Reviewer's report
Title:Nrf2-mediated heme oxygenase-1 induction of PPI confers adaptive
survival response to NSAID-induced gastric damages
Version: 1Date:9 July 2012
Reviewer: Young-Joon Surh
Reviewer's report:
This manuscript describes the induction of the stress-responsive enzyme heme
oxygenase-1 (HO-1) by the proton pump inhibitor pantoprazole through activation
of Nrf2. In an in vitro cell culture study, pantoprazole induced activation of Nrf2 as
evidenced by increased nuclear translocation and subsequent ARE binding of
this transcription factor. The typical NSAID, indomethacin enhanced the
transcription of some proinflammatory and adhesion genes, which was
suppressed by pantaprazole. In an in vivo animal gastritis model, patoprazole
protected against indomethacin-induced gastric erosion, which was attenuated
by the pharmacologic HO-1 inhibitor. Overall, the finding are interesting and
provide the novel protective effects of proton pump inhibitors against
NASAIDs-induced gastric damage. There
Are several issues that should be incorporated into the manuscript for the better
revision.
1. Abstract, line 4: its acid suppressive action is not suffice to explain # its acid
suppressive action does not suffice to explain.
2. The role of Nrf2 and HO-1 in adaptive stress response need to be briefly
mentioned in a Background or Method session of the abstract
3. page 1, line 3 from the bottom: HO-1 … inductions after pantoprazole were
significantly associated with the increased expressions of … The underlined
words are used in a singular noun. The corresponding verb (were) also needs to
be corrected accordingly. Same correction need for the first line, p. 3
(expressions # expression) and many other locations throughout the text.
4. p. 2, line 4: .. because HO-1 inhibitor abolished these changes. In vivo mice
model of … # .. because a HO-1 inhibitor abolished these changes An in vivo
mice model of.. Numerous grammatical corrections are needed elsewhere
(Introduction, Material & Methods, Results and Discussion parts)
5. keap1 should be abbreviated as Keap1 (captital for the first letter).
6. There is large standard deviation in the mRNA expression of HO-1 shown in
Fig. 1A histogram. The average induction is less than 2 fold. In this respect, it
would be better not to include the mRNA data as Western blot data alone clearly
support the HO-1 induction by pantoprazole.
7. The number and the concentration unit should be apart (e.g., 300uM # 300
uM)
8. p. 8, line 15 & 16: As seen in Figure 2D, 3 uM pantoprazole exerted clear
scavenging action of DMPO-adduct-generating hydroxyl radicals. This
concentration of the compound is not the one used in the experiment
9. p. 8, line 19-21: These chemical results drawn from ESR were further
validated with biological test using DCF-DA fluorescence measurement, showing
that pantoprazole showed significant DCF-DA reduction in a dose dependent
manner (p<0.05, Figure 2B). Fig 2B does not reflect the statement in this
sentence. The ROS scavenging activity of pantoprazole may not be associated
with its anti-inflammatory and gastroprotectective effects against indomethacine
and the EPR data does not necessarily be included in the manuscript. If the
authors would like to relate the antioxidant effects of this PPI inhibitor with its
protective effects on indomathacin-induced inflammation, a series of experiments
using a conventional antioxidant will be necessary.
10. The manuscript title: Nrf2-mediated heme oxygenase-1 induction of PPI
confers adaptive survival response to NSAID-induced gastric damages
The title is rather general and does not properly reflect the work the authors
conducted. As the authors used indomethacin as a typical NASID and
pantoprazole as a representative PPI inhibitor, the title should specify the names
of compounds used. In addition, the majority of data are derived from in vitro cell
culture studies. The suggested title would be:
title: A possible involvement of Nrf2-mediated heme oxygenase-1 upregulation in
protective effect of the proton pump inhibitor pentoprazole against
indomethacin-induced gastric damage in rats
11. While scientifically sound, the manuscript needs editorial and grammatical
improvement.
