Potential Therapeutic Implication of Herbal Medicine in Mitochondria-Mediated Oxidative Stress-Related Liver Diseases
, Md. Ataur Rahman 1,2,3,†, Md. Hasanur Rahman 1,2, Jong Woo Kim 1,2, Min Choi 1,2, Jeong Woo Kim 1,2, Jinwon Choi 1,2, Myunghan Moon 1,2, Kazi Rejvee Ahmed 1,2 and Bonglee Kim 1,2,*Round 1
Reviewer 1 Report
In this review article, the authors summarize in detail the molecular mechanisms for an association of oxidative stress and/or mitochondrial dysfunction in the liver with onset and progression of both nonalcoholic fatty liver disease and alcoholic liver disease. Although an extensive and intensive discussion on the above association was made by the citation of enough volume of scientific papers, the authors described only a small volume of statement regarding herbal medicine, that is the main theme of this article. A number of comments are made below.
1.The authors described the useful and beneficial effects of herbal medicine on liver diseases in terms of fat metabolism, e.g., a reduction of fat content in the liver. However, the survival outcome of subjects with liver diseases is largely dependent upon the status of liver fibrosis rather than steatosis. There are many papers which reported this important issue. They should refer to the anti-fibrotic effects of herbal medicine, which in turn make an emphasis on clinical usefulness in the field of liver diseases.
2.Nonalcoholic fatty liver disease (NAFLD) is interpreted as systemic disease. Not only liver but also other organs such as intestine, adipose tissue, and or muscle interplay onset and progression of NAFLD. The authors described that Sophocarpine modifies adipokine profile. The readers may have interest in the beneficial effects of herbal medicine on other organs other than liver, especially for visceral adipose tissues.
3.Figure 5 in the text summarized the effects of herbal medicine on mitochondria in the liver. In this figure, herbal medicine may modify the TG and NEFA profiles which are attributable to the mitochondrial functional changes. However, this statement sounds insufficient. The authors should give more information to show that potent ingredients of herbal medicine directly affect and/or the mitochondrial function.
Author Response
In this review article, the authors summarize in detail the molecular mechanisms for an association of oxidative stress and/or mitochondrial dysfunction in the liver with onset and progression of both nonalcoholic fatty liver disease and alcoholic liver disease. Although an extensive and intensive discussion on the above association was made by the citation of enough volume of scientific papers, the authors described only a small volume of statement regarding herbal medicine, that is the main theme of this article. A number of comments are made below.
>> (Response) First of all, we would like to express our sincere gratitude for the time and effort the reviewer had put into reviewing our manuscript. We have incorporated changes based on the reviewer comments provided in the manuscript which revised parts are highlighted by RED color in the entire revised manuscript.
1.The authors described the useful and beneficial effects of herbal medicine on liver diseases in terms of fat metabolism, e.g., a reduction of fat content in the liver. However, the survival outcome of subjects with liver diseases is largely dependent upon the status of liver fibrosis rather than steatosis. There are many papers which reported this important issue. They should refer to the anti-fibrotic effects of herbal medicine, which in turn make an emphasis on clinical usefulness in the field of liver diseases.
>> (Response) We are grateful the reviewer nice comments. We responded anti-fibrotic effects of herbal medicine into the entire revised manuscript (page 8, line 178-182; page 11, line 137-140; page 12, line 272-282; page 15, line 331-333; page16, line 372-376; page 20, line 482-495; page 21, line 501-506).
- Nonalcoholic fatty liver disease (NAFLD) is interpreted as systemic disease. Not only liver but also other organs such as intestine, adipose tissue, and or muscle interplay onset and progression of NAFLD. The authors described that Sophocarpine modifies adipokine profile. The readers may have interest in the beneficial effects of herbal medicine on other organs other than liver, especially for visceral adipose tissues.
>> (Response) We added beneficial effects of herbal medicine on other organs (page 16, line 372-376; page 19, line 444-457; page 20, line 474-496). We also added more information of sophocarpine modifies adipokine profile (page 19, line 458-464).
- Figure 5 in the text summarized the effects of herbal medicine on mitochondria in the liver. In this figure, herbal medicine may modify the TG and NEFA profiles which are attributable to the mitochondrial functional changes. However, this statement sounds insufficient. The authors should give more information to show that potent ingredients of herbal medicine directly affect and/or the mitochondrial function.
>> (Response) We modified and added more information in figure 5 (page 22). Additionally, we added effects of herbal several medicine on mitochondria in the liver in the section 8 (page 16-21, line 361-521).
