Review Reports
by
- Waqas Alam 1,
- Haroon Khan 1,* and
- Luciano Saso 4,*
- et al.
Reviewer 1: Anonymous Reviewer 2: Anonymous
Round 1
Reviewer 1 Report
The paper is improved but some questions still remain.
Are cruciferous vegetables like broccoli high in kaempferol? If so, why aren't they listed in Table 1?
It is still unclear what the kaempferol-rich diet referenced on line 209 consisted of.
The clinical trials section is still very unclear - e.g., how much kaempferol is in these diets? How do other components in these vegetables contribute to the positive effects.
Author Response
Dear Reviewer
I am highly thankful for keenly studying our article and positively suggesting some changes. I am sure the incorporations of these suggestions has greatly aided to the overall strength of our article.
Reviewer 1.
The paper is improved but some questions still remain.
Are cruciferous vegetables like broccoli high in kaempferol? If so, why aren't they listed in Table 1?
Reply: As per suggestions, the quantity of kaempferol in broccoli is added in table 1
It is still unclear what the kaempferol-rich diet referenced on line 209 consisted of.
Reply: The suggested changes have been made and kaempferol-rich diet is elaborated.
The clinical trials section is still very unclear - e.g., how much kaempferol is in these diets? How do other components in these vegetables contribute to the positive effects?.
Reply: The exact quantities of kaempferol have been added in the respective diets as per suggestions. As the study was done with controlled feeding design and cruciferous diet was evaluated from tested cruciferous botanical sources additionally the diet selection was done on the basis of glutathione s-transferase genotype which minimized potential confounding due to other factors that may affect inflammatory status. However, it is a review article so we are bound to presented the results of research findings reported. As the effects of other components are not explored yet therefore, we can’t specifically mention other components.
Reviewer 2 Report
The authors review the recent literature for the antioxidant and anti-inflammatory properties of the flavonoid kaempferol. I would like to commend the authors in addressing almost all of the previous comments. The manuscript is now much improved, although a few grammatical issues were introduced as shown below.
Major comments:
Some of the paragraphs are too short (only 1, 2, or 3 sentences) and should be combined with an adjacent paragraph to improve the flow for the reader.
Minor comments: wording
Line 22: this review was -> this article is
Line 22: review of an updated literature review -> updated review of the literature
Line 52: includes -> include
Line 53: This review was aimed -> The aim of this review is
Line 67: Remove the words “as under”
Line 113: of was -> was
Line 117: microgram -> microgram per ml
Line 146: prevent -> prevents the
Line 147: cytokine have been incubated with the -> cytokines have been incubated with
Lines 152 and 181: pro inflammatory -> proinflammatory
Line 156: IL-B -> IL-1B
Line 168: decreased -> that decreased
Line 171: it -> kaempferol
Line 182: andICAM-1 -> and ICAM-1
Line 183: up regulated -> upregulated
Line 197: It has been reported that there are receptors (RAGE) -> RAGE is the receptor
Line 213: iso energetic -> isoenergetic
Line 225: are the -> are
Line 226: Nanotechnology is an innovative technique -> New innovative techniques use nanotechnology
Line 242: reduces the -> reduces
Line 254: interferes in -> interferes with
Line 256: remove the words “as an anti-inflammatory agent” [redundant with next line]
Line 256: it has been revealed -> it was revealed that many reports showed
Line 260: Inflammation -> Unresolved inflammation
Line 262: but why -> why
Line 263: questioned mark, needed to be answer -> question needing an answer
Author Response
Dear Editor/Reviewer
I am highly thankful for keenly studying our article and positively suggesting some changes. I am sure the incorporations of these suggestions has greatly aided to the overall strength of our article.
Reviewer 2.
Major comments:
Some of the paragraphs are too short (only 1, 2, or 3 sentences) and should be combined with an adjacent paragraph to improve the flow for the reader.
Reply: As per suggestion, we have combined the said paragraphs and highlighted.
Minor comments: wording
Line 22: this review was -> this article is
Reply: Needful correction is done and highlighted.
Line 22: review of an updated literature review -> updated review of the literature
Reply: Needful correction is done and highlighted.
Line 52: includes -> include
Reply: Needful correction is done and highlighted.