Reviewer's report
Title:Nrf2-mediated heme oxygenase-1 induction of PPI confers adaptive
survival response to NSAID-induced gastric damages
Version: 1Date:9 July 2012
Reviewer: Young-Joon Surh
Reviewer's report:
This manuscript describes the induction of the stress-responsive enzyme heme
oxygenase-1 (HO-1) by the proton pump inhibitor pantoprazole through activation
of Nrf2. In an in vitro cell culture study, pantoprazole induced activation of Nrf2 as
evidenced by increased nuclear translocation and subsequent ARE binding of
this transcription factor. The typical NSAID, indomethacin enhanced the
transcription of some proinflammatory and adhesion genes, which was
suppressed by pantaprazole. In an in vivo animal gastritis model, patoprazole
protected against indomethacin-induced gastric erosion, which was attenuated
by the pharmacologic HO-1 inhibitor. Overall, the finding are interesting and
provide the novel protective effects of proton pump inhibitors against
NASAIDs-induced gastric damage. There
Are several issues that should be incorporated into the manuscript for the better
revision.
1. Abstract, line 4: its acid suppressive action is not suffice to explain # its acid
suppressive action does not suffice to explain.
2. The role of Nrf2 and HO-1 in adaptive stress response need to be briefly
mentioned in a Background or Method session of the abstract
3. page 1, line 3 from the bottom: HO-1 … inductions after pantoprazole were
significantly associated with the increased expressions of … The underlined
words are used in a singular noun. The corresponding verb (were) also needs to
be corrected accordingly. Same correction need for the first line, p. 3
(expressions # expression) and many other locations throughout the text.
4. p. 2, line 4: .. because HO-1 inhibitor abolished these changes. In vivo mice
model of … # .. because a HO-1 inhibitor abolished these changes An in vivo
mice model of.. Numerous grammatical corrections are needed elsewhere
(Introduction, Material & Methods, Results and Discussion parts)
5. keap1 should be abbreviated as Keap1 (captital for the first letter).
6. There is large standard deviation in the mRNA expression of HO-1 shown in
Fig. 1A histogram. The average induction is less than 2 fold. In this respect, it
would be better not to include the mRNA data as Western blot data alone clearly
support the HO-1 induction by pantoprazole.
7. The number and the concentration unit should be apart (e.g., 300uM # 300
uM)
8. p. 8, line 15 & 16: As seen in Figure 2D, 3 uM pantoprazole exerted clear
scavenging action of DMPO-adduct-generating hydroxyl radicals. This
concentration of the compound is not the one used in the experiment
9. p. 8, line 19-21: These chemical results drawn from ESR were further
validated with biological test using DCF-DA fluorescence measurement, showing
that pantoprazole showed significant DCF-DA reduction in a dose dependent
manner (p<0.05, Figure 2B). Fig 2B does not reflect the statement in this
sentence. The ROS scavenging activity of pantoprazole may not be associated
with its anti-inflammatory and gastroprotectective effects against indomethacine
and the EPR data does not necessarily be included in the manuscript. If the
authors would like to relate the antioxidant effects of this PPI inhibitor with its
protective effects on indomathacin-induced inflammation, a series of experiments
using a conventional antioxidant will be necessary.
10. The manuscript title: Nrf2-mediated heme oxygenase-1 induction of PPI
confers adaptive survival response to NSAID-induced gastric damages
The title is rather general and does not properly reflect the work the authors
conducted. As the authors used indomethacin as a typical NASID and
pantoprazole as a representative PPI inhibitor, the title should specify the names
of compounds used. In addition, the majority of data are derived from in vitro cell
culture studies. The suggested title would be:
title: A possible involvement of Nrf2-mediated heme oxygenase-1 upregulation in
protective effect of the proton pump inhibitor pentoprazole against
indomethacin-induced gastric damage in rats
11. While scientifically sound, the manuscript needs editorial and grammatical
improvement.
