Influence of Nitrosyl Iron Complex with Thiosulfate Ligands on Therapeutically Important Targets Related to Type 2 Diabetes Mellitus

Round 1

Reviewer 1 Report

In this manuscript, the authors explore the potential of a novel molecule that releases NO (nitric oxide) to interact with specific targets related to type 2 diabetes, with the aim of enhancing the therapeutic effectiveness of a potential treatment. The manuscript exhibits a well-written and organized structure, and the subject matter holds significant interest for a wide range of individuals involved in comprehending the molecular mechanisms underlying diabetes development.

 

 

Nevertheless, I believe that the introduction could benefit from enhancements to provide a more comprehensive overview of the field. For example, the authors should consider referencing relevant studies that highlight the significance of natural compounds in diabetes treatment. To illustrate, they could include references to papers investigating the effects of curcumin (J. Am. Chem. Soc., 139 (2017), pp. 13720-13734), resveratrol (Biochimica et Biophysica Acta (BBA) – Biomembranes, Volume 1860, Issue 9, September 2018, Pages 1793-1802), and green tea extracts (Proc. Natl. Acad. Sci. U. S. A., 110 (2013), pp. 3743-3748).

good english, but some improvement would be advisable. Please refer to an English speaking person

Author Response

Dear Reviewer,

 

We would like to express our appreciation for your comments and suggestions on our manuscript submitted for publication in Membranes. Please, check our answers for your comments and suggestions.

 

Comments and Suggestions for Authors

In this manuscript, the authors explore the potential of a novel molecule that releases NO (nitric oxide) to interact with specific targets related to type 2 diabetes, with the aim of enhancing the therapeutic effectiveness of a potential treatment. The manuscript exhibits a well-written and organized structure, and the subject matter holds significant interest for a wide range of individuals involved in comprehending the molecular mechanisms underlying diabetes development.

 

Nevertheless, I believe that the introduction could benefit from enhancements to provide a more comprehensive overview of the field. For example, the authors should consider referencing relevant studies that highlight the significance of natural compounds in diabetes treatment. To illustrate, they could include references to papers investigating the effects of curcumin (J. Am. Chem. Soc., 139 (2017), pp. 13720-13734), resveratrol (Biochimica et Biophysica Acta (BBA) – Biomembranes, Volume 1860, Issue 9, September 2018, Pages 1793-1802), and green tea extracts (Proc. Natl. Acad. Sci. U. S. A., 110 (2013), pp. 3743-3748

Answer

Thank you for your comment. Relevant reference is added to the first paragraph of Introduction [Ref. 8, Sciacca, M.; Chillemi, R.; Sciuto, S.; Greco, V.; Messineo, C.; Kotler, S.A.; Lee, D.K.; Brender, J.R.; Ramamoorthy, A.; La Rosa, C.; Milardi, D. A blend of two resveratrol derivatives abolishes hIAPP amyloid growth and membrane damage. Biochim Biophys Acta Biomembr. 2018, 1860, 1793-1802. doi: 10.1016/j.bbamem.2018.03.012].

Reviewer 2 Report

This manuscript study is focused on Iron complex based NO-donors drug nitrosyl iron complex Na2[Fe2(S2O3)2(NO)4]∙4H2O (TNIC-ThS) as an effective antidiabetic agent. It can be accepted for publication after addressing the following minor points. 

1. Is any experiential evidence that shows/proves the NIC- 235 ThS molecules interact with membrane lipids? 

2. How much NO was released from the NO donor TNIC-ThS. 

3. What about the toxicity of NO donor before and after NO release 

4. What about the rate and Half-life time of NO release. 

 English language is fine. 

Author Response

Dear Reviewer,

 

We would like to express our appreciation for your comments and suggestions on our manuscript submitted for publication in Membranes. Please, check our answers for your comments and suggestions.

 

Comments and Suggestions for Authors

This manuscript study is focused on Iron complex based NO-donors drug nitrosyl iron complex Na2[Fe2(S2O3)2(NO)4]∙4H2O (TNIC-ThS) as an effective antidiabetic agent. It can be accepted for publication after addressing the following minor points.

 

1. Is any experiential evidence that shows/proves the NIC- 235 ThS molecules interact with membrane lipids?

 

2. How much NO was released from the NO donor TNIC-ThS.

 

3. What about the toxicity of NO donor before and after NO release

 

4. What about the rate and Half-life time of NO release.

 

Answers

 

1. 1. Thank you for your comment.

No, there are no data shown direct interaction of TNIC-ThS molecules with membrane lipids. The goal of our study was to understand the interactions of TNIC-ThS with PC membrane and, in particular, to assess the level of spontaneous insertion of the complex into the lipid bilayer.

2. Thank you for your comment.

The electrochemical method was used to study the NO-donor ability of TNIC-ThS. It was shown that 500 s after the dissolution of TNIC-ThS the amount of generated NO were ~34 nM [B.L. Psikha, E.A. Saratovskikh, I.V. Sulimenkov, A.S. Konyukhova, N.A. Sanina. Reactions of water-soluble binuclear tetranitrosyl iron complexes of the μ-S structural type with adenosine triphosphoric acid: Kinetics and reaction mechanism. Inorganica Chimica Acta, Volume 531, 2022, 120709, doi.org/10.1016/j.ica.2021.120709].

3. Thank you for your comment.

Since TNIC-ThS rapidly decomposes under physiological conditions, which is accompanied by NO release, we believe that in vivo toxicology studies mentioned in this work fully shows the toxicity of both the initial complex itself and products formed during the hydrolysis of TNIC-ThS.

4. Thank you for your comment.

The processes of TNIC-ThS decomposition under anaerobic and aerobic conditions differ significantly since nitrosyl iron complexes interact with oxygen. The initial absorption spectrum of the complex under aerobic conditions does not have the maxima characteristic of binuclear complexes at wavelengths of 310 and 360 nm, which indicates its rapid transformation in aqueous solutions. Comparison of the effective constants k calculated from the equation y(t)=y0+A1exp(-kt) shows that under aerobic conditions the complex decay 6 times faster (k _{aerobic conditions} = 5.9∙10^-4 s^-1, k _{anaerobic conditions} =1,1∙10^-4 s^-1) [1.Faingold I.I., Poletaeva D.A., Soldatova Y.V., Smolina A.V., Pokidova O.V., Kulikov A.V., Sanina N.A., Kotelnikova R.A. Effects of albumin-bound nitrosyl iron complex with thiosulfate ligands on lipid peroxidation and activities of mitochondrial enzymes in vitro. Nitric Oxide. 2021 Dec 1;117:46-52. doi: 10.1016/j.niox.2021.10.002; 2. O. Pokidova, T. Rudneva, B. Tretyakov, R. Kotelnikova, A. Kotelnikov, S. Aldoshin, Influence of hemoglobin and albumin on the NO donation effect of tetranitrosyl iron complex with thiosulfate, Nitric Oxide 94 (2020) 69–72, https://doi.org/10.1016/j.niox.2019.10.010.]

Author Response File: Author Response.docx