined to systematically filter relevant studies.

A team-based approach is planned for screening, review stages, and data extraction to ensure objectivity.

Data will be charted using a standardized format and synthesized both narratively and quantitatively.

Findings will be disseminated through publication, adding value to the existing literature.

Responses to Specific Questions:

Quality Assessment of Studies: We acknowledge your concern regarding the quality assessment of individual studies in our scoping review. Please note that our review is focused on mapping the breadth of literature rather than conducting a formal quality assessment. The methodology follows the Arksey, H., & O’Malley, L. (2005) framework, which does not include the adoption of a quality assessment for studies. We aim to adhere to this established methodology. Furthermore, this scoping review serves as a preliminary step toward a systematic review. Upon completion of the scoping review, we plan to conduct a systematic review where we will incorporate a quality assessment tool to evaluate the included studies.

Handling Disagreements Between Reviewers: We acknowledge your concern regarding the handling of disagreements between reviewers. This aspect is addressed in the study selection section of the methods section. We have now comprehensively detailed the process for handling disagreements between reviewers.

Language Bias: We acknowledge your comment regarding the inclusion of studies published in various languages. We will attempt to include studies published in any language in the scoping review. However, the translation of these studies will rely on online translation tools. If we are unable to accurately translate certain articles, they will be excluded from the review. This limitation will be duly acknowledged in the limitations section of the manuscript. We have mentioned our approach to including any language of studies in the scoping review in the manuscript in Table 3.

Grey Literature: We acknowledge the importance of including grey literature sources to capture additional relevant data. We have mentioned our approach to including grey literature in the manuscript in the search strategy section of the methods section.

Qualitative Analysis: We appreciate your emphasis on the importance of qualitative analysis. While we initially proposed only narrative analysis, we recognize the value of incorporating additional qualitative data analysis methods, such as thematic synthesis, to provide deeper contextual insights. We have addressed this in the “Collating, summarizing, and reporting the results” section of the manuscript.

Response to recommendations:

Develop and apply a quality assessment tool to appraise the rigor of primary studies: We wish to clarify that our scoping review does not include a formal quality assessment of individual studies, as per the methodology outlined by Arksey and O’Malley (2005), which does not prescribe such an assessment. Implementing changes to this methodology at this stage poses challenges.

Detail a clear process for resolving any disagreements between reviewers: We have embraced this recommendation and detailed a clear process for resolving disagreements between reviewers in the manuscript.

Consider translating abstracts of relevant non-English studies to broaden scope: Regarding language bias, we have accepted the recommendation to consider translating abstracts of relevant non-English studies using online tools. If translation accuracy cannot be ensured, studies will be excluded as outlined in the manuscript.

Include searches of dissertations, conference abstracts, and trials registries: We have accepted to include searches of grey literature sources such as dissertations, conference abstracts, and trial registries, as also specified in the manuscript.

Consider qualitative data analysis methods like thematic synthesis: We have embraced the suggestion to incorporate qualitative data analysis methods like thematic synthesis, which has been highlighted in the manuscript.

Engage stakeholders to ensure findings are meaningful: Upon completion of our study, we plan to consult various stakeholders to ensure that our findings are meaningful and impactful.

Pilot test all tools and processes on a sample of studies to address any issues early: Recognizing its importance, we have conducted pilot testing on our tools, including the data extraction chart, to address any potential issues early in the process.

We are committed to enhancing the transparency, rigor, and inclusivity of our scoping review methodology based on your valuable feedback. Please do not hesitate to reach out if you have any further questions or suggestions.
Competing Interests: No competing interests were disclosed. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 08 Jul 2024

Richard Lobo, Pharmacognosy, Manipal Academy of Higher Education, Manipal, 576104, India

08 Jul 2024

Author Response
Dear Reviewer,
Thank you for your detailed and constructive feedback on our scoping review protocol. We appreciate your insights and suggestions, which will undoubtedly strengthen the rigor and comprehensiveness of ... Continue reading
Dear Reviewer,
Thank you for your detailed and constructive feedback on our scoping review protocol. We appreciate your insights and suggestions, which will undoubtedly strengthen the rigor and comprehensiveness of our study. Below are our responses and actions based on your specific points:

Acknowledgment: We acknowledge your positive feedback on several aspects of our protocol:

The research question is clearly defined using the PCC framework, providing a robust context and scope.

An extensive search strategy is outlined, utilizing relevant databases and search terms to comprehensively capture available literature.

Clear inclusion/exclusion criteria are defined to systematically filter relevant studies.