Please review this paper.
user
Reviewer's report
Title:Nrf2-mediated heme oxygenase-1 induction of PPI confers adaptive
survival response to NSAID-induced gastric damages
Version: 1Date:9 July 2012
Reviewer: Young-Joon Surh
Reviewer's report:
This manuscript describes the induction of the stress-responsive enzyme heme
oxygenase-1 (HO-1) by the proton pump inhibitor pantoprazole through activation
of Nrf2. In an in vitro cell culture study, pantoprazole induced activation of Nrf2 as
evidenced by increased nuclear translocation and subsequent ARE binding of
this transcription factor. The typical NSAID, indomethacin enhanced the
transcription of some proinflammatory and adhesion genes, which was
suppressed by pantaprazole. In an in vivo animal gastritis model, patoprazole
protected against indomethacin-induced gastric erosion, which was attenuated
by the pharmacologic HO-1 inhibitor. Overall, the finding are interesting and
provide the novel protective effects of proton pump inhibitors against
NASAIDs-induced gastric damage. There
Are several issues that should be incorporated into the manuscript for the better
revision.
1. Abstract, line 4: its acid suppressive action is not suffice to explain # its acid
suppressive action does not suffice to explain.
2. The role of Nrf2 and HO-1 in adaptive stress response need to be briefly
mentioned in a Background or Method session of the abstract
3. page 1, line 3 from the bottom: HO-1 … inductions after pantoprazole were
significantly associated with the increased expressions of … The underlined
words are used in a singular noun. The corresponding verb (were) also needs to
be corrected accordingly. Same correction need for the first line, p. 3
(expressions # expression) and many other locations throughout the text.
4. p. 2, line 4: .. because HO-1 inhibitor abolished these changes. In vivo mice
model of … # .. because a HO-1 inhibitor abolished these changes An in vivo
mice model of.. Numerous grammatical corrections are needed elsewhere
(Introduction, Material & Methods, Results and Discussion parts)
5. keap1 should be abbreviated as Keap1 (captital for the first letter).
6. There is large standard deviation in the mRNA expression of HO-1 shown in
Fig. 1A histogram. The average induction is less than 2 fold. In this respect, it
would be better not to include the mRNA data as Western blot data alone clearly
support the HO-1 induction by pantoprazole.
7. The number and the concentration unit should be apart (e.g., 300uM # 300
uM)
8. p. 8, line 15 & 16: As seen in Figure 2D, 3 uM pantoprazole exerted clear
scavenging action of DMPO-adduct-generating hydroxyl radicals. This
concentration of the compound is not the one used in the experiment
9. p. 8, line 19-21: These chemical results drawn from ESR were further
validated with biological test using DCF-DA fluorescence measurement, showing
that pantoprazole showed significant DCF-DA reduction in a dose dependent
manner (p<0.05, Figure 2B). Fig 2B does not reflect the statement in this
sentence. The ROS scavenging activity of pantoprazole may not be associated
with its anti-inflammatory and gastroprotectective effects against indomethacine
and the EPR data does not necessarily be included in the manuscript. If the
authors would like to relate the antioxidant effects of this PPI inhibitor with its
protective effects on indomathacin-induced inflammation, a series of experiments
using a conventional antioxidant will be necessary.
10. The manuscript title: Nrf2-mediated heme oxygenase-1 induction of PPI
confers adaptive survival response to NSAID-induced gastric damages
The title is rather general and does not properly reflect the work the authors
conducted. As the authors used indomethacin as a typical NASID and
pantoprazole as a representative PPI inhibitor, the title should specify the names
of compounds used. In addition, the majority of data are derived from in vitro cell
culture studies. The suggested title would be:
title: A possible involvement of Nrf2-mediated heme oxygenase-1 upregulation in
protective effect of the proton pump inhibitor pentoprazole against
indomethacin-induced gastric damage in rats
11. While scientifically sound, the manuscript needs editorial and grammatical
improvement.
assistant