Review for 10.1186/s12876-022-02213-0 (2022)

Title: Corticosteroid suppresses urea-cycle-related gene expressions in ornithine
transcarbamylase deficiency
Version: 1 Date: 14 Dec 2021
Reviewer's report:
This study is very important for clinicians and patients. However, there are many issues to be
resolved for publication. Please review it carefully.
Major points
1. Title does not appropriate. Your data did not present the mechanism directly and lack of
data. Hence, please change your title(ex. Corticosteroid changes gene expression associated urea
cycle in OTCD etc….)
2. The purpose of this study to evaluate the effect of corticosteroids on urea cycle enzyme
expression and urea cycle-associate metabolites. However, you mentioned in abstract and
introduction that The mechanism has been considered nitrogen overload due to the catabolic
effect of corticosteroids. Hence, you have to investigate or analyze for catabolic and anabolic
state before and after DEX administration in OTC mice. Gene expression and metabolic analysis
related with catabolism/anabolism(ex. Autophagy, mTOR, PI3K, S6K, elF-4E, 4E-BP1, elF-4E
etc) and pathological change in muscle and liver should be included in data at least. If not, it
never to be concluded any result.
3. Introduction is insufficient and please included more information related with corticosteroid
and metabolism to urea cycle.
4. Your data including Case series and animal investigation and these presentation is very
confusing for us. Two cases in this study, there are no any amino acid change nor other
metabolome analysis. In addition, you mentioned that corticosteroid causes hyperammonemia
is well known, clinical presentation is not needed for this study. Please change the composition
of this manuscript (eg. Move clinical presentation to supplemental data or delete it and/or to the
other case reports journal)
5. Figure 3 dose not any new data in this study and already established data in. Hence, this figure
should be deleted.
6. Discussion is extremely poor. You have to consider not only liver and also both kidney muscle
and intestine metabolism. Plasma amino acids are maintain by collaboration with these all tissue
and you have to investigate metabolomic analysis or consider them if you cannot do it.
Minor points
1. In abstract, you wrote “by the loss of function in any of the enzymes associated with
ureagenesis.”, which is true but confusing. Loss of function means functional loss and does not
include deletion in genetic science. In addition, “in any of the enzymes” is also confusing. In
urea cycle disease, the each specific enzyme should be reliable for the each disease. Hence,
please change this sentence appropriately.
2. In abstract, you wrote “Corticosteroid is well known to induce life-threatening
hyperammonemia”. However, that is not concluded, only suggested to avoid it. Hence, you have
to change this sentence appropriately.
3. “Urea cycle disorders (UCDs)” is written in Background and also abstract.
4. In material and method of biochemical analyses, you wrote that serum levels of ammonia
were measured using a Fuji-Drychem chemical analyzer (Fuji Film, Tokyo, Japan). You have
to added the detail Number (eg. 100N, NX10 or other ?). It is important for researchers and we
cannot assess the information accuracy. Please re-write and check your paper thoroughly.
5. In material and method of Metabolomic analysis by LSI Medience Co., you wrote the
metabolimic analysis. However, we cannot believe LSI Medience Co. can whole metabolome
analysis and you have to wrote it correctly (eg. 33 ? Amino acid analysis or Acyl-carnitine
analysis etc…).