Therapeutic Applications of Curcumin Nanomedicine Formulations in Cardiovascular Diseases

Round 1

Reviewer 1 Report

The authors in this manuscript have reviewed literature on the therapeutic effects of Curcumin in various diseases and the limitations to efficacy. They have proposed use of nanoparticles as a mechanism of delivery to overcome the limited water solubility of the drug. The review is well summarizes the preclinical and clinical studies with curcumin and the formulations used. It provides a good reference material for researchers interested in these kind of studies.

Author Response

Thank you for the overall appreciation of our work.

Reviewer 2 Report

The article addresses the effects of curcumin on cardiovascular diseases and the difficulties for drug delivery, mainly because the chemical characteristics of CUR. It is very interesting text and I am confident that it is important for researchers that have the problem with research and development not only regarding to CUR, but also can be related to other products with similar chemical characteristics.

About the article, I have some considerations:

1. Line 107, it is informed about the compounds that are formed during CUR degradation. Are these compounds formed at the same time or there are specific reactions that form each of them?
2. Line 104. To be more informative, define class II drug.
3. Line 127. correct: “used to deliver” and not “used for to deliver”…
4. Line 190, item 2.2: The text is very informative, however there are some redundancies. For example, lines 191-200, the information could be just that several studies have been observed beneficial effects of CUR in atherosclerosis in several animal models. Additionally, mechanisms were not informed. Therefore, in the current format, the text is very descriptive about several studies, but there is no evolution in the information. I believe that from line 191-206 could be reduced to only 5-6 lines, to the main information.
5. Line 211, “In another study, CUR significantly enhanced oxidized low-density lipoprotein”. Double check this information. The uptake of oxLDL by macrophages is the main mechanism of foam cell formation. How does CUR increase oxLDL uptake and reduce atherosclerotic plaques?
6. Line 217, “Similar reduction of oxLDL uptake…” Why similar reduction? In line 211 is mentioned that CUR enhanced oxLDL uptake.
7. Line 226, “CUR intake markedly decreased elevated Th2 and Th17 cell numbers as well as Tregs in the spleen.” Is it correct to say that there is a reduction in Th2 and T reg cells in the spleens?
8. Line 264, “myocardial ischemia model induced by the ligation”. Inform the ligation model used in the study.
9. Line 301. Correct the word enalapril
10. Line 307. Double check the information. How colorectal cancer pathway is involved in cardioprotective effects of CUR?
11. Line 313. “consumed CUR for defined period of time”. Define how was the administration of the treatment.
12. Line 332, “Similar positive effects were found in clinical trials”. Inform the number of participants in these clinical trials. Was there improvement in all of them?
13. Line 596, “H9C2 cell lines;”. Define these cells, are they cardiomyocyte cell line?

Author Response

The article addresses the effects of curcumin on cardiovascular diseases and the difficulties for drug delivery, mainly because the chemical characteristics of CUR. It is very interesting text and I am confident that it is important for researchers that have the problem with research and development not only regarding to CUR, but also can be related to other products with similar chemical characteristics.
Answer: Thank you for the overall appreciation of our work.
About the article, I have some considerations:
1. Line 107, it is informed about the compounds that are formed during CUR degradation. Are these compounds formed at the same time or there are specific reactions that form each of them?
Answer: These compounds are formed through reduction reactions

2. Line 104. To be more informative, define class II drug.
Answer: The requested change was done

3. Line 127. correct: “used to deliver” and not “used for to deliver”…
Answer: Corrected

4. Line 190, item 2.2: The text is very informative, however there are some redundancies. For example, lines 191-200, the information could be just that several studies have been observed beneficial effects of CUR in atherosclerosis in several animal models. Additionally, mechanisms were not informed. Therefore, in the current format, the text is very descriptive about several studies, but there is no evolution in the information. I believe that from line 191-206 could be reduced to only 5-6 lines, to the main information.
Answer: All the requested changes were done.

5. Line 211, “In another study, CUR significantly enhanced oxidized low-density lipoprotein”. Double check this information. The uptake of oxLDL by macrophages is the main mechanism of foam cell formation. How does CUR increase oxLDL uptake and reduce atherosclerotic plaques?
Answer: The requested explanation was added.

6. Line 217, “Similar reduction of oxLDL uptake…” Why similar reduction? In line 211 is mentioned that CUR enhanced oxLDL uptake.
Answer: The correct term would be “ameliorated” and not “enhanced”. Indeed, CUR inhibited SR-A-mediated oxLDL uptake and promoted ABCA1-dependent cholesterol efflux. This information was added in the revised version of the manuscript.

7. Line 226, “CUR intake markedly decreased elevated Th2 and Th17 cell numbers as well as Tregs in the spleen.” Is it correct to say that there is a reduction in Th2 and T reg cells in the spleens?
Answer: We changed this sentence. In fact, “decreased elevated” is not the better option, we changed by “helped to normalize”.

8. Line 264, “myocardial ischemia model induced by the ligation”. Inform the ligation model used in the study.
Answer: The requested information was added

9. Line 301. Correct the word enalapril
Answer: Corrected

10. Line 307. Double check the information. How colorectal cancer pathway is involved in cardioprotective effects of CUR?
Answer: Is has been suggested the existence of a link between myocardial infarction and colorectal cancer. Indeed, in rats, three differentially expressed genes (c-fos, Smad2 and Tgfbr2) were found to be associated with colorectal cancer, and specifically the expression of c-fox and smad2 is up-regulated during myocardial infarction. On the other side, the down-regulation of c-fox protein expression may protect myocardium against myocardial ischemia/reperfusion, and the phosphorylation of Smad2 is associated with cardiac fibrosis

11. Line 313. “consumed CUR for defined period of time”. Define how was the administration of the treatment.
Answer: The treatment was given per os.

12. Line 332, “Similar positive effects were found in clinical trials”. Inform the number of participants in these clinical trials. Was there improvement in all of them?
Answer: The requested information was added in the revised version of the manuscript.

13. Line 596, “H9C2 cell lines;”. Define these cells, are they cardiomyocyte cell line?
Answer: These are myoblastic cells.

Reviewer 3 Report

n this manuscript, the authors proposed an extensive review on the protective effect of Curcumin, as well as the status quo and prospect of the formulation and therapeutic applications of Curcumin nanomedicine in multiple cardiovascular diseases. In general, the matter is of high interest and dissertated intensively with abundant references. Meanwhile, the overall quality of English language is at a high level. Nevertheless, the following issues need to be addressed.

Some figures need to be selected from the cited literatures or created to closely elucidate how Curcumin execute beneficial effects on cardiovascular diseases.

Some paragraphs in Part 2 are rather long and need to be well re-organized.

Author Response

In this manuscript, the authors proposed an extensive review on the protective effect of Curcumin, as well as the status quo and prospect of the formulation and therapeutic applications of Curcumin nanomedicine in multiple cardiovascular diseases. In general, the matter is of high interest and dissertated intensively with abundant references. Meanwhile, the overall quality of English language is at a high level. Nevertheless, the following issues need to be addressed.
Answer: Thank you for the overall appreciation of our work.
Some figures need to be selected from the cited literatures or created to closely elucidate how Curcumin execute beneficial effects on cardiovascular diseases.
Answer: Thank you so much for your valuable comments. Since we have limited by the journal to reply to the comments we have to send it in the current form now and it is not possible for us now.
Some paragraphs in Part 2 are rather long and need to be well re-organized.
Answer: Section 2 was completely revised and improved.