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This review resulted from the graduate-level course "How to Read and Evaluate Scientific Papers and Preprints" from the University of São Paulo, which aimed to provide students with the opportunity to review scientific articles, develop critical and constructive discussions on the endless frontiers of knowledge, and understand the peer review process. 

PROS

• This manuscript presents a comprehensive explanation of the complexity of NAD⁺ in the cell along with its functions, in a highly didactic manner. Additionally, it explains the NAD⁺ cycle, encompassing biosynthesis, consumption and degradation, and explores its connections to neurodegenerative disorders.

• There is a clear explanation of the initial steps: the introductory steps are well-illustrated, offering a detailed account of the primary culture's origin and the acquisition of ADP-ribose for subsequent experiments.

• The approach and explanation involving H₂O₂, and its relationship with PARP, are interesting.

Comments

FIGURES & LEGENDS

• Figures are referenced within the text, yet some do not actually exist (e.g., 1I).

• Some legends are identical to the main text (e.g., Figure 3K), while others lack legends altogether (e.g., S5H).

• The interpretation of Figure 3A is challenging, and could benefit from a more clear presentation. Similarly, understanding S2A is complex. I believe it could benefit from a more clear statement of the conclusions made from it.

RESULTS & CONCLUSIONS

• I have concerns about applying the same treatment across various compounds within the cell, as seen with ADP ribose and its metabolites, AMP and R5P. Since these are degradation products of ADP-ribose, the authors should conduct a screening to ascertain the optimal treatment dosage and establish that cell survival is exclusively influenced by ADP-ribose treatment.

• Likewise, employing the same ADP-ribose treatment across different cell types (such as astrocytes, cardiomyocytes, cardiac fibroblasts, and neurons) poses a problem since cells can react differently to the stimulus. To address this, the authors could conduct a screening for each cell line to demonstrate that only the viability of neurons is affected.

• Some conclusions lack sufficient explanations. For instance, the authors used ferroptosis inhibitors among other cell death inhibitors after ADP-ribose treatment and deduced a connection to ferroptosis, as it was the only inhibitor that promoted cell survival. To support this, the authors could knock out cells sensitive to 4-HNE, treat them with ADP-ribose, and measure cell survival.

• At times, the authors omit pertinent details or present explanations gaps. For instance, there is a lack of explanation regarding the rationale for measuring metabolites inosine, deoxyinosine, cytidine, adenosine, and uridine (part of the "ADP-ribose inhibits the Activity of ENT1" result).

Competing interests

The author declares that they have no competing interests.