A team-based approach is planned for screening, review stages, and data extraction to ensure objectivity.

Data will be charted using a standardized format and synthesized both narratively and quantitatively.

Findings will be disseminated through publication, adding value to the existing literature.

Responses to Specific Questions:

Quality Assessment of Studies: We acknowledge your concern regarding the quality assessment of individual studies in our scoping review. Please note that our review is focused on mapping the breadth of literature rather than conducting a formal quality assessment. The methodology follows the Arksey, H., & O’Malley, L. (2005) framework, which does not include the adoption of a quality assessment for studies. We aim to adhere to this established methodology. Furthermore, this scoping review serves as a preliminary step toward a systematic review. Upon completion of the scoping review, we plan to conduct a systematic review where we will incorporate a quality assessment tool to evaluate the included studies.

Handling Disagreements Between Reviewers: We acknowledge your concern regarding the handling of disagreements between reviewers. This aspect is addressed in the study selection section of the methods section. We have now comprehensively detailed the process for handling disagreements between reviewers.

Language Bias: We acknowledge your comment regarding the inclusion of studies published in various languages. We will attempt to include studies published in any language in the scoping review. However, the translation of these studies will rely on online translation tools. If we are unable to accurately translate certain articles, they will be excluded from the review. This limitation will be duly acknowledged in the limitations section of the manuscript. We have mentioned our approach to including any language of studies in the scoping review in the manuscript in Table 3.

Grey Literature: We acknowledge the importance of including grey literature sources to capture additional relevant data. We have mentioned our approach to including grey literature in the manuscript in the search strategy section of the methods section.

Qualitative Analysis: We appreciate your emphasis on the importance of qualitative analysis. While we initially proposed only narrative analysis, we recognize the value of incorporating additional qualitative data analysis methods, such as thematic synthesis, to provide deeper contextual insights. We have addressed this in the “Collating, summarizing, and reporting the results” section of the manuscript.

Response to recommendations:

Develop and apply a quality assessment tool to appraise the rigor of primary studies: We wish to clarify that our scoping review does not include a formal quality assessment of individual studies, as per the methodology outlined by Arksey and O’Malley (2005), which does not prescribe such an assessment. Implementing changes to this methodology at this stage poses challenges.

Detail a clear process for resolving any disagreements between reviewers: We have embraced this recommendation and detailed a clear process for resolving disagreements between reviewers in the manuscript.

Consider translating abstracts of relevant non-English studies to broaden scope: Regarding language bias, we have accepted the recommendation to consider translating abstracts of relevant non-English studies using online tools. If translation accuracy cannot be ensured, studies will be excluded as outlined in the manuscript.

Include searches of dissertations, conference abstracts, and trials registries: We have accepted to include searches of grey literature sources such as dissertations, conference abstracts, and trial registries, as also specified in the manuscript.

Consider qualitative data analysis methods like thematic synthesis: We have embraced the suggestion to incorporate qualitative data analysis methods like thematic synthesis, which has been highlighted in the manuscript.

Engage stakeholders to ensure findings are meaningful: Upon completion of our study, we plan to consult various stakeholders to ensure that our findings are meaningful and impactful.

Pilot test all tools and processes on a sample of studies to address any issues early: Recognizing its importance, we have conducted pilot testing on our tools, including the data extraction chart, to address any potential issues early in the process.

We are committed to enhancing the transparency, rigor, and inclusivity of our scoping review methodology based on your valuable feedback. Please do not hesitate to reach out if you have any further questions or suggestions.
Dear Reviewer,
Thank you for your detailed and constructive feedback on our scoping review protocol. We appreciate your insights and suggestions, which will undoubtedly strengthen the rigor and comprehensiveness of our study. Below are our responses and actions based on your specific points:

Acknowledgment: We acknowledge your positive feedback on several aspects of our protocol:

The research question is clearly defined using the PCC framework, providing a robust context and scope.

An extensive search strategy is outlined, utilizing relevant databases and search terms to comprehensively capture available literature.

Clear inclusion/exclusion criteria are defined to systematically filter relevant studies.

A team-based approach is planned for screening, review stages, and data extraction to ensure objectivity.

Data will be charted using a standardized format and synthesized both narratively and quantitatively.

Findings will be disseminated through publication, adding value to the existing literature.