Line 53: This review was aimed -> The aim of this review is
Reply: Needful correction is done and highlighted.
Line 67: Remove the words “as under”
Reply: Needful correction is done and highlighted.
Line 113: of was -> was
Reply: Needful correction is done and highlighted.
Line 117: microgram -> microgram per ml
Reply: Needful correction is done and highlighted.
Line 146: prevent -> prevents the
Reply: Needful correction is done and highlighted.
Line 147: cytokine have been incubated with the -> cytokines have been incubated with
Reply: Needful correction is done and highlighted.
Lines 152 and 181: pro inflammatory -> proinflammatory
Reply: Needful correction is done and highlighted.
Line 156: IL-B -> IL-1B
Reply: Needful correction is done and highlighted.
Line 168: decreased -> that decreased
Reply: Needful correction is done and highlighted.
Line 171: it -> kaempferol
Reply: Needful correction is done and highlighted.
Line 182: andICAM-1 -> and ICAM-1
Reply: Needful correction is done and highlighted.
Line 183: up regulated -> upregulated
Reply: Needful correction is done and highlighted.
Line 197: It has been reported that there are receptors (RAGE) -> RAGE is the receptor
Reply: Needful correction is done and highlighted.
Line 213: iso energetic ->isoenergetic
Reply: Needful correction is done and highlighted.
Line 225: are the -> are
Reply: Needful correction is done and highlighted.
Line 226: Nanotechnology is an innovative technique -> New innovative techniques use nanotechnology
Reply: Needful correction is done and highlighted.
Line 242: reduces the -> reduces
Reply: Needful correction is done and highlighted.
Line 254: interferes in -> interferes with
Reply: Needful correction is done and highlighted.
Line 256: remove the words “as an anti-inflammatory agent” [redundant with next line]
Reply: Needful correction is done and highlighted.
Line 256: it has been revealed -> it was revealed that many reports showed
Reply: Needful correction is done and highlighted.
Line 260: Inflammation -> Unresolved inflammation
Reply: Needful correction is done and highlighted.
Line 262: but why -> why
Reply: Needful correction is done and highlighted.
Line 263: questioned mark, needed to be the answer -> question needing an answer
Reply: Needful correction is done and highlighted.
Round 2
Reviewer 1 Report
The authors have satisfied all my questions.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
As requested, I reviewed the manuscript (ID molecules-851119) "Kaempferol as a dietary anti-inflammatory agent: Clinical prospects", by W Alam, H Khan, A Shah, O Cauli and L Saso.
The manuscript deals with the ameliorative effects of natural drugs used in novel therapeutic strategies against inflammatory onsets and inflammatory diseases, with a direct focus on the flavonoid kaempferol. The main traits of kaempferol chemistry and biochemistry are described. Major attention is given to kaempferol anti-inflammatory actions, with a description of the related literature based on in vitro as well as in vivo research approaches and clinical studies.
The review manuscript is well conceived, with balance among the different sections.
Overall, the discussed issues contain all the elements for comprehension of the subject, for understanding the cited results and for finding hints to deepen information.
The reading sounds like a good and comprehensible continuum, and there’s no feeling of fragmented information. The manuscript is quite conceived for giving the necessary keywords to enter the investigated subject, and actually reaches this goal.
On this basis, the authors demonstrated scientific mastery of the research.
I only recommend a minor-but-fine revision of the English form throughout the entire document, for reaching a better final shape.
Reviewer 2 Report
Major comments: The review summarizes the anti-inflammatory actions and plant sources of the flavonoid kaempferol. Most of this information provided can be found scattered throughout the literature in other review articles. The authors have assimilated this information from over 200 references and organized it in a logical manner. So, this review does provide some value to the literature. However, the English grammar and word usage are very poor and extensive improvements by a fluent English speaker/writer are needed. I have made extensive required changes as shown below.
Most clinical trials mentioned were with flavonoid-rich diets, not with pure kaempferol supplements, so the positive anti-inflammatory health effects cannot be ascribed directly to kaempferol. A table summarizing the clinical results would be helpful to clarify this point.
