Autophagy and Apoptosis in Inflammatory Bowel Disease

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this study, authors investigated the roles of autophagy and apoptosis in Inflammatory bowel disease. In this review paper, research on these two pathways is presented. After a general overview of autophagy and apoptosis, their association with IBD including the important mitophagy and ferroptosis is discussed. The influence of autophagy and apoptosis related genes is also discussed. Finally, the interplay of autophagy and apoptosis in IBD is presented and implications for treatment applications are examined. In general, this review paper is interesting and well-written. Here are some comments from this reviewer.

1. Authors talked about apoptosis and ferroptosis in this review, how about necroptosis and pyroptosis?

2. Ferroptosis is different from apoptosis, how come authors only mentioned apoptosis in the title and abstract?

3. Vitamin D and vitamin D receptor play critical roles in IBD development, this signaling should also be discussed.

Author Response

Reviewer 1

We thank the reviewer for the comments.

 Here are some comments from this reviewer.

1.Authors talked about apoptosis and ferroptosis in this review, how about necroptosis and pyroptosis?

It was felt that the detailed description of other forms of cellular death such as necroptosis and pyroptosis would distract from the scope of the paper which was the analysis of autophagy and apoptosis. However, the other forms were briefly mentioned by referring to ref. 292,293.

2. Ferroptosis is different from apoptosis, how come authors only mentioned apoptosis in the title and abstract?

Ferroptosis is mentioned in the abstract and was analyzed in the text because of the intersection with autophagy and apoptosis.

3. Vitamin D and vitamin D receptor play critical roles in IBD development, this signaling should also be discussed.

We included a discussion of vitamin D and receptors as suggested.

All changes are highlighted in yellow.

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Reviewer 2 Report

Comments and Suggestions for Authors

First of all, I appreciate the opportunity to review this interesting scientific article.

This is a detailed review of the role that apoptosis and autophagy play in inflammatory bowel disease. Each of the objectives to be carried out in this article, the evidence available so far and promising research points for the future are described widely and in detail. Overall, I find it to be a well-written, adequately referenced and relevant review.

I would only have two minor comments:

In the abstract, I would recommend placing the authors' conclusion regarding this topic, since it would seem more than anything like a summarized introduction and not a general summary.

It would be more visually attractive, and perhaps could serve to reduce the large amount of text a little, to use a schematic illustration to describe the important definitions (e.g. apoptosis, autophagy, etc.).

These comments are intended to improve the presentation of the article, but without a doubt, it could be published in its current form (the suggestion I make regarding the abstract seems to me to be the most important).

Author Response

Reviewer 2

We thank the reviewer for the comments

I would only have two minor comments:

In the abstract, I would recommend placing the authors' conclusion regarding this topic, since it would seem more than anything like a summarized introduction and not a general summary.

We did that

It would be more visually attractive, and perhaps could serve to reduce the large amount of text a little, to use a schematic illustration to describe the important definitions (e.g. apoptosis, autophagy, etc.).

We agree with this comment. It is exactly the reason for inclusion of Figs 1 and 2.

All changes are highlighted in yellow.

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Reviewer 3 Report

Comments and Suggestions for Authors

In this interesting review, the themes are covered abundantly, however, some topics are excessively verbose, sometimes repeated and sometimes deviating from the core topic. It would have been better to combine some points which, instead, appear to be separate. While I appreciate the authors for their efforts in trying to explain a complicated topic in a second language, they were not perfectly successful in composing the review for a journal whose language is English. This manuscript could be better understood if it were better constructed. It is often necessary to read sentences and paragraphs several times before you can understand their meaning. The comments above are not a complete list of what needs to be fixed. I strongly suggest that it be read, edited, and then reread by the authors to ensure their meaning has been conveyed correctly.

Suggestions:

Many sentences should be rewritten paying more attention to the English grammar. For example:

Line 46: “Autophagy is important in the survival of cells” could be written as it follows “Autophagy is a key process for cell survival and tissues homeostasis”.

Line 74: “Recent progress in other forms of these two fundamental pathways”. What do you mean by other forms? You could rewrite it as “Recently discovered forms of programmed cell death such as ferroptosis and mitophagy, and their implications in the treatment of IBD will also be discussed”.

Line 80: “Proteins, lipids damaged organelles and pathogens are degraded and the products re-circulate and re-used in new synthesis.” This sentence doesn’t have a bibliographic reference, also the grammar should be revised. For example: “the products are re-used in new synthesis” in the synthesis of what exactly? You could rewrite it as follows “Proteins, lipids, damaged organelles, and pathogens are often degraded and re-used for the synthesis of cellular costituents”.

Line 122: “from the cytoplasm to the OMM”.

Line 150: “BCL-2, BCL- 149 XL and MCL1 allowing to the lethal BAX and BAK to aggregate in the OMM”.

Line 278: “In addition, LOX and the Free iron pool promote, through the Fenton reaction, promote the conversion of PE-PUFA into PE-PUFA-OOH”.