Responses to Specific Questions:

Quality Assessment of Studies: We acknowledge your concern regarding the quality assessment of individual studies in our scoping review. Please note that our review is focused on mapping the breadth of literature rather than conducting a formal quality assessment. The methodology follows the Arksey, H., & O’Malley, L. (2005) framework, which does not include the adoption of a quality assessment for studies. We aim to adhere to this established methodology. Furthermore, this scoping review serves as a preliminary step toward a systematic review. Upon completion of the scoping review, we plan to conduct a systematic review where we will incorporate a quality assessment tool to evaluate the included studies.

Handling Disagreements Between Reviewers: We acknowledge your concern regarding the handling of disagreements between reviewers. This aspect is addressed in the study selection section of the methods section. We have now comprehensively detailed the process for handling disagreements between reviewers.

Language Bias: We acknowledge your comment regarding the inclusion of studies published in various languages. We will attempt to include studies published in any language in the scoping review. However, the translation of these studies will rely on online translation tools. If we are unable to accurately translate certain articles, they will be excluded from the review. This limitation will be duly acknowledged in the limitations section of the manuscript. We have mentioned our approach to including any language of studies in the scoping review in the manuscript in Table 3.

Grey Literature: We acknowledge the importance of including grey literature sources to capture additional relevant data. We have mentioned our approach to including grey literature in the manuscript in the search strategy section of the methods section.

Qualitative Analysis: We appreciate your emphasis on the importance of qualitative analysis. While we initially proposed only narrative analysis, we recognize the value of incorporating additional qualitative data analysis methods, such as thematic synthesis, to provide deeper contextual insights. We have addressed this in the “Collating, summarizing, and reporting the results” section of the manuscript.

Response to recommendations:

Develop and apply a quality assessment tool to appraise the rigor of primary studies: We wish to clarify that our scoping review does not include a formal quality assessment of individual studies, as per the methodology outlined by Arksey and O’Malley (2005), which does not prescribe such an assessment. Implementing changes to this methodology at this stage poses challenges.

Detail a clear process for resolving any disagreements between reviewers: We have embraced this recommendation and detailed a clear process for resolving disagreements between reviewers in the manuscript.

Consider translating abstracts of relevant non-English studies to broaden scope: Regarding language bias, we have accepted the recommendation to consider translating abstracts of relevant non-English studies using online tools. If translation accuracy cannot be ensured, studies will be excluded as outlined in the manuscript.

Include searches of dissertations, conference abstracts, and trials registries: We have accepted to include searches of grey literature sources such as dissertations, conference abstracts, and trial registries, as also specified in the manuscript.

Consider qualitative data analysis methods like thematic synthesis: We have embraced the suggestion to incorporate qualitative data analysis methods like thematic synthesis, which has been highlighted in the manuscript.

Engage stakeholders to ensure findings are meaningful: Upon completion of our study, we plan to consult various stakeholders to ensure that our findings are meaningful and impactful.

Pilot test all tools and processes on a sample of studies to address any issues early: Recognizing its importance, we have conducted pilot testing on our tools, including the data extraction chart, to address any potential issues early in the process.

We are committed to enhancing the transparency, rigor, and inclusivity of our scoping review methodology based on your valuable feedback. Please do not hesitate to reach out if you have any further questions or suggestions.
Competing Interests: No competing interests were disclosed. Close
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Version 2

VERSION 2 PUBLISHED 22 May 2024

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	1	2
Version 2 (revision) 08 Jul 24	read	read
Version 1 22 May 24	read

Tamer A. Addissouky, Menoufia University, Shebeen El-Kom, Egypt
Anju Dhiman, Maharshi Dayanand University Rohtak, Rohtak, India

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3 Views

22 Apr 2025 | for Version 2

Anju Dhiman, Department of Pharmaceutical Sciences, Maharshi Dayanand University Rohtak, Rohtak, Haryana, India

3 Views Cite this report Responses(0)

Approved

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Phytomedicines

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

5 Views

12 Jul 2024 | for Version 2

Tamer A. Addissouky, Menoufia University, Shebeen El-Kom, Menofia Governorate, Egypt

5 Views Cite this report Responses(0)

Approved

This manuscript can be indexed.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

biomedical

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

20 Views

14 Jun 2024 | for Version 1

Tamer A. Addissouky, Menoufia University, Shebeen El-Kom, Menofia Governorate, Egypt

20 Views Cite this report Responses(1)

Approved With Reservations

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

biomedical

Respond to this report

Responses (1)

Author Response

08 Jul 2024

Richard Lobo, Pharmacognosy, Manipal Academy of Higher Education, Manipal, 576104, India

Dear Reviewer,
Thank you for your detailed and constructive feedback on our scoping review protocol. We appreciate your insights and suggestions, which will undoubtedly strengthen the rigor and comprehensiveness of our study. Below are our responses and actions based on your specific points:

Acknowledgment: We acknowledge your positive feedback on several aspects of our protocol:

The research question is clearly defined using the PCC framework, providing a robust context and scope.
An extensive search strategy is outlined, utilizing relevant databases and search terms to comprehensively capture available literature.
Clear inclusion/exclusion criteria are defined to systematically filter relevant studies.
A team-based approach is planned for screening, review stages, and data extraction to ensure objectivity.
Data will be charted using a standardized format and synthesized both narratively and quantitatively.
Findings will be disseminated through publication, adding value to the existing literature.

