Reviewer's report
Title:Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor,
alleviates liver injury induced by acetaminophen overdose in mice
Version: 2Date:10 September 2012
Reviewer: Thomas Schreiter
Reviewer's report:
Reviewer's report
The manuscript entitled “Ozagrel hydrochloride, a selective thromboxane A2
synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in
mice” submitted by Tomishima et al. presents very interesting results for
treatment of hepatic injury caused by acetaminophen overdose. Since this drug
has already been used for clinical therapy of other diseases it seems superior to
others that were only applied for research and animal experiments yet. It would
expand the therapy options for APAP-induced acute liver failure.
The experiments were carried out carefully and the manuscript is written quite
well.
Still there are some issues that should be addressed by the authors:
Major Compulsory Revisions
1) As the authors cited in reference [27], thromboxane A2 synthase inhibitors
have already been shown to reduce APAP-induced liver injury in mice, e.g. OKY
1581. The reviewer found that ozagrel hydrochloride was also named OKY 046.
Is there a structural relation between them, e.g. a further development for better
patient tolerance? These points connecting the former research better with the
actual one should be accounted for in the introduction.
2) A striking finding was that expression of Bim mRNA was not reduced by
ozagrel. The authors should suggest a more detailed explanation for this than
just “downstream of Bim expression”? For example, Bim binds to anti-apoptotic
molecules like Bcl-2 and Bcl-XL to activate apoptosis. If ozagrel upregulates
these binding partners, elevated Bim would be neutralized. Ozagrel could also
affect the phosphorylation state of Bim protein.
3) The authors showed by quite sophisticated experiments that ozagrel does not
ameliorate APAP-induced toxicity by inhibiting CYP2E1 activity or restoring
GSH-levels. Do they have an idea how it works instead? Any suggestion could
be discussed.
4) In the discussion the authors state that ozagrel was protective despite being
administered 60 min after APAP injection (page 8, lane16) “in the present study”.
In all experiments throughout the manuscript ozagrel was applied 30 min after
APAP injection. The authors should point out that this observation was from
another set of experiments referred to in suppl. fig. 1S.
Minor Essential Revisions
Figure legend 1B: If there are only two parameters in graph, a range for the
number of mice (n=5-11) is not recommended. It can be written precise (e.g.
mice with ozagrel (200mg/ml, n=5) or saline (n=11)…
Page 6, lane 30: …mice were dead (might be changed to) died or deceased
Page 6, lane 33: Representative H&E stainings (plural) of histological sections…
Page 8, lane 23: Reilly et al is [26] and not [28]
Page 9, lane 12: Two sentences in turn start with In addition. One should be
replaced by moreover or furthermore.
Discretionary Revisions
Figure2: Label bars are too prominent and should be reduced to give more view
to the stainings or be put outside like in figure 4.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
Reviewer's report
Title:Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor,
alleviates liver injury induced by acetaminophen overdose in mice
Version: 2Date:10 September 2012
Reviewer: Thomas Schreiter
Reviewer's report:
Reviewer's report
The manuscript entitled “Ozagrel hydrochloride, a selective thromboxane A2
synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in
mice” submitted by Tomishima et al. presents very interesting results for
treatment of hepatic injury caused by acetaminophen overdose. Since this drug
has already been used for clinical therapy of other diseases it seems superior to
others that were only applied for research and animal experiments yet. It would
expand the therapy options for APAP-induced acute liver failure.
The experiments were carried out carefully and the manuscript is written quite
well.
Still there are some issues that should be addressed by the authors:
Major Compulsory Revisions
1) As the authors cited in reference [27], thromboxane A2 synthase inhibitors
have already been shown to reduce APAP-induced liver injury in mice, e.g. OKY
1581. The reviewer found that ozagrel hydrochloride was also named OKY 046.
Is there a structural relation between them, e.g. a further development for better
patient tolerance? These points connecting the former research better with the
actual one should be accounted for in the introduction.
2) A striking finding was that expression of Bim mRNA was not reduced by
ozagrel. The authors should suggest a more detailed explanation for this than
just “downstream of Bim expression”? For example, Bim binds to anti-apoptotic
molecules like Bcl-2 and Bcl-XL to activate apoptosis. If ozagrel upregulates
these binding partners, elevated Bim would be neutralized. Ozagrel could also
affect the phosphorylation state of Bim protein.