Reviewer 2 Report
The aim of the review: “Potential Therapeutic Implication of Herbal Medicine in Mitochondria- Mediated Oxidative Stress Related Live Diseases”, as form the title, seems to regard the potential of herbal medicine for the treatment of liver disease relatable to oxidative stress.
In general, English is good and the text is well written. Anyway, the review is greatly dealing with the causes and factors responsible for oxidative stress in the liver, with the consequent implications for the development of liver damage and progression of disease to severe pathology. Particular attention is given to mitochondria as sources of oxidative species and related oxidative stress. These parts are excessive as compared with the part of the text on beneficial roles of herbs and derivatives, against what seems to be promised from the title. To comply with the title and related expectations to the reader, the text on herbs and derivatives should be implemented by improving and enlarging the description of derivatives, how and from which herbs are derived, and their possible mechanisms of action. On the other hand, a smaller rearrangement of the text could be sufficient, if accompanied by the adaptation of the title to what actually is described in the review. In both cases, a major revision is suggested, to provide a duly rearranged and revised text.
Author Response
The aim of the review: “Potential Therapeutic Implication of Herbal Medicine in Mitochondria- Mediated Oxidative Stress Related Live Diseases”, as form the title, seems to regard the potential of herbal medicine for the treatment of liver disease relatable to oxidative stress.
>> (Response) First of all, we would like to express our sincere gratitude for the time and effort the reviewer had put into reviewing our manuscript.
In general, English is good and the text is well written. Anyway, the review is greatly dealing with the causes and factors responsible for oxidative stress in the liver, with the consequent implications for the development of liver damage and progression of disease to severe pathology. Particular attention is given to mitochondria as sources of oxidative species and related oxidative stress. These parts are excessive as compared with the part of the text on beneficial roles of herbs and derivatives, against what seems to be promised from the title. To comply with the title and related expectations to the reader, the text on herbs and derivatives should be implemented by improving and enlarging the description of derivatives, how and from which herbs are derived, and their possible mechanisms of action. On the other hand, a smaller rearrangement of the text could be sufficient, if accompanied by the adaptation of the title to what actually is described in the review. In both cases, a major revision is suggested, to provide a duly rearranged and revised text.
>> (Response) We are grateful to the reviewer wonderful suggestions. We have incorporated changes based on the reviewer comments and suggestions provided in the manuscript which revised parts are highlighted by RED color in the entire revised manuscript. We implemented and improving the description of herbal derivatives and how herbs are regulated in particular molecular target of action to mitochondria as a source of oxidative species and related oxidative stress in liver disease via their possible mechanisms of action. Additionally, we also added and modified huge portion of our manuscript suggested by the reviewer. Finally, we added one more section ‘9. The antioxidant effect of herbal medicines via suppression of lipid peroxidation to thiolation migration in oxidative damage’ (page 22, line 528-582).
Reviewer 3 Report
Title: Potential Therapeutic Implication of Herbal Medicine in Mitochondria-Mediated Oxidative Stress Related Live Diseases.
First, the authors summarized the role of mitochondria in liver diseases and the importance of this organelle in the production of reactive oxygen species. The authors reviewed some herbal medicines and drugs derived from plants for alcoholic liver disease and nonalcoholic liver disease treatment. I have some concerns about this manuscript.
1.- It is very badly written and disorganized. Therefore, it is not easy to follow. There are some repeated sentences, see, for example, lines 91-97.
2.- The aim is not easy to understand. The title suggests that the authors are going to focus on ROS produced in mitochondria and the role of plant-derived antioxidants on these ROS and their importance in liver disease treatment. However, the authors just talk about some natural antioxidants for liver diseases, mainly alcoholic and nonalcoholic liver diseases. This topic has been extensively reviewed by several authors.
3.- Many herbal medicines were not described in detail. For example, naringenin, silymarin, L-theanine, hesperidin, caffeine, quercetin, etc.
4.- It is now recognized that most plant-derived antioxidants act, in addition to their free radical scavenging ability, by improving the Nrf2 signaling pathway. Unfortunately, this effect was not reviewed in this manuscript.
5.- Oxidative stress, inflammation, fibrosis, and liver cancer are associated. The role of free radicals on inflammation, fibrosis, and liver cancer was not deeply discussed. The importance of plant-derived antioxidants on proinflammatory signaling pathways, such as NF-kappaB/NLRP3 inflammasome, was not reviewed.
Author Response
Title: Potential Therapeutic Implication of Herbal Medicine in Mitochondria-Mediated Oxidative Stress Related Live Diseases.
