The Role of Structural Bioinformatics in Understanding Tumor Necrosis Factor α-Interacting Protein Mechanisms in Chronic Inflammatory Diseases: A Review
, Rafael Pereira Lemos 1, Tatiane Senna Bialves 1, Carlo Jose Freire Oliveira 2 and Raquel C. de Melo-Minardi 1,*
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript provides insights into the role of tumor necrosis factor-alpha (TNF-α) in chronic inflammatory diseases, exploring its interactions with other molecules from a structural biology perspective. The discussion aims to contribute valuable information for the development of new drugs or treatment approaches. My comments are as follows:
1. To enhance the article's impact, it is suggested to include specific application examples of the bioinformatics methods and tools mentioned (Instructions on bioinformatics procedures in the text should correspond to the numbers shown in the figures). Integrating these examples into figures can help illustrate the innovative or significant aspects of the research.
2. Upon the initial reference to tumor necrosis factor-alpha (TNF-α), please consider providing its full name, "Tumor Necrosis Factor-alpha," followed by the abbreviation "TNF-α" in subsequent mentions. Ensure consistent usage of professional terms and abbreviations throughout the article to avoid reader confusion.
3. It seems there is a numbering inconsistency in the section titles. Following the suggested corrections, it should be "7. Bioinformatics approaches" and the sub-item numbering should be adjusted accordingly. Additionally, for the item "4.2.1. Alphafold," if there is no subsequent sub-item "4.2.2," please remove the ".1" sub-item.
Author Response
Dear Editor,
Thank you for your decision letter. We are pleased to resubmit a revised version of our review article titled "The role of structural bioinformatics in understanding the mechanisms of proteins interacting with TNF-α in chronic inflammatory diseases: a review”.
We greatly appreciate constructive criticism and address all reviewer comments to the best of our ability given time constraints. We found that the comments brought new insights to our work and that addressing them greatly enriched and strengthened the document. Having noticed that some aspects were confusing to reviewers, we amended the manuscript to make it as clear as possible and suitable for publication in this prestigious journal. On the following pages, we outline point-by-point responses to the comments by the reviewers, as well as the corresponding changes to the manuscript, all of which are highlighted in the main text.
Thank you for receiving the revised version of our manuscript. We hope it will be received favorably and look forward to hearing from you in the near future.
Best regards,
Luana Luiza Bastos, Diego Mariano, Rafael Pereira Lemos, Tatiane
Senna Bialves, Carlo José Freire Oliveira and Raquel Cardoso De Melo-Minardi
Reviewer 1
1-To enhance the article's impact, it is suggested to include specific application examples of the bioinformatics methods and tools mentioned (Instructions on bioinformatics procedures in the text should correspond to the numbers shown in the figures). Integrating these examples into figures can help illustrate the innovative or significant aspects of the research.
A topic entitled "Bioinformatics applied to research on TNF-α associated with inflammatory diseases" line 723 was created in the text, to highlight the studies in which bioinformatics tools were used in research on TNF-α associated with inflammatory diseases, present in the previous file . New studies were added as suggested in lines 809-887.
2- Upon the initial reference to tumor necrosis factor-alpha (TNF-α), please consider providing its full name, "Tumor Necrosis Factor-alpha," followed by the abbreviation "TNF-α" in subsequent mentions. Ensure consistent usage of professional terms and abbreviations throughout the article to avoid reader confusion.
All appearances of TNF-α were checked and corrected, we quote some lines in which the corrections were made 44, 52, 142, 195, 303, 587,737, 738, 742, 757, 387.
3- It seems there is a numbering inconsistency in the section titles. Following the suggested corrections, it should be "7. Bioinformatics approaches" and the sub-item numbering should be adjusted accordingly. Additionally, for the item "4.2.1. Alphafold," if there is no subsequent sub-item "4.2.2," please remove the ".1" sub-item.
The numbering of topic 7. "Limitations in TNF-α research" line 88 was corrected, as well as the topics onwards, line 523 topic 8. "Bioinformatics approaches and the others". The subitem "4.2.1. Alphafold," was removed and the topic numbering was corrected to line 666.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe paper provides a comprehensive overview of TNF-α in the body's inflammatory responses and immune defense against various pathogens and tumors. Primarily produced by immune cells, TNF-α can also be generated by a broad range of cells during inflammatory conditions. Its functioning hinges on the interaction with TNF-R1 and TNF-R2 receptors, which are critical in mediating diverse cellular activities. Furthermore, the paper delves into the therapeutic use of TNF-α inhibitors, which are employed to treat chronic inflammatory diseases by obstructing its interaction with receptors. However, it highlights challenges such as immunogenic responses to these inhibitors. Additionally, it underscores the pivotal contribution of bioinformatics in this realm, particularly emphasizing the AlphaFold deep learning model. This model is transformative in predicting protein structures, thereby significantly enhancing drug discovery and the development of novel treatments for diseases associated with TNF-α. This bioinformatics approach thus stands as a cornerstone in advancing our molecular-level understanding of chronic inflammatory conditions. I would suggest the review paper can be accepted after addressing the following questions.