3) The authors showed by quite sophisticated experiments that ozagrel does not
ameliorate APAP-induced toxicity by inhibiting CYP2E1 activity or restoring
GSH-levels. Do they have an idea how it works instead? Any suggestion could
be discussed.
4) In the discussion the authors state that ozagrel was protective despite being
administered 60 min after APAP injection (page 8, lane16) “in the present study”.
In all experiments throughout the manuscript ozagrel was applied 30 min after
APAP injection. The authors should point out that this observation was from
another set of experiments referred to in suppl. fig. 1S.
Minor Essential Revisions
Figure legend 1B: If there are only two parameters in graph, a range for the
number of mice (n=5-11) is not recommended. It can be written precise (e.g.
mice with ozagrel (200mg/ml, n=5) or saline (n=11)…
Page 6, lane 30: …mice were dead (might be changed to) died or deceased
Page 6, lane 33: Representative H&E stainings (plural) of histological sections…
Page 8, lane 23: Reilly et al is [26] and not [28]
Page 9, lane 12: Two sentences in turn start with In addition. One should be
replaced by moreover or furthermore.
Discretionary Revisions
Figure2: Label bars are too prominent and should be reduced to give more view
to the stainings or be put outside like in figure 4.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
Please review this paper.
user
Reviewer's report
Title:Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor,
alleviates liver injury induced by acetaminophen overdose in mice
Version: 2Date:10 September 2012
Reviewer: Thomas Schreiter
Reviewer's report:
Reviewer's report
The manuscript entitled “Ozagrel hydrochloride, a selective thromboxane A2
synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in
mice” submitted by Tomishima et al. presents very interesting results for
treatment of hepatic injury caused by acetaminophen overdose. Since this drug
has already been used for clinical therapy of other diseases it seems superior to
others that were only applied for research and animal experiments yet. It would
expand the therapy options for APAP-induced acute liver failure.
The experiments were carried out carefully and the manuscript is written quite
well.
Still there are some issues that should be addressed by the authors:
Major Compulsory Revisions
1) As the authors cited in reference [27], thromboxane A2 synthase inhibitors
have already been shown to reduce APAP-induced liver injury in mice, e.g. OKY
1581. The reviewer found that ozagrel hydrochloride was also named OKY 046.
Is there a structural relation between them, e.g. a further development for better
patient tolerance? These points connecting the former research better with the
actual one should be accounted for in the introduction.
2) A striking finding was that expression of Bim mRNA was not reduced by
ozagrel. The authors should suggest a more detailed explanation for this than
just “downstream of Bim expression”? For example, Bim binds to anti-apoptotic
molecules like Bcl-2 and Bcl-XL to activate apoptosis. If ozagrel upregulates
these binding partners, elevated Bim would be neutralized. Ozagrel could also
affect the phosphorylation state of Bim protein.
3) The authors showed by quite sophisticated experiments that ozagrel does not
ameliorate APAP-induced toxicity by inhibiting CYP2E1 activity or restoring
GSH-levels. Do they have an idea how it works instead? Any suggestion could
be discussed.
4) In the discussion the authors state that ozagrel was protective despite being
administered 60 min after APAP injection (page 8, lane16) “in the present study”.
In all experiments throughout the manuscript ozagrel was applied 30 min after
APAP injection. The authors should point out that this observation was from
another set of experiments referred to in suppl. fig. 1S.
Minor Essential Revisions
Figure legend 1B: If there are only two parameters in graph, a range for the
number of mice (n=5-11) is not recommended. It can be written precise (e.g.
mice with ozagrel (200mg/ml, n=5) or saline (n=11)…
Page 6, lane 30: …mice were dead (might be changed to) died or deceased
Page 6, lane 33: Representative H&E stainings (plural) of histological sections…
Page 8, lane 23: Reilly et al is [26] and not [28]
Page 9, lane 12: Two sentences in turn start with In addition. One should be
replaced by moreover or furthermore.
Discretionary Revisions
Figure2: Label bars are too prominent and should be reduced to give more view
to the stainings or be put outside like in figure 4.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
assistant