Epigenetic Factors in Eutopic Endometrium in Women with Endometriosis and Infertility

Round 1

Reviewer 1 Report

In the present review the authors aimed at summarising the molecular mechanisms underlying epigenetic modificcations occuring in the eutopic endometrium and affecting embryo implantation capacity in women with endometirosis. The manuscript is clear and well written and represent the most comprehensive review of the topic present in literature and is worth of publication in the current form.

Author Response

Thank you very much for the submission review. We are very pleased that the manuscript has been positively assessed. 

Reviewer 2 Report

It is a very valuable manuscript that gives knowledge about the molecular pathomechanisms of endometriosis. I found only some minor issues, which are rested below:

Please do not use the subsection in the introduction.

The objective should also be included in the introduction section

In objectives, please describe more clearly the main aims of the paper.

To summarize it will be great to prepare some table o graphic scheme.

 

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 3 Report

Endometriosis is a common disease in women of reproductive age, and its pathogenesis seems to be largely affected by hormone imbalance, inflammation, oxidative stress, and autophagy dysregulation. These pathophysiological disturbances interact with one another through mechanisms that are still awaiting elucidation. It affects 8%-10% of women in their reproductive years, and represents a major clinical problem with deleterious social, sexual and reproductive consequences. Current treatment options include pain relief, hormonal intervention and surgical removal. However, these treatments are deemed unsatisfactory owing to varying success, significant side effects and high recurrence rates. In endometriosis, metformin might modify the stroma-epithelium communication via Wnt2/β-catenin. In addition recent evidence indicates that Sulforaphane (SFN), a natural free radical scavenger, can reduce oxidative stress (OS) through mediating nuclear factor (erythroid-derived 2)-like 2 (NF-E2-related factor 2 or NRF2)/antioxidant response element (ARE) signaling pathway and the downstream antioxidant enzymes. SFN protects human GCs against OS by reducing the intracellular ROS production and the following apoptosis through a mechanism by which NRF2 increases the antioxidant enzymes such as SOD and CAT. This result may have a potential application in assisted reproduction cycles by improving the quality of GCs and the embedded oocyte, especially in polycystic ovary syndrome (PCOS), as well as endometriosis patients. Green tea and its major bioactive component, (-)-epigallocatechin gallate (EGCG), possess diverse biological properties, particularly anti-angiogenic, anti-proliferation, anti-metastasis, and apoptosis induction. In recent years, preclinical studies have proposed the use of green tea to inhibit the growth of endometriosis. Herein, the aim of this review is to summarize the potential therapeutic effects of green tea on molecular and cellular mechanism through inflammation, oxidative stress, invasion and adhesion, apoptosis and angiogenesis in endometriosis. Interplay and coordination of redox interactions with endogenous and exogenous antioxidant defence systems is an emerging area of reserach interest in anticancer and antidegenerative therapeutics. Moreover, particular attention has been given to providing an assessment of the quantitative features of the dose-response relationships and underlying mechanisms that could account for the biphasic nature of the hormetic response after exposure to redox active agents, such as free radical oxygen species and redox active gases involved in the neurobiology of resilience mechanisms with inflammatory/antinflammatory impact on brain stress resistance. The hormetic dose response should be seen as a reliable feature of the dose response for oxygen free radicals and their redox regulated transcriptional factors as well as antioxidant compounds and appears to have an important impact on brain pathophysiology and stress resistance mechanisms to oxidative and inflammatory insult and neurodegenerative damage. This is an interesting paper. The study is well-conceived and well-executed. This reviewer is satisfied with the significance of this study, the care in which the study was performed, and the implications of the results for human health. However, although the results presented are convincing, the work raises some concerns which will need to be addressed. The questions posed are of extremely high interest, but the paper does not give adequate definitive information, therefore pending addressing some major question is possible to accept for publication. Major concerns: 1. Given the relationship between redox status and the vitagene network and its possible biological relevance in cellular and tissue protection, Authors while interpetrating results should discuss appropriately this aspect and make proper connection with emerging principles of hormesis. Indeed, preconditioning signal leading to cellular protection through Hormesis is an important redox dependent aging-associated to free radicals species accumulation, redox active enzymes involved in stress tolerance relevant to degenerative/ cytoprotective mechanisms. This aspect should be highlighted in the discussion and references properly added ((Calabrese et al., 2007 Nature Neuroscience 8, 766; Cornelius C., Immun Ageing . 2013 Apr 25;10(1):15. doi: 10.1186/1742-4933-10-15; Trovato et al., Immun Ageing 2018 Feb 14;15:8. doi: 10.1186/s12979-017-0108-1; Pennisi M., Journal of Neuroscience Research, 95 (7) ,1360-1372, 2017).