Minor comments:
English grammar and word usage
Line 3 (title): Clinical -> clinical
Line 14: Now a day’s -> Current
Line 14: well thought-out as the -> carefully chosen as a
Line 16: Phytochemicals -> phytochemicals
Line 16: In vivo and In Vitro -> in vivo and in vitro
Line 16: Among them -> Among them,
Line 18: which has the potency -> having the ability
Line 19: the fruits -> fruits
Line 19: Kaempferol is found in vegetables and food it is also found in the -> It is also found in
Line 20: Remove the words “and reported scientifically”
Line 21: Remove the words “as such”
Line 21: sources, -> sources and
Line 22: and specially focusing -> specifically focusing on
Line 23: paper was aimed to provide -> review was aimed at providing
Line 24, 26, 75, 77: Kaempferol -> kaempferol
Line 25: the available updated literature -> an updated literature review
Line 25: Natural -> natural
Line 32: the class -> a class
Line 33: kind -> kinds
Line 36: indispensable -> are indispensable
Line 39: Remove the word “systems”
Line 40: product -> products
Line 40: natural plants -> plants
Line 41: Remove the words “of plants”
Line 42: carbon ring -> the structure of their carbon rings
Line 43: which are -> and these divisions include
Line 43: majorly contributes -> are major contributors
Line 44: also helps in the -> helps
Line 45: effect -> effects
Line 45: proved -> shown
Line 47: oxides -> oxide
Line 49: tageretin, Luteolin -> luteolin [remove first instance of misspelled tangeretin]
Line 50: tangeritin -> tangeretin [keep second instance of misspelled tangeretin]
Line 50: sub group -> sub-group
Line 51: of flavonoids -> and of flavonoids
Line 51: ketone -> a ketone
Line 52: hydroxyl -> a hydroxyl
Line 52: ring -> central oxygen containing 6-member ring
Line 54: design an article which summarizes comprehensively -> comprehensively summarize
Line 55: Kaempferol majorly focusing -> kaempferol majorly focusing on
Line 56: effect -> effects
Line 59: the fruits -> fruits
Line 59: Kaempferol is found in vegetables and food it is also found in the -> It is also found in
Line 60: Remove the words “and reported scientifically”
Line 61: Remove the words “as such”
Line 62: sources, -> sources and
Line 62: and specially focusing -> specifically focusing on
Line 62: effect -> effects
Line 66: plant -> the plant
Line 67: are richly -> is richly
Line 76: coworker -> coworkers
Line 77: derivative -> derivatives
Line 78: Sephadex LH-20 scolumn -> a Sephadex LH-20 column
Line 78: co researchers -> co-researchers
Line 79: High speed counter current -> high-speed countercurrent
Line 80: leaves -> leaf
Line 80: two phase solvents -> a two-phase solvent
Line 82: MS, NMR -> MS,
Line 84: which are -> which is
Line 86: 4-coumaroyl-CoA -> 4-coumaroyl-CoA are used
Line 87: Chalcones -> Chalcone
Line 87: formation of -> formation of the
Line 88: enzyme Chalcone -> enzyme chalcone
Line 88: converts -> converts the
Line 88: flavonoid naringenin into flavanone naringenin -> naringenin chalcone into naringenin flavanone
Line 90: by the help of -> using the catalytic activity of the
Line 91: the help of flavonol synthase and kaempferol is formed -> flavonol synthase
Line 95: absorption -> Absorption
Line 96: new -> newly
Line 98: it is necessary for its therapeutic effects -> for its therapeutic effects it is necessary for it
Line 101: are lipophillic -> is lipophilic [misspelled]
Line 102: from -> from the
Line 104: active -> by active
Line 105: sulfate -> by sulfate
Line 106: enzyme -> enzymes
Line 106: colon -> the colon
Line 107: converted -> convert it
Line 108: systemic -> the systemic
Line 108: the distributed -> then distributed
Line 109: were -> was
Line 110: co researcher -> co-researchers
Line 111: human -> humans
Line 111: find out -> found
Line 111: of 57.86 nM was found -> was 57.86 nM
Line 112: about 15 ng/ml plasma concentration of kaempferol -> a plasma concentration of 15 ng/mL kaempferol
Line 114: different researchers -> several studies
Line 114: nano or micro gram -> the nano- or microgram range
Line 115: range -> effects
Line 116: This -> Thus,
Line 116: might me -> is
