CYC27 Synthetic Derivative of Bromophenol from Red Alga Rhodomela confervoides: Anti-Diabetic Effects of Sensitizing Insulin Signaling Pathways and Modulating RNA Splicing-Associated RBPs
Round 1
Reviewer 1 Report
In this manuscript authors have studied the in vivo activity of synthetic derivative (CYC27) of marine bromophenol BDB (3-bromo-4,5-bis(2,3-dibromo-4,5-dihydroxybenzyl)pyrocatechol), which was isolated from red alga Rhodomela confervoides and they also studied their mechanism of action in diabetic treatment. This study focuses on the serious issue of Type 2 diabetes mellitus (T2DM) and associated risks. The study has significance importance and it can also be interest to the readers.
Their BDB derivative CYC27 shows approx. 2-fold improvement as compared to the parent compound, but two-fold improvement is not considered significant. In my opinion authors must have included at least 1 or two more derivatives which they found promising during the SAR study since compounds usually behave differently during in vitro and in vivo studies. I would suggest adding at least one or two more compound along with parent compound.
The manuscript is written well but at some places they have oversold the results. If we compare their results with existing drug Rosiglitazone, the hypoglycemic activity is increased but not better than Rosiglitazone. The same pattern was seen for the Effects of CYC27 on dyslipidemia.
In experimental section either mention the synthetic procedure for the synthesis of CYC27 or give a reference next to it.
Author Response
Dear professors,
Thank you very much for giving us the opportunity to revise and resubmit our manuscript entitled “CYC27, a synthetic derivative of bromophenol from red alga Rhodomela confervoides: Anti-diabetic effects via sensitizing the insulin signaling pathway and modulating RNA splicing-associated RBPs” (ID: marinedrugs-411516). And we also appreciate the reviewers very much for their positive and constructive comments and suggestions, which will help us improve the manuscript to a better scientific level. We have reviewed the comments carefully and supplemented several data accordingly which we hope meet with approval. Our responses are given in a point-by-point manner below. Changes to the manuscript are highlighted by using the "Track Changes" function in Microsoft Word.
Meanwhile, we have supplemented the approval of the ethics committee in the section 4.2.
Reviewer’s comments:
Reviewer 1:
In this manuscript authors have studied the in vivo activity of synthetic derivative (CYC27) of marine bromophenol BDB (3-bromo-4,5-bis(2,3-dibromo-4,5-dihydroxybenzyl)pyrocatechol), which was isolated from red alga Rhodomela confervoides and they also studied their mechanism of action in diabetic treatment. This study focuses on the serious issue of Type 2 diabetes mellitus (T2DM) and associated risks. The study has significance importance and it can also be interest to the readers.
1-Their BDB derivative CYC27 shows approx. 2-fold improvement as compared to the parent compound, but two-fold improvement is not considered significant. In my opinion authors must have included at least 1 or two more derivatives which they found promising during the SAR study since compounds usually behave differently during in vitro and in vivo studies. I would suggest adding at least one or two more compound along with parent compound.
Response: We agree with the reviewer that two-fold improvement is not considered significant. In the previous study, we have synthesized a series derivatives based on the natural product BDB, and the SAR also discussed（Jiang, B., et al. Arch Pharm (Weinheim), 2012.345(6): 444-453）. In this paper, we focus on the anti-diabetic effects of CYC27 by sensitizing the insulin signaling pathway and modulating RNA splicing-associated RBPs.
2-The manuscript is written well but at some places they have oversold the results. If we compare their results with existing drug Rosiglitazone, the hypoglycemic activity is increased but not better than Rosiglitazone. The same pattern was seen for the Effects of CYC27 on dyslipidemia.
Response: Thank you very much for your careful review. Rosiglitazone has powerful and long-lasting hypoglycemic effect compared with other T2DM drugs, such as the first line drug metformin. Although there are 12 types of FDA approved hypoglycemic drugs, 63% of T2DM patients still do not receive effective treatment, so the development of innovative diabetes drugs is still a top priority. In this paper, CYC27 significantly decreased FBG, GHb, GSA, TC and TG (p<0.01 or p<0.05 compared with vehicle). We also stated that “In detail, CYC27 significantly lowered FBG levels from the 3rd week, while Rosiglitazone significantly decreased blood glucose levels from the first week (p < 0.01).”
3-In experimental section either mention the synthetic procedure for the synthesis of CYC27 or give a reference next to it.
