Title: Vitamin D3/VDR alleviates double-stranded RNA virus -induced biliary epithelial cell
damage by inhibiting autophagy
Version: 4 Date: 13 Nov 2024
Reviewer's report:
In this study, Cheng et al. investigated the effects of Vitamin D3 and VDR on double-
stranded RNA (dsRNA)-induced biliary epithelial cell (BEC) damage, proposing that VDR
activation mitigates dsRNA-induced damage and apoptosis by inhibiting autophagy, both in
vitro and in vivo. They suggest that the 1,25-VD3/VDR/Src axis alleviated poly(I:C)-induced
HIBEC damage and apoptosis through the PLA2/PKC/ERK pathway. However, there appear
to be several substantial over-interpretations, and some conclusions lack supporting evidence.
Specific comments are provided below:
1. To facilitate readability, it is recommended to separate the main text from the figure legends.
Including figure numbers directly in the text will reduce the need for readers to frequently cross-
reference the results with figure legends.
2. Figure 6 is missing from the manuscript, making it challenging to fully understand the results.
Please ensure that all referenced figures are included in the final version to allow for a thorough
assessment of the data.
3. In the in vitro study, poly(I:C) induced HIBEC damage and apoptosis through autophagy
promotion, and both chloroquine and 1,25-VD3 were found to mitigate poly(I:C)-induced
HIBEC injury and apoptosis by autophagy inhibition. The authors also indicate that VDR
knockdown counteracts the protective effect of 1,25-VD3 against poly(I:C)-induced HIBEC
damage. A clearer explanation of the interaction between chloroquine and VDR in this context
is needed, specifically addressing their respective roles and potential overlap in mechanism.
4. The in vitro study employed poly(I:C) to induce HIBEC damage, while the in vivo model
involved RRV injection to induce hepatic jaundice in newborn mice. Given that poly(I:C) and
RRV both affect dsRNA signaling, but through pathways beyond TLR3, a detailed rationale for
using these different agents is needed to support experimental feasibility and relevance.
5. The manuscript contains inconsistencies in abbreviation usage, specifically between
"IBDECs" and "HIBEC." Please ensure that all abbreviations are consistent throughout the text
or provide clarification on any distinctions.
6. In Figures 2E, 3E, and 4B, axis labels need to be corrected for consistency and accuracy. This
will improve clarity and ease of interpretation for the readers.
Title: Vitamin D3/VDR alleviates double-stranded RNA virus -induced biliary epithelial cell
damage by inhibiting autophagy
Version: 4 Date: 13 Nov 2024
Reviewer's report:
In this study, Cheng et al. investigated the effects of Vitamin D3 and VDR on double-
stranded RNA (dsRNA)-induced biliary epithelial cell (BEC) damage, proposing that VDR
activation mitigates dsRNA-induced damage and apoptosis by inhibiting autophagy, both in
vitro and in vivo. They suggest that the 1,25-VD3/VDR/Src axis alleviated poly(I:C)-induced
HIBEC damage and apoptosis through the PLA2/PKC/ERK pathway. However, there appear
to be several substantial over-interpretations, and some conclusions lack supporting evidence.
Specific comments are provided below:
1. To facilitate readability, it is recommended to separate the main text from the figure legends.
Including figure numbers directly in the text will reduce the need for readers to frequently cross-
reference the results with figure legends.
2. Figure 6 is missing from the manuscript, making it challenging to fully understand the results.
Please ensure that all referenced figures are included in the final version to allow for a thorough
assessment of the data.
3. In the in vitro study, poly(I:C) induced HIBEC damage and apoptosis through autophagy
promotion, and both chloroquine and 1,25-VD3 were found to mitigate poly(I:C)-induced
HIBEC injury and apoptosis by autophagy inhibition. The authors also indicate that VDR
knockdown counteracts the protective effect of 1,25-VD3 against poly(I:C)-induced HIBEC
damage. A clearer explanation of the interaction between chloroquine and VDR in this context
is needed, specifically addressing their respective roles and potential overlap in mechanism.
4. The in vitro study employed poly(I:C) to induce HIBEC damage, while the in vivo model
involved RRV injection to induce hepatic jaundice in newborn mice. Given that poly(I:C) and
RRV both affect dsRNA signaling, but through pathways beyond TLR3, a detailed rationale for
using these different agents is needed to support experimental feasibility and relevance.
5. The manuscript contains inconsistencies in abbreviation usage, specifically between
"IBDECs" and "HIBEC." Please ensure that all abbreviations are consistent throughout the text
or provide clarification on any distinctions.
6. In Figures 2E, 3E, and 4B, axis labels need to be corrected for consistency and accuracy. This
will improve clarity and ease of interpretation for the readers.
Please review this paper.
user
Title: Vitamin D3/VDR alleviates double-stranded RNA virus -induced biliary epithelial cell
damage by inhibiting autophagy
Version: 4 Date: 13 Nov 2024
Reviewer's report:
In this study, Cheng et al. investigated the effects of Vitamin D3 and VDR on double-
stranded RNA (dsRNA)-induced biliary epithelial cell (BEC) damage, proposing that VDR
activation mitigates dsRNA-induced damage and apoptosis by inhibiting autophagy, both in
vitro and in vivo. They suggest that the 1,25-VD3/VDR/Src axis alleviated poly(I:C)-induced
HIBEC damage and apoptosis through the PLA2/PKC/ERK pathway. However, there appear
to be several substantial over-interpretations, and some conclusions lack supporting evidence.
Specific comments are provided below:
1. To facilitate readability, it is recommended to separate the main text from the figure legends.
Including figure numbers directly in the text will reduce the need for readers to frequently cross-
reference the results with figure legends.
2. Figure 6 is missing from the manuscript, making it challenging to fully understand the results.
Please ensure that all referenced figures are included in the final version to allow for a thorough
assessment of the data.
3. In the in vitro study, poly(I:C) induced HIBEC damage and apoptosis through autophagy
promotion, and both chloroquine and 1,25-VD3 were found to mitigate poly(I:C)-induced
HIBEC injury and apoptosis by autophagy inhibition. The authors also indicate that VDR
knockdown counteracts the protective effect of 1,25-VD3 against poly(I:C)-induced HIBEC
damage. A clearer explanation of the interaction between chloroquine and VDR in this context
is needed, specifically addressing their respective roles and potential overlap in mechanism.
4. The in vitro study employed poly(I:C) to induce HIBEC damage, while the in vivo model
involved RRV injection to induce hepatic jaundice in newborn mice. Given that poly(I:C) and
RRV both affect dsRNA signaling, but through pathways beyond TLR3, a detailed rationale for
using these different agents is needed to support experimental feasibility and relevance.
5. The manuscript contains inconsistencies in abbreviation usage, specifically between
"IBDECs" and "HIBEC." Please ensure that all abbreviations are consistent throughout the text
or provide clarification on any distinctions.
6. In Figures 2E, 3E, and 4B, axis labels need to be corrected for consistency and accuracy. This
will improve clarity and ease of interpretation for the readers.
assistant