Line 117: the production of some active metabolites, -> some active metabolites produced
Line 124: immune -> the immune
Lines 125, 127, 129, 131: inflammation -> inflammatory
Line 126: Remove the word “system”
Line 126: Phosphodiesterase -> phosphodiesterase
Line 128: of protein kinase -> by protein kinases,
Line 130: via -> via the
Line 130: in -> in the
Line 132: effect -> effects [both instances (2 places) in this line]
Line 132 and 134: mechanism -> mechanisms
Line 133: is summarized as under -> are summarized below
Line 134: as -> as an
Line 135: In vitro studies -> In Vitro Studies
Line 136: Cyclo-oxygenase -> The cyclooxygenase
Line 136: the mediators -> mediators
Line 137: inflammation site -> site of inflammation
Line 139: causes -> cause
Line 141: cytokine has -> cytokines have
Line 141: Remove the words “change liver cell”
Line 142: level was found to be -> levels were
Line 142: coworker -> coworkers
Line 143: inhibit -> inhibits
Line 143: evaluated -> found
Line 144: like inflammation process -> such as inflammation
Line 144: is -> has been
Line 145: accelerate different -> deactivate
Line 146: is also -> has also been
Line 146: Tumor -> tumor
Line 146: a pro inflammatory cytokine -> proinflammatory cytokines
Line 147: is also produce by -> are also produced in response to
Line 148: LPS in -> the administration of LPS to
Line 149: results -> resulted
Line 149: It is -> It was
Line 150: is -> were
Line 150: the diabetic neuropathic -> diabetic neuropathy
Line 155: the mechanistic pathway like -> compensatory responses like the
Line 155: subside -> decrease
Line 157: has been -> is
Line 158: inhibiting -> inhibitory
Line 159: impaired -> impair
Line 160: causes the over expression of -> increases
Line 160 and 162: Nrf-2 -> Nrf2
Line 161: co administration -> co-administration
Line 162: results -> resulted
Line 162: which further reduces the synthesis of ROS -> decreased ROS levels
Line 163: Haemooxygenase-1 -> heme oxygenase-1
Line 163: prevents -> prevented
Line 164: are involved -> is involved
Line 164: level -> levels
Line 167: epithelial cell -> epithelial cells
Line 168: In Vivo Studies -> In Vivo Studies [Italicize]
Line 169: Currently atherosclerosis is well accepted and -> Atherosclerosis is
Line 172: adhesion -> the long-term adhesion
Line 173: with arterial endothelium for long term -> to the arterial endothelium
Line 173: endothelium -> endothelial
Line 173: stimulates -> stimulates accumulation of leukocytes
Line 174: cytokines, growth factors, -> growth factors and
Line 174: Remove the words “accumulation of leukocytes and”
Line 175: progress -> stimulate
Line 177: (ICAM-1) -> ICAM-1
Line 177: proved -> shown
Line 177: (ICAM-1) -> and ICAM-1
Line 180: co researchers -> coworkers
Line 181: as -> as an
Line 183: Remove the words “Progression of”
Line 186: Kaempferol as the potential -> kaempferol as a potential
Line 187: coworker -> coworkers
Line 188: potential -> a potential
Line 188: the nuclear -> nuclear
Line 191: the Reactive species -> reactive oxygen and nitrogen species
Line 191: the cellular physiology -> cellular macromolecules
Line 192: AGE upon -> AGE. Upon [Break into 2 sentences]
Line 193: caused the activation of Reactive Oxygen Species -> causes increased production of reactive oxygen species
Line 193: enzymes level -> enzyme levels
Line 194: production -> activation
Line 194: Remove the word “synthase”
Line 195: the oxidative -> oxidative
Line 196 and 197: Remove the words “the chemical mediators like”
Line 198: figure out -> discovered
Line 199: Oxidase -> oxidase
Line 199: it -> kaempferol
Line 200: skin -> decreasing skin
Line 200: via downstream regulation oxidative biomarker -> and downstream oxidative biomarkers
Line 200: rat with knee osteoarthritic in -> rats with knee osteoarthritis (OA) in a
Line 202: Remove the words “cell therapy”
Line 206: done on disease models for kaempferol anti-inflammatory -> performed on diseased subjects to test for anti-inflammatory effects of kaempferol
Line 207: co researchers -> co-researchers
Line 207: patient -> patients testing
Line 208: iso energetic -> isoenergetic
