Plant Terpenoids in Cardioprotection: An Overview of Their Therapeutic Potential

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Comments to the Authors

The manuscript entitled “Plant terpenoids in cardioprotection: An overview of their 2 therapeutic potential.” has been reviewed.

 

The manuscript investigates the efficacy of terpenoids as potential cardioprotective agents. While the results are presented with sufficient detail, the methodology governing the literature selection and review process requires further elaboration.

In the discussion section, the authors effectively articulate the relationship between the biological activities of terpenoids and their cardioprotective potential, providing a sound exploration of the underlying mechanisms of action. However, to enhance the manuscript’s impact, it is recommended that a dedicated paragraph be included prior to the conclusions to address emerging potential research trends. Specifically, the authors should discuss innovative delivery systems aimed at improving the stability and bioavailability of these compounds. This could include the potential of microencapsulated oils, advanced nanotechnology-based delivery platforms, or alternative pharmaceutical formulations.

Consequently, the manuscript is considered suitable for publication, pending these minor revisions.

 

Additionally:

 

Lines 87: The introduction cites preliminary studies on Andalusian thyme oil as an example of the interest in conducting a review of the potential of terpenoids as cardioprotective agents. This section should be expanded slightly, citing ethnobotanical sources where possible. 

 

Line 94: The manuscript is structured as a ‘literature review’ and therefore lacks the specific methodological details of a systematic review, such as a detailed description of the keyword combinations used, the Boolean operators selected, the inclusion and exclusion criteria for articles, etc. In my opinion, the current section entitled ‘Materials and Methods’ should be omitted, stating in the final part of the introduction that the manuscript is a literature review and that the authors have selected the articles considered most relevant over the last 20 years. Otherwise, the decision to present the article as a systematic review would require major revision.

 

Line 652: Before setting out the conclusions, it would be advisable to add a paragraph to the manuscript suggesting what further research should be carried out in the future. This will enhance the article’s scientific novelty and distinguish it from a rigorous and comprehensive review of previous work

 

 

Author Response

Dear Review,

Here we enclose the revised version of the manuscript cimb-4234704 and our responses to the reviewers' comments (in red). We have tried to do our best to answer all the questions through the text and their considerations. We are very grateful for your help.

 

The manuscript entitled “Plant terpenoids in cardioprotection: An overview of their 2 therapeutic potential.” has been reviewed.

 

The manuscript investigates the efficacy of terpenoids as potential cardioprotective agents. While the results are presented with sufficient detail, the methodology governing the literature selection and review process requires further elaboration.

In the discussion section, the authors effectively articulate the relationship between the biological activities of terpenoids and their cardioprotective potential, providing a sound exploration of the underlying mechanisms of action. However, to enhance the manuscript’s impact, it is recommended that a dedicated paragraph be included prior to the conclusions to address emerging potential research trends. Specifically, the authors should discuss innovative delivery systems aimed at improving the stability and bioavailability of these compounds. This could include the potential of microencapsulated oils, advanced nanotechnology-based delivery platforms, or alternative pharmaceutical formulations.

 

Consequently, the manuscript is considered suitable for publication, pending these minor revisions.

 

Additionally:

 

Lines 87: The introduction cites preliminary studies on Andalusian thyme oil as an example of the interest in conducting a review of the potential of terpenoids as cardioprotective agents. This section should be expanded slightly, citing ethnobotanical sources where possible. 

We thank the reviewer for this valuable suggestion. In accordance with the comment, we have expanded the introductory section to better contextualize the traditional use of Thymbra capitata and references describing the traditional medicinal use of have been introduced. These additions strengthen the rationale for reviewing terpenoids as cardioprotective agents. The revised text can be found in the Introduction (lines 116-121).

 

Line 94: The manuscript is structured as a ‘literature review’ and therefore lacks the specific methodological details of a systematic review, such as a detailed description of the keyword combinations used, the Boolean operators selected, the inclusion and exclusion criteria for articles, etc. In my opinion, the current section entitled ‘Materials and Methods’ should be omitted, stating in the final part of the introduction that the manuscript is a literature review and that the authors have selected the articles considered most relevant over the last 20 years. Otherwise, the decision to present the article as a systematic review would require major revision.

We thank the reviewer for this valuable appreciation. We agree that the manuscript corresponds to a narrative literature review rather than a systematic review. Accordingly,  the Materials and Methods section has been removed and a new paragraph has been added at the end of the introduction clarifying the nature of the review and summarizing the criteria used to select the articles. This paragraph retains the essential information from the previous section, but it has been refined to better fit the structure of a narrative review.

