Oxidative Stress in Non-Alcoholic Fatty Liver Disease
, Eleonora Croce, Davide Di Benedetto, Vincenzo Cantaluppi, Cristoforo Comi, Pier Paolo Sainaghi, Rosalba Minisini, Elena Grossini and Mario Pirisi
Round 1
Reviewer 1 Report
The present manuscript is a review on the role of oxidative stress in NAFLD. In general the information provided is updated an relevant. However, the manuscript is very poorly organized. It should be better structured. This is simple, first a nice account on NAFLD indicating the main biologycal players and pathways (so, more extensive than it is now and better structured), then evidences on the presence of oxidative stress, then evidences on the role of oxidative stress on disease progression, then the possible sources an evidence that they are relevant in the disease, then the biomarkers, explaining what is their normal function, how they relate to ros, evidence to their disregulation in the disease and technical applications with thechnical challenges and limitations.
Author Response
1) The present manuscript is a review on the role of oxidative stress in NAFLD. In general the information provided is updated an relevant. However, the manuscript is very poorly organized. It should be better structured. This is simple, first a nice account on NAFLD indicating the main biological players and pathways (so, more extensive than it is now and better structured), then evidences on the presence of oxidative stress, then evidences on the role of oxidative stress on disease progression, then the possible sources an evidence that they are relevant in the disease, then the biomarkers, explaining what is their normal function, how they relate to ros, evidence to their disregulation in the disease and technical applications with technical challenges and limitations.
The general scheme of the manuscript has been extensively changed as suggested. More in detail:
Section 1 (“Introduction”) has now been extended and better organized.
Section 2 is now named “Evidences on the presence of oxidative stress in NAFLD” (with the following subsections: “Evidence for a Role of Oxidative Stress in NAFLD”; “Redox regulation of lipid metabolism in NAFLD”; “Oxidative stress and antioxidant markers in NAFLD and other metabolic diseases”).
Section 3 is now named “Evidences on the role of oxidative stress on NAFLD progression”, and contains a completely new introductory section, followed by the following subsections: “Markers of immunological responses to inflammation and oxidative stress during NAFLD evolution”; “Mitochondrial oxidative injury as a key pathway that links saturated fat intake to the development and progression of NAFLD” (chapter shifted from the original manuscript sequence); “Gut microbiota and oxidative stress in NAFLD, with possible therapeutic implications” (chapter shifted from the original manuscript sequence); “Relationship of oxidative stress and the development and/or progression of NAFLD-HCC” (new section, as required by an other reviewer).
The last subsection of chapter 3 (precisely, 3.5) is named “Biomarkers of oxidative stress in NAFLD/NASH”, and contains all the reviewer’s suggestions.
The following chapter #4 was not mentioned in the reviewer’s suggestions, and is named “Genetic polymorphisms and oxidative stress in NAFLD/NASH”.
The last chapter (“Therapeutic potential of targeting oxidative stress in NAFLD patients”) is completely new as required by an other reviewer and, in a logical sense, closes the review after all the previous chapters before the “Conclusions” part.
As required, English language and style were carefully rechecked and corrected throughout the manuscript.
Reviewer 2 Report
In this review Smirne and colleagues have covered several major points about the implications of OS on NAFLD. Overall, this is a well-written literature review that provides essential information about the topic. However, I have several suggestions that could improve it:
1) In the introduction. Please provide a more recent review about NAFLD prevalence in the population. The cited article is from 2016 and there are many others that have been recently published (including several ones from the same authors).
2) In general, the authors should try to describe better define NASH. For instance, in the introduction they describe that is characterized by the presence of fibrosis. This is not true, as in many times NASH livers don't show fibrosis. Also, in figure 1 the authors include a square showing the progression of NAFLD to NASH; again, please be more accurate and indicate simple steatosis or NAFL (non-alcoholic fatty liver). Please carefully revise the rest of the text to avoid this kind of mistakes in the document.
3) I miss a part about therapeutic potential of targeting OS in NAFLD patients. Also please, add a section about the possible implication of the NRF2 pathway in NAFLD physiopathology.
4) Finally, a section about the relationship of OS and the development and/or progression of NAFLD-HCC could be of great value for the reader.
Author Response
In this review Smirne and colleagues have covered several major points about the implications of OS on NAFLD. Overall, this is a well-written literature review that provides essential information about the topic. However, I have several suggestions that could improve it:
1) In the introduction. Please provide a more recent review about NAFLD prevalence in the population. The cited article is from 2016 and there are many others that have been recently published (including several ones from the same authors).
The 2016 reference has been replaced with three more recent citations, the first two referring to the general population and the latter one to the subset of diabetic subjects.
2) In general, the authors should try to describe better define NASH. For instance, in the introduction they describe that is characterized by the presence of fibrosis. This is not true, as in many times NASH livers don't show fibrosis. Also, in figure 1 the authors include a square showing the progression of NAFLD to NASH; again, please be more accurate and indicate simple steatosis or NAFL (non-alcoholic fatty liver). Please carefully revise the rest of the text to avoid this kind of mistakes in the document.
NASH has been better defined and, in particular, it has been better clarified that, although characterized by inflammation, it can lead to liver fibrosis in only a minority of cases. Based on these premise, Introduction section has been expanded, indicating the main biological players and pathways of NAFLD. Figure 1 has also been modified as suggested.
3) I miss a part about therapeutic potential of targeting OS in NAFLD patients. Also please, add a section about the possible implication of the NRF2 pathway in NAFLD physiopathology.
An extensive new section on state of the art on effective therapeutics against NAFLD-related OS is now presented in Section 5, in addition to what was already described on prebiotic and probiotic role (please see Section 3.3.2).
NRF2 pathway is now extensively analyzed in various parts of the manuscript (please see sections #1, 3 and 5).
4) Finally, a section about the relationship of OS and the development and/or progression of NAFLD-HCC could be of great value for the reader.
A new section on relationship of oxidative stress and the development and/or progression of NAFLD-HCC has now been added (please see Section 3.4).
As required, English language and style were carefully rechecked and corrected throughout the manuscript.
Round 2
Reviewer 2 Report
All my comments have been amended