Author Response

The content of this review does not relate to our submission. As suggested by the editors, after unsuccessful attempts to contact the reviewer, we did not respond to the Review Report No.3.

Reviewer 4 Report

The authors have discussed in detail about the various epigenetic mechanisms in eutopic endometrium in the group of patients with both endometriosis and infertility. Additional suggestions for improvements are as follows:

 

1. The novelty of the article should be clearly highlighted as number of excellent reviews have already been published on this topic.
2. More references from last few years should be added to improve visibility and quality of current work.
3. The search strategy used for the literature review should be indicated.
4. The pharmacological strategies to target various epigenetic enzymes implicated in endometriosis should be discussed.
5. The authors should provide their own justification and relevance of the study. This will help the readers to understand the importance of the paper.
6. The manuscript should be carefully checked for typographical errors.

Author Response

Please see the attachment

 

Author Response File: Author Response.docx

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The review summarizes epigenetic mechanisms in eutopic endometrium. I believe this topic is not interesting and difficult to follow  for the readers of IJMS. The topic falls into medicinal category and should be submitted to a more specialized journal in that field. Also, English should be extensively revised since many partes are difficult to understand

Author Response

Thank you for reading our manuscript and valuable comments on it.

            The topic of our study is the molecular basis of two diseases that are probably linked by epigenetic pathogenesis. Infertility is a civilization disease of the 21st century. Endometriosis is a disease that affects even every 10th woman in the world. The actual incidence of endometriosis is unknown. This is due, among other things, to the lack of a non-invasive and sensitive diagnostic method. Laparoscopy is still the gold standard in the diagnosis of endometriosis.

            Endometriosis is an enigmatic disease that raises many questions. We still do not know an effective treatment for this disease. The epigenetic background of endometriosis is currently the subject of intense research. The results of molecular studies of the epigenetic code in the eutopic endometrium indicate significant differences in the methylome and the histone code between the group suffering from endometriosis and the group without endometriosis.

            The International Journal of Molecular Sciences is a journal dedicated to studies in the field of molecular biology, cell biology, molecular medicine. The Epigenetic Society is also associated with IJMC.

            Epigenetics research is currently a particularly interesting research topic in many scientific disciplines, especially in medicine. We hope that the issue we have developed will be an interesting and inspiring topic for the readers of the journal.

            To meet the possible difficulties associated with professional terminology in the field of epigenetics, the first part of the review was devoted to discussing the basic issues in this subject. We presented in the most accessible way the most important information on epigenetic mechanisms: DNA methylation, histone modification, miRNA interference, and discussed the most important enzyme proteins involved in chromatin modifications that lead to changes in gene expression. We believe that the proper names of genes and proteins specific for endometrial receptivity and endometriosis will be known to researchers interested in the discussed issue.

            The work was again subjected to linguistic analysis. The working language has been simplified. We believe that these changes will contribute to a clearer message of the issues discussed. All introduced modifications can be tracked with the use of the 'track changes' tool.

            Thank you again for your comments on the manuscript. We hope that the introduced changes will improve the quality of the work, increase its readability and become a source of inspiration for further scientific discoveries in this field of medicine.

Reviewer 2 Report

Epigenetic factors in eutopic endometrium in infertile women with endometriosis may be very important to introduce newe treatment modalities in the future. Association with decreased endometrial αvβ3 integrin expression for endometrial receptivity  should be also analyzed. Key epigenetic changes should be highlighted from clinical point of view.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

I appreciate the effort made by the authors. However, I have not changed my mind. As indicated in my first report, I believe the topic falls into medicinal category and should be submitted to a more specialized journal in that field.

Reviewer 2 Report

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