 

Line 652: Before setting out the conclusions, it would be advisable to add a paragraph to the manuscript suggesting what further research should be carried out in the future. This will enhance the article’s scientific novelty and distinguish it from a rigorous and comprehensive review of previous work

We appreciate the reviewer’s suggestion. In response, we have added a new section at the end of the manuscript and before the conclusion entitled “Perspective and Future Research”. This section highlights the need for further studies to address aimed at addressing the current gaps found in the translation of basic research findings into clinical trials. We specifically emphasize the need of incorporating human-based models to improve translational relevance, suggesting human induced pluripotent stem cells derived cardiomyocytes as in vitro model for basic research in cardiotoxicity and cardioprotection.

In this section we have also tackled the reviewer’s recommendation regarding the innovative delivery systems to improve the stability and bioavailability of these compounds as a strategy to optimize the bioavailability of terpenoids and essential oils and therefore their therapeutic potential. We believe that incorporating these perspectives strengthens the scientific contribution of the manuscript.

 

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript contains vast sections of general information on biochemistry/pathology, whereas molecular effects of triterpenoids, which is supposed to be the main value of the review, are scarse.

Author Response

Dear Review,

Here we enclose the revised version of the manuscript cimb-4234704 and our responses to the reviewers' comments (in red). We have tried to do our best to answer all the questions through the text and their considerations. We are very grateful for your help.

 

The manuscript contains vast sections of general information on biochemistry/pathology, whereas molecular effects of triterpenoids, which is supposed to be the main value of the review, are scarse.

We appreciate the reviewer’s constructive observation. In response, we have substantially revised the manuscript to ensure that the molecular effects of triterpenoids take part in the review. Additional examples of triterpenoids (betulin, lupeol, lupeol acetate, celastrol, corosolic acid, dioscin, ginsenoside Rg3, maslinic acid, ursolic acid, oleanolic acid, betulinic acid) have been added throughout the manuscript with emphasis on their specific molecular targets and cardioprotective signalling pathways. Lines 255-285, 358-366, 396-400, 451-460, 510-517, 610-615, 665-666

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have prepared a seemingly thorough review of the therapeutic possibilities of plant terpenoids/essential oils in the treatment of cardiovascular disease, providing for antioxidant, anti-inflammatory, antiarrhythmic and anti-remodelling properties.

The review will be of potential interest to readers working in the fields of medicinal natural products, alternative medicine, and drug discovery where nature can inspire the synthesis of innovative agents to treat and prevent disease.

Some revisions are recommended to further improve the manuscript as it is further considered for acceptance for publication, as follows: 

Page 1 lines 34-35: the  statement "essential oils are the most important in terms of healing properties" may be too strong, especially reviewing the content of reference #2 that is cited in support of the statement. I would suggest softening this to "essential oils may be among the  more important in terms of healing properties".

Page 17, line 280-282 and Page 23, lines 374-375: there is duplicative wording  in describing storax, the resin from Liquidamber orientalis. The detail of the background to storax neds citing just once.

Page 42 within the section Conclusions please add comment as to the challenges of translation of naturally sourced  materials into therapeutic practice, including sustainability (can the plant source be cultivated), utility of the plant source (is the active ingredient present in the plant at a level at which its isolation for therapeutic use is workable commercially?), effectiveness- mot invitro work  may not replicate in treatment of human disease due to metabolism poor bioavailability etc of the active component, chemical synthesis of natural products as therapeutic agents may be difficult due to molecular complexity, stereochemistry that makes for very costly end product. Nonetheless a further positive conclusion can be that biologically active agents from plants can make for excellent templates for starting points in medicinal chemistry.

Author Response

Dear Review,

Here we enclose the revised version of the manuscript cimb-4234704 and our responses to the reviewers' comments (in red). We have tried to do our best to answer all the questions through the text and their considerations. We are very grateful for your help.

 

The authors have prepared a seemingly thorough review of the therapeutic possibilities of plant terpenoids/essential oils in the treatment of cardiovascular disease, providing for antioxidant, anti-inflammatory, antiarrhythmic and anti-remodelling properties.

The review will be of potential interest to readers working in the fields of medicinal natural products, alternative medicine, and drug discovery where nature can inspire the synthesis of innovative agents to treat and prevent disease.