Line 279: “the p62/keap1/Nrf2/HO-1 system decreases ferroptosis”.

Line 1010: “BH3-mimetics that either selectively target the BCL-2-Beclin1 interaction”.

There may be other grammar mistakes, so I recommend the authors to check the whole text.

Abbreviations are sometimes used before they are defined. No abbreviation or acronym should be used in the text unless it has been previously defined. For example, CALCOCO2 on line 105 is not defined (Calcium-binding and coiled-coil domain-containing protein 2).

Fig. 1 has no reference, was it taken from a paper, or was it made by the authors? Also, instead of using a red arrow, you could have used a blunt arrow (┴) which indicates inhibition. 

Comments on the Quality of English Language

As written in the main comment, there may be grammatical errors, so I advise authors to check the entire text.

Author Response

Reviewer 3

We thank the reviewer for the comments

In this interesting review, the themes are covered abundantly, however, some topics are excessively verbose, sometimes repeated and sometimes deviating from the core topic. It would have been better to combine some points which, instead, appear to be separate. While I appreciate the authors for their efforts in trying to explain a complicated topic in a second language, they were not perfectly successful in composing the review for a journal whose language is English. This manuscript could be better understood if it were better constructed. It is often necessary to read sentences and paragraphs several times before you can understand their meaning. The comments above are not a complete list of what needs to be fixed. I strongly suggest that it be read, edited, and then reread by the authors to ensure their meaning has been conveyed correctly.

We agree that some topics are indeed extensive and some repetition were deliberately done. We felt that very few gastroenterologists are familiar with this complicated subject. We thought that only some experts such as the reviewers could follow an abbreviated text without an overview of autophagy and apoptosis. When a repetition was used, we declared that it was mentioned before.

Suggestions:

Many sentences should be rewritten paying more attention to the English grammar. For example:

Line 46: “Autophagy is important in the survival of cells” could be written as it follows “Autophagy is a key process for cell survival and tissues homeostasis”.

Line 74: “Recent progress in other forms of these two fundamental pathways”. What do you mean by other forms? You could rewrite it as “Recently discovered forms of programmed cell death such as ferroptosis and mitophagy, and their implications in the treatment of IBD will also be discussed”.

Line 80: “Proteins, lipids damaged organelles and pathogens are degraded and the products re-circulate and re-used in new synthesis.” This sentence doesn’t have a bibliographic reference, also the grammar should be revised. For example: “the products are re-used in new synthesis” in the synthesis of what exactly? You could rewrite it as follows “Proteins, lipids, damaged organelles, and pathogens are often degraded and re-used for the synthesis of cellular costituents”.

Line 122: “from the cytoplasm to the OMM”.

Line 150: “BCL-2, BCL- 149 XL and MCL1 allowing to the lethal BAX and BAK to aggregate in the OMM”.

Line 278: “In addition, LOX and the Free iron pool promote, through the Fenton reaction, promote the conversion of PE-PUFA into PE-PUFA-OOH”.

Line 279: “the p62/keap1/Nrf2/HO-1 system decreases ferroptosis”.

Line 1010: “BH3-mimetics that either selectively target the BCL-2-Beclin1 interaction”.

There may be other grammar mistakes, so I recommend the authors to check the whole text.

All the above have been corrected and the whole text has been re-checked and some grammar or syntax mistakes have been attended to.

Abbreviations are sometimes used before they are defined. No abbreviation or acronym should be used in the text unless it has been previously defined. For example, CALCOCO2 on line 105 is not defined (Calcium-binding and coiled-coil domain-containing protein 2).

All acronyms have been explained by the complete name of the abbreviation.

Fig. 1 has no reference, was it taken from a paper, or was it made by the authors? Also, instead of using a red arrow, you could have used a blunt arrow (┴) which indicates inhibition. 

Fig 1 was made by the authors.

All changes are highlighted in yellow.

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Reviewer 4 Report

Comments and Suggestions for Authors

Kouroumalis and colleagues presented a review focused on the roles of autophagy and apoptosis in inflammatory bowel disease (IBD). After a detailed discussion of the molecular mechanisms underlying autophagy, apoptosis and their interactions, the authors switch to the effects of dysregulation of specific signaling pathways involved in apoptosis and autophagy on the development of IBD. Considerable attention is given to the role of mutations affecting autophagy and apoptosis in the pathology of IBD. The final part of the review is dedicated to pharmacological approaches to IBD treatment, which target autophagy and apoptosis. This is a very detailed review based on a vast body of publications. It could be further improved if the authors provide a few paragraphs discussing the animal models of IBD. In the current manuscript, this topic is addressed rather superficially.

Author Response

Reviewer 4

We thank the reviewer for the comments

It could be further improved if the authors provide a few paragraphs discussing the animal models of IBD. In the current manuscript, this topic is addressed rather superficially.

We included paragraphs on animal models a suggested.

All changes are highlighted in yellow