The Effects of Curcumin on Inflammasome: Latest Update

Round 1

Reviewer 1 Report

The topic of the research article is of great interest. However, I would not recommend publishing the article in its current format as it requires lots of improvement. The main drawbacks of this manuscript

 Below are several specific comments.
1. The English writing should be further improved, as there are many grammatical or typing errors.

2. The whole manuscript is mixed between American English and British English. The authors even use British English or American English. For consistency, consider replacing it with the American English spelling.

3. Some references not according to journal instructions

4. Reference no. 86 should be 2021 not 2012

5-The authors used around 115 references as it's well-known that a review paper should use the last 5 years of literature, to obtain the most relevant information. The percentages of the last 5 years of references were 53.9 % (62 references) while old references were. 46.1 % (53 references).

6. Some types, grammar, and style errors need to be corrected listed below

line 18 changes protein to proteins

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line 93 adds a comma after hsp90

line 99 removes the comma after Caspase-1

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line 102 changes are to is

line 109 changes activate to activates

line 111 changes (IALRs) to (ALRs)

line 114 adds and before AIM2    

line 114 changes carboxyl terminal to carboxyl-terminal 

line 115 changes recognizes to recognize

line 116 changes NATCHT to NACHT

line 126 adds are before known

line 126 changes activates to activate

line 135 adds a before cellular

line 144 changes tumour to tumor

line 156 changes defence to defense

line 156 changes Bacillus anthraces to Bacillus anthracis

line 158 changes toxin to toxins       

line 161 changes best characterized to best-characterized

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line 180 changes signalling to signaling

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Line 189 changes pro-caspsase-1 to pro-caspase-1

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line 222 changes channel, resulting in an increase in to channels, increasing

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lines 448 and 449 change signalling to signaling

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line 464 changes nanocurcumin to nano curcumin

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line 519 adds the before CIA and adds a comma after model

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line 531 changes Curcumin loaded to Curcumin-loaded

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line 561 changes were resulted to have resulted in

line 563 changes treat to treating

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line 567 changes formulation to formulations

line 567 changes demonstrated to demonstrating

Line 576 who discovered it???

Line 577 changes ration to ratio

Line 580 changes curcumin loaded to curcumin-loaded

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line 606 changes prevent to preventing

line 607 changes address to clinic application on to  address the clinical application of  

line 607 changes for treat to to treat

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Major points

1. The inflammasome section is not properly described. Firstly, the inflammasome classification, according to the current literature classifies inflammasome in canonical, non-canonical and alternative inflammasome. The author should discuss all three types of inflammasome in pathophysiology contexts and their molecular mechanisms.

2. The authors report that, “based on the nucleotide-binding oligomerization domain, the inflammasome can be classified into four groups (NODs, NLRPs, NLRC4 and NLRC5)”, however, NOD domains include NLRPs as well as NLRCs and do not constitute a different group. Moreover, Pyrin inflammasome is not mentioned at all – “pyrin is quite distinct among inflammasome-forming receptors and only shares the PYD domain with other inflammasomes” [Function and mechanism of the pyrin inflammasome, Rosalie Heilig and Petr Broz, 2017, European Journal of Immunology, https://doi.org/10.1002/eji.201746947], therefore is classified as an additional independent inflammasome.  In my opinion the author should discuss more deeply these aspects to give comprehensive description of the field of the inflammasome as well as their involvements in diseases.

3. At today the non-canonical inflammasome is better characterize than before, although not as good as the canonical inflammasome, however the authors mention the activation of caspase-11 as a marker for the non-canonical one. Caspase-11 is murine caspase not human; its human homologous are caspase-4 and -5 which are not mentioned at all.

4. The 2 steps that lead to the fully activation of the inflammasome, which are common to all the canonical inflammasomes are not described. For instance, the engagement of TLRs for the “priming step” is not described; LPS, which primes the most well characterized inflammasome (NLRP3) is not even mentioned in the inflammasome paragraph.

The molecular mechanism of activation of the speck formation is missed. All the inflammasomes form a single speck, however, NLRP3 speck is located at the perinuclear region and co-localize with MTOC, which makes this inflammasome different from others, where the single speck is within the cytosol w/o a specific structural cytosolic marker. Moreover, the fully activation of NLRP3 needs TGN, ox-mtDNA, NEK7 and cytoskeleton rupture which makes this inflammasome unique. All these aspects should be discussed more in detail.

The authors report that exists three models for NLRP3 inflammasome activation, however, all these activators bring to ROS production. The presence of ROS as intermediated is not a separated model but belong to all the mechanisms described today. Moreover, the bacterial toxin, nigericin, which represent one of the most potent stimuli, is missing. Here, several references are missing too.

The description of GSDMD should be put in the inflammasome section.

Finally, the role of the axis NLRP3-NETs-SARS-CoV2 should be also mentioned as a new potential target.

Minor points

In Fig.1 Active Caspase 1 is spelled wrongly; NLRC5 is not drawn

The single speck is 0.8-1 um not 1 uM

In Fig.2 the NLRP3 inflammasome has been drawn with NEK7 protein, which is needed for the fully activation, but it is not reported in the text; NLRP3, the 3 is missing in the inactive form

Author Response

Please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The authors have appropriately corrected the manuscript according to the comments

Reviewer 2 Report

I believe the manuscript has been sufficiently improved to warrant
publication in Molecules