Some revisions are recommended to further improve the manuscript as it is further considered for acceptance for publication, as follows: 

Page 1 lines 34-35: the  statement "essential oils are the most important in terms of healing properties" may be too strong, especially reviewing the content of reference #2 that is cited in support of the statement. I would suggest softening this to "essential oils may be among the  more important in terms of healing properties".

Thanks for the suggestion, it is right that the sentence is too strong. It has been replaced by the following sentence following the reviewer suggestions “essential oils may be among the more important components in terms of healing properties”

Page 17, line 280-282 and Page 23, lines 374-375: there is duplicative wording  in describing storax, the resin from Liquidamber orientalis. The detail of the background to storax neds citing just once.

Thanks for the appreciation, it has been removed from lines 374-375

Page 42 within the section Conclusions please add comment as to the challenges of translation of naturally sourced  materials into therapeutic practice, including sustainability (can the plant source be cultivated), utility of the plant source (is the active ingredient present in the plant at a level at which its isolation for therapeutic use is workable commercially?), effectiveness- mot invitro work  may not replicate in treatment of human disease due to metabolism poor bioavailability etc of the active component, chemical synthesis of natural products as therapeutic agents may be difficult due to molecular complexity, stereochemistry that makes for very costly end product. Nonetheless a further positive conclusion can be that biologically active agents from plants can make for excellent templates for starting points in medicinal chemistry.

We thank the reviewer for this valuable comment. Since another reviewer raised a similar point, a new section has been added before the conclusion, it is entitled “Perspective and Future Research” and it addresses, among other issues, the major challenges associated with translating naturally sourced compounds into therapeutic practice. It also discusses the sustainability and scalability of plant sources due to the limited yield of active ingredients as well as the difficulties associated with the chemical synthesis of structurally complex terpenoids. It incorporates alternative production strategies based on heterologous biosynthesis in microorganisms and plants. Since the poor bioavailability of these compounds is another gap for their clinical use, we have included information regarding the delivery systems based on micro- and nanoencapsulated essential oils and terpenes, as well as nano-technology-based delivery platforms. Eventually, the reviewer’s suggestion to highlight the utility of plant‑derived bioactive molecules as templates for medicinal chemistry have been included. We believe these additions strengthen the manuscript by providing a broader perspective of the field. Nevertheless, if the reviewer considers this information should be increased or relocated in another section we are open to do such changes.

 

Reviewer 4 Report

Comments and Suggestions for Authors

1. Kindly rephrase this sentence from the abstract “Of all the compounds that comprise essential oils, terpenoids are the most abundant and confer most of their biological properties.”
2. Kindly rewrite the abstract part to a more informative one.
3. Kindly check for any grammar or spelling mistakes.
4. Figure 1 seems to be copied from another research article which is ethically upright. Kindly replace.
5. Tables are great way to summarize literature however authors should provide dosage and IC₅₀ values for each listed article.
6. Table 1, add the English and common names for the plants. Apply this to all tables
7. The writing style seems to focus just on the number of cited articles without highlighting their main findings.
8. Some symbols like α β should be italic. Check please.
9. In the “plant” column in tables. The authors sometimes write it as the plant name, genus name or family name so this column should be unified or the authors may state the plant name and its family each time.
10. This study may benefit from adding more illustrative figures for the main enzymes involved in each activity or the key active plants.
11. Kindly draw the structures of the bioactive terpenoids listed in tables in separate figures and number them in text.
12. The English writing for the whole manuscript should be revised by a native English speaker.
13. Some declarations at the end of the manuscript were left empty.
14. In references part, write any plant, animal, microbe name as italic.

Author Response

Dear reviewer,

Here we enclose the revised version of the manuscript cimb-4234704 and our responses to the reviewers' comments (in red). We have tried to do our best to answer all the questions through the text and their considerations. We are very grateful for your help.

 

1.    Kindly rephrase this sentence from the abstract “Of all the compounds that comprise essential oils, terpenoids are the most abundant and confer most of their biological properties.”

Thank you to the reviewer for this valuable suggestion. The sentence has been rephrased.

2.    Kindly rewrite the abstract part to a more informative one. 
Thanks to the reviewer for this valuable recommendation. The abstract has been substantially revised to provide a more informative and comprehensive overview of the scope, key mechanisms, and relevance of terpenoid based cardioprotection. 