First, the authors summarized the role of mitochondria in liver diseases and the importance of this organelle in the production of reactive oxygen species. The authors reviewed some herbal medicines and drugs derived from plants for alcoholic liver disease and nonalcoholic liver disease treatment. I have some concerns about this manuscript.
>> (Response) First of all, we would like to express our sincere gratitude for the time and effort the reviewer had put into reviewing our manuscript. We have incorporated changes based on the reviewer comments provided in the manuscript which revised parts are highlighted by RED color in the entire revised manuscript.
1.- It is very badly written and disorganized. Therefore, it is not easy to follow. There are some repeated sentences, see, for example, lines 91-97.
>> (Response) We are thankful to the reviewer for the meaningful suggestions. For English language, we massively checked English language and reviewed to improve the quality of our manuscript. Additionally, we deleted repeated sentences and added relevant information to the entire manuscript and highlighted by RED color.
2.- The aim is not easy to understand. The title suggests that the authors are going to focus on ROS produced in mitochondria and the role of plant-derived antioxidants on these ROS and their importance in liver disease treatment. However, the authors just talk about some natural antioxidants for liver diseases, mainly alcoholic and nonalcoholic liver diseases. This topic has been extensively reviewed by several authors.
>> (Response) We are grateful to the reviewer opinion. We added clear aim of our study in last portion of abstract and introduction (page 2, line 38-43; page 3, line 67-74). Additionally, we massive modified and organized our revised manuscript to make an important relation of ROS production in mitochondria-mediated liver disease with potential treatment via herbal medicine and highlighted by RED color.
3.- Many herbal medicines were not described in detail. For example, naringenin, silymarin, L-theanine, hesperidin, caffeine, quercetin, etc.
>> (Response) We added the mentioned herbal medicines in the last paragraph of section 8 (page 21, line 508-521).
4.- It is now recognized that most plant-derived antioxidants act, in addition to their free radical scavenging ability, by improving the Nrf2 signaling pathway. Unfortunately, this effect was not reviewed in this manuscript.
>> (Response) We added some points plant-derived antioxidants which act their free radical scavenging ability via improving the Nrf2 signaling pathway in liver disease (page 8, line 168-175).
5.- Oxidative stress, inflammation, fibrosis, and liver cancer are associated. The role of free radicals on inflammation, fibrosis, and liver cancer was not deeply discussed. The importance of plant-derived antioxidants on proinflammatory signaling pathways, such as NF-kappaB/NLRP3 inflammasome, was not reviewed.
>> (Response) We added oxidative stress, inflammation, fibrosis, free radicals on inflammation and liver cancer in association with plant-derived antioxidants via proinflammatory signaling pathways, such as NF-kappaB/NLRP3 inflammasome in section 5 with recent references (page 9, line 206-225).
Round 2
Reviewer 1 Report
The authors have responded satisfactorily to the reviewer's comments in the revised paper. I do not have other comments any more. Thank you for giving a chance to review this interesting paper.
Author Response
The authors have responded satisfactorily to the reviewer's comments in the revised paper. I do not have other comments any more. Thank you for giving a chance to review this interesting
>> (Response) We are grateful the reviewer nice comments.
Reviewer 2 Report
The review: “Potential Therapeutic Implication of Herbal Medicine in Mitochondria- Mediated Oxidative Stress Related Live Diseases”, has been duly revised and implemented in particular as to the literature regarding potential and mechanisms of medicinal herbs used for the therapeutics of liver diseases mediated by mitochondria-related oxidative stress. Only, in the Abstract the sentence at lines 28-30: “However, antioxidant treatment has not been very effective for liver disease.” seems out of place here. It could be moved down, to line 36, following the sentence ending as “…look into liver disease treatment.
Author Response
The review: “Potential Therapeutic Implication of Herbal Medicine in Mitochondria- Mediated Oxidative Stress Related Live Diseases”, has been duly revised and implemented in particular as to the literature regarding potential and mechanisms of medicinal herbs used for the therapeutics of liver diseases mediated by mitochondria-related oxidative stress. Only, in the Abstract the sentence at lines 28-30: “However, antioxidant treatment has not been very effective for liver disease.” seems out of place here. It could be moved down, to line 36, following the sentence ending as “…look into liver disease treatment.
>> (Response) First of all, we would like to express our sincere gratitude for the time and effort the reviewer had put into reviewing our manuscript. We have incorporated changes based on the reviewer comments provided in the manuscript in abstract which revised parts are highlighted by RED color in the revised manuscript (page 2, line 35-36).
Reviewer 3 Report
The manuscript was improved.
Author Response
The manuscript was improved.
We are grateful to the reviewer.