Responses to Specific Questions:

Quality Assessment of Studies: We acknowledge your concern regarding the quality assessment of individual studies in our scoping review. Please note that our review is focused on mapping the breadth of literature rather than conducting a formal quality assessment. The methodology follows the Arksey, H., & O’Malley, L. (2005) framework, which does not include the adoption of a quality assessment for studies. We aim to adhere to this established methodology. Furthermore, this scoping review serves as a preliminary step toward a systematic review. Upon completion of the scoping review, we plan to conduct a systematic review where we will incorporate a quality assessment tool to evaluate the included studies.
Handling Disagreements Between Reviewers: We acknowledge your concern regarding the handling of disagreements between reviewers. This aspect is addressed in the study selection section of the methods section. We have now comprehensively detailed the process for handling disagreements between reviewers.
Language Bias: We acknowledge your comment regarding the inclusion of studies published in various languages. We will attempt to include studies published in any language in the scoping review. However, the translation of these studies will rely on online translation tools. If we are unable to accurately translate certain articles, they will be excluded from the review. This limitation will be duly acknowledged in the limitations section of the manuscript. We have mentioned our approach to including any language of studies in the scoping review in the manuscript in Table 3.
Grey Literature: We acknowledge the importance of including grey literature sources to capture additional relevant data. We have mentioned our approach to including grey literature in the manuscript in the search strategy section of the methods section.
Qualitative Analysis: We appreciate your emphasis on the importance of qualitative analysis. While we initially proposed only narrative analysis, we recognize the value of incorporating additional qualitative data analysis methods, such as thematic synthesis, to provide deeper contextual insights. We have addressed this in the “Collating, summarizing, and reporting the results” section of the manuscript.

Response to recommendations:

Develop and apply a quality assessment tool to appraise the rigor of primary studies: We wish to clarify that our scoping review does not include a formal quality assessment of individual studies, as per the methodology outlined by Arksey and O’Malley (2005), which does not prescribe such an assessment. Implementing changes to this methodology at this stage poses challenges.
Detail a clear process for resolving any disagreements between reviewers: We have embraced this recommendation and detailed a clear process for resolving disagreements between reviewers in the manuscript.
Consider translating abstracts of relevant non-English studies to broaden scope: Regarding language bias, we have accepted the recommendation to consider translating abstracts of relevant non-English studies using online tools. If translation accuracy cannot be ensured, studies will be excluded as outlined in the manuscript.
Include searches of dissertations, conference abstracts, and trials registries: We have accepted to include searches of grey literature sources such as dissertations, conference abstracts, and trial registries, as also specified in the manuscript.
Consider qualitative data analysis methods like thematic synthesis: We have embraced the suggestion to incorporate qualitative data analysis methods like thematic synthesis, which has been highlighted in the manuscript.
Engage stakeholders to ensure findings are meaningful: Upon completion of our study, we plan to consult various stakeholders to ensure that our findings are meaningful and impactful.
Pilot test all tools and processes on a sample of studies to address any issues early: Recognizing its importance, we have conducted pilot testing on our tools, including the data extraction chart, to address any potential issues early in the process.

We are committed to enhancing the transparency, rigor, and inclusivity of our scoping review methodology based on your valuable feedback. Please do not hesitate to reach out if you have any further questions or suggestions.

View more View less

Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Identifying the role of Phytomolecules in the management of liver diseases by modulating NRF2 pathway: A Scoping Review Protocol

Abstract

Background

Methods

Conclusion

Keywords

Revised Amendments from Version 1

Introduction

Protocol

Methods

Review question

Eligibility criteria

Table 1. PCC framework.

Search strategy

Table 2. Search terms.

Study selection

Table 3. Inclusion and exclusion criteria.

Data charting

Collating, summarizing, and reporting the results

Discussion

Dissemination

Study status

Ethical considerations

Authors contribution

Data availability

Underlying data

Reporting guidelines

Acknowledgment

References

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