Line 209: Kaempferol rich -> kaempferol-rich [both instances]
Line 209: diet has -> diet
Line 212: clinical -> a clinical
Line 212: the inflammatory -> inflammatory
Line 214: Remove the word “down”
Line 216: kaempferol rich -> a kaempferol-rich
Line 217: against -> following the consumption of
Line 217: kaempferol rich -> kaempferol-rich
Line 217: like -> containing
Line 218: received -> received the
Line 221: Remove the words “confirm its”
Line 221: is shielded by capsule -> can be encapsulated using a
Line 222: ploy ethylene -> polyethylene
Line 224: low -> its low
Line 224: has poor-> had poor
Line 224: has low potential-> had a low
Line 226: Remove the word “still”
Line 226: evaluated the kaempferol as clinical -> evaluate kaempferol as a
Line 230: found a conflict in their conclusion -> a conflict in their conclusions
Line 231: thought it as -> found it to be
Line 231: was proved -> has been shown
Line 231: effect -> effects
Line 232: as -> as a
Line 232: perform key role in -> performs a key role in the
Line 232: Flavonoid reduces a free radical -> Flavonoids reduce free radicals
Line 233: hydrogen -> a hydrogen
Line 233: react with -> reacts with the
Line 234: antioxidant -> an antioxidant
Line 234: phenoxyl radical react with oxygen specie then it acts as -> the phenoxyl radical reacts with the oxygen species then it acts as a
Line 235: reduce -> reduces
Line 235: vital -> a vital
Line 236: radicals -> radical
Line 236: antioxidant -> changes in antioxidant
Line 238: researcher -> researchers
Line 240: are -> is
Line 241: screening -> screenings
Line 241: coworker -> coworkers
Line 242: were -> was
Line 243: This -> It
Line 243: kaempferol low oral bioavailability prevents -> low oral bioavailability of kaempferol prevented
Line 246: in -> with
Line 248: as -> as an
Line 248: agents -> agent
Line 249: potential anti-inflammatory effect -> anti-inflammatory activity
Line 249: proven a safest -> shown to be a safe
Line 250: In vivo and in vitro -> in vivo and in vitro [italicize]
Line 251: resolved all the aspects responsible for -> improved markers of
Line 252: issue -> issues
Line 253: the issue but they -> this issue but most
Line 253: Kaempferol -> kaempferol
Line 253: resolved all -> improved
Line 254: with less -> while posing minimal
Line 254: still -> why it is still
Line 255: questionable? -> questioned.
Line 257: done -> performed
Line 258: execute -> confirm
Line 260: supported of -> support from
Line 261: review -> the review
Line 263: Remove the words “Please add:”
Reviewer 3 Report
General Comments
This paper investigates the evidence for the beneficial effects of kaempferol. Suggestions for improvement are detailed below.
1) The grammar and English in the manuscript is poor, and it makes most of the paper unreadable. The paper should be edited by a native English speaker.
2) The title does not really capture what the review is about – the manuscript does not focus on clinical prospects but rather the evidence for kaempferol’s anti-inflammatory properties.
3) Table 1 is not useful for the overall review. If kept, it should be moved to the supplement. More useful would be a table with some foods or beverages that contain kaempferol and in what quantities. After all, the title says “dietary”, and after reading the paper I still have no clue how to obtain kaempferol from the diet.
4) Is kaempferol a flavonoid? If so, why are flavanols discussed on lines 51-52?
5) On line 116, change “me” to “be”.
6) The in vitro section of the manuscript (7.1) reads like a long list of descriptions with no discussion on what any of it means. As an example, what does it mean to inhibit COX2?
7) It is unclear what the kaempferol-rich diet referenced on line 209 consisted of.
8) When discussing the clinical trials on lines 211-219, it is unclear how much kaempferol is in these diets, or how other components in these vegetables might be contributing to the positive effects.
9) The statement on line 251 that “Kaempferol resolved ALL the aspects responsible for inflammation” cannot even begin to be true, as all aspects cannot be measured. This should be rephrased.