Response: We have supplemented the reference of synthetic procedure for CYC27 in section 4.1.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
The study by Jiao Luo et al. investigates the effect of the CYC27, a synthetic derivative of bromophenol from red algae, on metabolic parameters in the Leptin receptor-deficient obesity-induced metabolic disease mouse model. They show rather than being a weight loss drug, CYC27 improves humoral parameters of metabolic disease, and mechanistic studies in cultured myotubes suggest that CYC27 acts at least in part as an insulin sensitizer. The study is well performed and the manuscript well written. I have a couple suggestions the authors may want to consider.
Minor points:
1. Ideally, for a complete picture the plasma insulin levels should be provided.
2. In the end, the proteomic analysis is interesting but the changes could be secondary to the improvements in insulin signaling. So, whether this is mechanistically relevant remains unclear and the authors should be more careful when interpreting their findings into that direction.
3. Recently, a novel regulator of insulin resistance – independently of weight gain – has been described, and it is possible that this marine drug is a potential ligand of Nfe2l1 (Bartelt et al. Nature Medicine 2018), as Nfe2l1 has been described to interact with a variety of natural compounds. This should be discussed.
Author Response
Dear professors,
Thank you very much for giving us the opportunity to revise and resubmit our manuscript entitled “CYC27, a synthetic derivative of bromophenol from red alga Rhodomela confervoides: Anti-diabetic effects via sensitizing the insulin signaling pathway and modulating RNA splicing-associated RBPs” (ID: marinedrugs-411516). And we also appreciate the reviewers very much for their positive and constructive comments and suggestions, which will help us improve the manuscript to a better scientific level. We have reviewed the comments carefully and supplemented several data accordingly which we hope meet with approval. Our responses are given in a point-by-point manner below. Changes to the manuscript are highlighted by using the "Track Changes" function in Microsoft Word.
Meanwhile, we have supplemented the approval of the ethics committee in the section 4.2.
Reviewer 2:
The study by Jiao Luo et al. investigates the effect of the CYC27, a synthetic derivative of bromophenol from red algae, on metabolic parameters in the Leptin receptor-deficient obesity-induced metabolic disease mouse model. They show rather than being a weight loss drug, CYC27 improves humoral parameters of metabolic disease, and mechanistic studies in cultured myotubes suggest that CYC27 acts at least in part as an insulin sensitizer. The study is well performed and the manuscript well written. I have a couple suggestions the authors may want to consider.
Minor points:
1-Ideally, for a complete picture the plasma insulin levels should be provided.
Response: Thank you very much for your positive and supportive comments on our manuscript. We have supplemented the data of serum insulin levels at the 7th week in Figure 2D.
2-In the end, the proteomic analysis is interesting but the changes could be secondary to the improvements in insulin signaling. So, whether this is mechanistically relevant remains unclear and the authors should be more careful when interpreting their findings into that direction.
Response: Great thanks for your professional review work on our manuscript. We will accept your suggestions and carefully study the direction about RNA splicing-associated RBPs after accumulating more discoveries and experiences in this area.
3-Recently, a novel regulator of insulin resistance – independently of weight gain – has been described, and it is possible that this marine drug is a potential ligand of Nfe2l1 (Bartelt et al. Nature Medicine 2018), as Nfe2l1 has been described to interact with a variety of natural compounds. This should be discussed.
Response: Thank you very much for your professional comments. The study constructed by Bartelt et al (2018) has great reference value for us, and we have discussed and cited the paper in our revised manuscript.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
I am happy with the changes made to this manuscript at some places but I am still looking for authors response about including at least 1 or two more derivatives which they found promising during the SAR study.
Author Response
Response: Thank you very much for your professional comments. In the previous study, we have synthesized a series derivatives based on the natural product BDB. Among the derivatives, compound CYC27 showed the most potent PTP1B inhibition (IC50=0.89 uM), the other derivatives did not show more potent inhibition than BDB（Jiang, B., et al. Arch Pharm (Weinheim), 2012.345(6): 444）. Hence, CYC27 was chosen to study the in vitro and in vivo effect in our present study, and the results reported sufficient to draw a conclusion that CYC27 indeed could significantly lower the blood glucose level and lipid level in diabetic mice and sensitize the insulin signaling pathway. Although two-fold improvement of CYC27 is not very significant compared to the parent compound, the hypoglycemic effect of CYC27 gives us confidence and motivation for the future study. Given that the natural product BDB exhibited moderated PTP1B inhibition, we will continue to study the in vitro and in vivo effects. More research results will be reported in future researches.
Author Response File: Author Response.pdf
