Role of Oxidative Stress in Liver Disorders
, Leire Goicoechea 1,2,3,†, Sandra Torres 1,2,3, Carmen Garcia-Ruiz 1,2,3,4,* and José C. Fernandez-Checa 1,2,3,4
Round 1
Reviewer 1 Report
Overall, this is a good review article describing role of oxidative stress in various liver diseases. Considering this a broad topic, several relevant aspects are covered with reasonable details. I have following minor comments for improvement:
1) In section 4 – “Cell death regulation in the liver”, I would suggest giving more emphasis on how oxidative stress regulates various forms of cell death to be consistent with the overall theme; for details of various cell death mechanisms various other reviews can be referred.
2) In Figure 3, please add various numbers in the figure as described in the legend for this figure.
3) Please check for typos. E.g. “Insuline” in Fig. 1 and 3; “Isoformes” in Fig. 2; “in-formation” in line 636; “supple-mentary” in line 638.
Author Response
We want to start by thanking the reviewers for their valuables comments, that we have taking into consideration and that for sure have improved the present review.
Reviewer 1
Overall, this is a good review article describing role of oxidative stress in various liver diseases. Considering this a broad topic, several relevant aspects are covered with reasonable details. I have following minor comments for improvement:
1) In section 4 – “Cell death regulation in the liver”, I would suggest giving more emphasis on how oxidative stress regulates various forms of cell death to be consistent with the overall theme; for details of various cell death mechanisms various other reviews can be referred.
Suggestion accepted. Reviewer 2, has also suggested to include information on the role of free radicals in the different cell death types, so in order to meet both recommendations, additional information detailing the role of ROS in the regulation of cell death has been included in this section. In addition, we have included a new figure summarizing it (Please, see Figure 3 in the revised version of the manuscript).
2) In Figure 3, please add various numbers in the figure as described in the legend for this figure.
As suggested by the reviewer, we have now added the numbers in the Figure-now Figure 4 in the revised manuscript-(Please, see Figure 4 in the revised version of the manuscript).
3) Please check for typos. E.g. “Insuline” in Fig. 1 and 3; “Isoformes” in Fig. 2; “in-formation” in line 636; “supple-mentary” in line 638.
We apologize for the errors and thank the reviewer for pointing them out. Typos have been corrected in the revised version of the manuscript. See Figure 1, Figure 2 and Figure 4 (former Figure 3), in the revised version.
Author Response File: 
Author Response.docx
Reviewer 2 Report
1) In the section on mode of cell death, it may be useful to include some information on the role of free radicals in the various cell death types and also include a figure summarizing this.
2) Lines 199-208- In the section on apoptosis in NASH & NAFLD it may be useful to provide information on sequential events if available. Though JNK is mentioned at the end of the section, its relationship to apoptosis in this context is not evident and could be added.
3) Figure 1- It may be useful to include a picture of the intestine to highlight that the epithelial cells depicted on the right are intestinal.
4) Line 72- Consider changing the sentence “….where superoxide anion is generated by the transfer of electrons to oxygen during the respiratory chain to produce ATP” to “where superoxide anion can be generated as a by-product of transfer of electrons to oxygen…”
5) Line 74: “membrane nicotinamide adenine dinucleotide phosphate oxidase (NADPH)”- should be “membrane nicotinamide adenine dinucleotide phosphate (NADPH) oxidase”
6) Line 139: “…mechanisms, react with” should be “…mechanisms, they react with”
Author Response
We want to start by thanking the reviewers for their valuables comments, that we have taking into consideration and that for sure have improved the present review.
Reviewer 2
1) In the section on mode of cell death, it may be useful to include some information on the role of free radicals in the various cell death types and also include a figure summarizing this.
Suggestion accepted. Pease, see response to reviewer 1’s first comment.
2) Lines 199-208- In the section on apoptosis in NASH & NAFLD it may be useful to provide information on sequential events if available. Though JNK is mentioned at the end of the section, its relationship to apoptosis in this context is not evident and could be added.
We have considered reviewer’s comment and we have added additional information to emphasize the relation between JNK-apoptosis and NASH & NAFLD (see lines 341-354 in the revised manuscript).
3) Figure 1- It may be useful to include a picture of the intestine to highlight that the epithelial cells depicted on the right are intestinal.
As suggested by the reviewer, we have now added a picture of the intestine in Figure 1.
4) Line 72- Consider changing the sentence “….where superoxide anion is generated by the transfer of electrons to oxygen during the respiratory chain to produce ATP” to “where superoxide anion can be generated as a by-product of transfer of electrons to oxygen…”
Thank you for this important point. Sentence has been changed as suggested (Please, see lines 74-75 in the revised version).
5) Line 74: “membrane nicotinamide adenine dinucleotide phosphate oxidase (NADPH)”- should be “membrane nicotinamide adenine dinucleotide phosphate (NADPH) oxidase”
We thank you very much for bringing this to our attention. Sentence has been corrected (Please, see lines 76-77 in the revised version).
6) Line 139: “…mechanisms, react with” should be “…mechanisms, they react with”
Following the reviewer suggestion, we have modified this sentence in the revised version of the manuscript (Please, see line 142 in the revised version).
Author Response File: Author Response.docx
Reviewer 3 Report
This review is rich in content and charts, and systematically introduces the relationship between oxidative stress and various liver diseases. The pathogenesis of NAFLD believes that oxidative stress is an important factor of "two hits" or "multiple hits", which is also applicable to other liver diseases. However, this article does not mention the relationship between oxidative stress and viral hepatitis, nor does it suggest the role of cell aging in liver disease.
Author Response
We want to start by thanking the reviewers for their valuables comments, that we have taking into consideration and that for sure have improved the present review.
Reviewer 3
This review is rich in content and charts, and systematically introduces the relationship between oxidative stress and various liver diseases. The pathogenesis of NAFLD believes that oxidative stress is an important factor of “two hits" or "multiple hits", which is also applicable to other liver diseases. However, this article does not mention the relationship between oxidative stress and viral hepatitis, nor does it suggest the role of cell aging in liver disease.
We thank the reviewer for its valuable comment. We have now included, in section 5, the relationship between oxidative stress and viral hepatitis (Please, see lines 682 to 703 in the revised version) and the role of cell aging in liver disease (Please, see lines 157 to 245 in the revised version). In addition, Figure 4 (former Figure 3) has been modified to include “viral hepatitis” to the illustration.
Author Response File: Author Response.docx