1. While the paper provides a substantial overview of TNF-α, it could benefit from a more extensive review of current literature. In particular, incorporating recent studies on TNF-α's role in less common autoimmune diseases or its implications in non-immune cells would provide a more comprehensive understanding. Additionally, a comparison with other cytokines in similar pathways could contextualize TNF-α's unique roles and interactions.
2. The discussion of TNF-α's mechanism of action and its interaction with TNF-R1 and TNF-R2 receptors is informative but could be enhanced with more detailed diagrams or models. Visual representations would aid in elucidating these complex interactions and pathways, making the paper more accessible to readers from diverse backgrounds.
3. The paper touches on the therapeutic use of TNF-α inhibitors but could delve deeper into clinical applications. A comparison of different TNF-α inhibitors, their efficacy, side effects, and long-term outcomes in various inflammatory diseases would be valuable. Additionally, exploring potential future therapeutic targets within the TNF-α signaling pathway could provide insight into emerging treatments.
4. The mention of AlphaFold and bioinformatics is intriguing; however, this section can be expanded. It would be beneficial to include specific examples of how bioinformatics tools have been used in TNF-α research, perhaps highlighting case studies where these tools have led to novel insights or therapeutic approaches.
5. The paper mentions immunogenic responses to TNF-α inhibitors but does not explore this in depth. A more detailed discussion on the prevalence, mechanisms, and management of these responses would be informative, especially considering their significance in clinical settings.
6. The paper would benefit from a section discussing the current limitations in TNF-α research and potential avenues for future studies. This could include challenges in translating in vitro and animal model findings to human physiology or the need for longitudinal studies to understand the long-term impacts of TNF-α modulation.
Author Response
Dear Editor,
Thank you for your decision letter. We are pleased to resubmit a revised version of our review article titled "The role of structural bioinformatics in understanding the mechanisms of proteins interacting with TNF-α in chronic inflammatory diseases: a review”.
We greatly appreciate constructive criticism and address all reviewer comments to the best of our ability given time constraints. We found that the comments brought new insights to our work and that addressing them greatly enriched and strengthened the document. Having noticed that some aspects were confusing to reviewers, we amended the manuscript to make it as clear as possible and suitable for publication in this prestigious journal. On the following pages, we outline point-by-point responses to the comments by the reviewers, as well as the corresponding changes to the manuscript, all of which are highlighted in the main text.
Thank you for receiving the revised version of our manuscript. We hope it will be received favorably and look forward to hearing from you in the near future.
Best regards,
Luana Luiza Bastos, Diego Mariano, Rafael Pereira Lemos, Tatiane
Senna Bialves, Carlo José Freire Oliveira and Raquel Cardoso De Melo-Minardi
Reviewer 2
1- While the paper provides a substantial overview of TNF-α, it could benefit from a more extensive review of current literature. In particular, incorporating recent studies on TNF-α's role in less common autoimmune diseases or its implications in non-immune cells would provide a more comprehensive understanding. Additionally, a comparison with other cytokines in similar pathways could contextualize TNF-α's unique roles and interactions.
The topic "4. TNF-α role in the body's inflammatory process", was expanded and less frequent chronic inflammatory diseases were added, the new data can be found in lines 288-392
2-The discussion of TNF-α's mechanism of action and its interaction with TNF-R1 and TNF-R2 receptors is informative but could be enhanced with more detailed diagrams or models. Visual representations would aid in elucidating these complex interactions and pathways, making the paper more accessible to readers from diverse backgrounds.
Figure 1 was adapted to improve understanding as suggested lines 95-96.
3-The paper touches on the therapeutic use of TNF-α inhibitors but could delve deeper into clinical applications. A comparison of different TNF-α inhibitors, their efficacy, side effects, and long-term outcomes in various inflammatory diseases would be valuable. Additionally, exploring potential future therapeutic targets within the TNF-α signaling pathway could provide insight into emerging treatments.
The suggested comparisons in relation to TNF-α inhibitors were added to the text at lines 503-540.
4-The mention of AlphaFold and bioinformatics is intriguing; however, this section can be expanded. It would be beneficial to include specific examples of how bioinformatics tools have been used in TNF-α research, perhaps highlighting case studies where these tools have led to novel insights or therapeutic approaches.
New information and a new case study regarding AlphaFold TNF-α research in chronic inflammatory diseases have been added in lines 677-693 and 871-887.
5-The paper mentions immunogenic responses to TNF-α inhibitors but does not explore this in depth. A more detailed discussion on the prevalence, mechanisms, and management of these responses would be informative, especially considering their significance in clinical settin.
More information regarding inhibitors has been added to the text as suggested. This information was entered on lines 412-420, 440-451,463-473, 486-492,498-502.
6-The paper would benefit from a section discussing the current limitations in TNF-α research and potential avenues for future studies. This could include challenges in translating in vitro and animal model findings to human physiology or the need for longitudinal studies to understand the long-term impacts of TNF-α modulation.
A new topic entitled "7. Limitations in TNF-α research" was added to the text, containing the suggestions made. The topic is present in lines 488-522.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe author has effectively addressed all of my concerns. I recommend that the paper be published in its current version.