3.    Kindly check for any grammar or spelling mistakes.
We thank the reviewer for this comment. The entire manuscript has been carefully checked, and grammar and spelling errors have been corrected throughout.

4.    Figure 1 seems to be copied from another research article which is ethically upright. Kindly replace.
I fully understand the reviewer’s point of view. Indeed, the authors were inspired by a figure previously published in the literature (Pazouki & Niinemets, 2016. Multi-Substrate Terpene Synthases: Their Occurrence and Physiological Significance. Front. Plant Sci. 7:1019. doi: 10.3389/fpls.2016.01019). However, as can be seen, our figure is substantially different. The original figure includes a larger number of compound names and enzymes, whereas our version presents only bullet point information summarizing the main features of both pathways (pathway name, cellular location, starting molecules, number of reactions, the key intermediate that gives the pathway its name, and the building blocks that serve as the structural basis for terpenoid synthesis). The figure has been slightly modified and a reference to the paper which has inspired the figure has been included.

 

5.    Tables are great way to summarize literature however authors should provide dosage and IC50 values for each listed article. 
We appreciate the suggestion regarding the inclusion of doses and IC₅₀ values from the cited studies. However, we consider that this information is outside the scope of the objectives of the review. Since our work focuses on analyzing the cardioprotective mechanisms proposed for plant derived-terpenes, as well as summarizing the general molecular mechanisms observed in the literature. Since our tables represent effects on a range of biological systems, many of which are complex with multiple targets and do not necessarily follow a simple sigmoidal relationship and information on IC50 is not available in the majority of the studies, we consider the inclusion of IC50 values of little comparative value. 
For this reason, our tables have been created as qualitative synthesis tools, highlighting the cardioprotective effects described and the mechanisms involved, which constitute the main focus of the review. We trust that this clarification helps to contextualize our methodological decision.

6.    Table 1, add the English and common names for the plants. Apply this to all tables 
We appreciate the reviewer´s observation and such changes have been done to improve the quality of tables

7.    The writing style seems to focus just on the number of cited articles without highlighting their main findings. 
We appreciate the reviewer´s observation. We agree that the large number of studies included in this review may have made some sections appear dense. In addition, many essential oil derived terpenes share similar cardioprotective molecular mechanisms. For those reasons the authors have emphasized representative examples in the main text while synthesizing the broader evidence in the tables

8.    Some symbols like α β should be italic. Check please.
We thank the reviewer for this comment. We have carefully checked the entire manuscript and corrected the formatting of all Greek symbols (mainly α, β and γ) to ensure they appear in italics where required

9.    In the “plant” column in tables. The authors sometimes write it as the plant name, genus name or family name so this column should be unified or the authors may state the plant name and its family each time. 
Thanks for the suggestion, it has been unified throughout the manuscript.

10.    This study may benefit from adding more illustrative figures for the main enzymes involved in each activity or the key active plants.
The authors highly appreciated the reviewer´s suggestion and in accordance with it two schematic figures (Fig 5 and Fig 6) have been included. Fig 5 summarizes the cellular mechanism altered in MI and the most common mechanism of action of essential oil-derived terpenes to prevent it. Fig 6 recapitulate the electrophysiological alterations commonly responsible for pro-arrhythmic events and the mechanisms of action of monoterpenes to avoid them.

11.    Kindly draw the structures of the bioactive terpenoids listed in tables in separate figures and number them in text.

We thank the reviewer for this helpful suggestion. In response, we have prepared a new figure containing the chemical structures of the main bioactive terpenoids discussed in the manuscript. These structures are now presented together in a dedicated figure for clarity. We have not correlated the compounds with numbers, because the compounds included in the table have simple names and we consider that keeping the names in the text facilitates comprehension for the reader. In addition, each compound has been numbered consistently with its appearance in the text. The new figure has been included as Table 10 in the revised version.

12.    The English writing for the whole manuscript should be revised by a native English speaker.
The manuscript has been read by an English native, and modifications are included throughout the text.

13.    Some declarations at the end of the manuscript were left empty.
We thank the reviewer for pointing this out. The final part of the manuscript has now been carefully reviewed and completed according to the journal’s requirements, if the reviewer considers that anything is still missing, we would be happy to address it.

14.    In references part, write any plant, animal, microbe name as italic. 
Thank you for your comment. We have carefully revised the Reference section. All scientific names of plants, animals, and microorganisms (including genera, species, and subspecies) have been consistently formatted in italics in accordance with standard biological nomenclature conventions.