My Paper

Environmental Science and Pollution Research
Ameliorating and pharmacological intervention potential of grape seeds extract against

lead and cadmium induced toxicity
--Manuscript Draft--
Manuscript Number: ESPR-D-20-13196R1
Full Title: Ameliorating and pharmacological intervention potential of grape seeds extract against
lead and cadmium induced toxicity
Article Type: Review Article
Corresponding Author: Shaukat Ali, Ph.D

Government College University Lahore
Lahore, PAKISTAN
Corresponding Author Secondary

Information:
Corresponding Author's Institution: Government College University Lahore
Corresponding Author's Secondary

Institution:
First Author: Rida Khan
First Author Secondary Information:
Order of Authors: Rida Khan
Shaukat Ali, Ph.D
Shumaila Mumtaz
Lubna Kanwal
Samaira Mumtaz
Tooba Nauroze
Order of Authors Secondary Information:
Funding Information:
Abstract: Being very toxic heavy metals like cadmium and lead have no precise, secure and
efficient therapeutic administration of their toxicity. It is revealed in the scientific
literature that experimentally induced metal toxicity in animals is lowered by several
medicinal plants and natural products. The present review attempts to assemble
experimental data on the ameliorative effects of grape seed extracts (GSE) and their
derivatives against lead and cadmium-induced toxicity. Several mechanisms are
involved in GSE ameliorating the effect against cadmium and lead toxicity like
antioxidant effect, reduction of apoptotic cells, prevention of DNA fragmentation,
regulating the expression of pro-apoptotic protein level (Bax-α), increase in anti-
apoptotic protein (Bcl-2), and hindering apoptotic signaling.
Response to Reviewers: Responses to Reviewers for Ref. Ms. No. ESPR-D-20-13196

Title: Ameliorating and pharmacological intervention potential of grape seeds extract
against lead and cadmium induced toxicity
Dear and respected. Prof. Dr. Mohamed M. Abdel-Daim

Editor-in-Chief
Thank you for the opportunity to submit a revised version of the manuscript. As
requested, we provide here a rebuttal to the reviewers’ comments. Please note that we
have made required changes (highlighted in red in revised manuscript).
Thanks again for your consideration.
Reviewer #1:
In this article, the authors reviewed the pharmacological potential of grape seeds
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extract against lead and cadmium induced toxicity. The novelty of this manuscript is
very poor. Authors cited only 1 paper from 2019 and no paper from 2020. The quality
of English is very poor, extensive English editing is necessary. The information
provided in this manuscript does not flow logically. The manuscript will require a
complete review following language editing.
Excellent suggestions. We are very happy to report that we have corrected all
mistakes. We have rewritten some sections of revised manuscript. Furthermore, we
are also pleased to mention that we have gone through the manuscript and revised it
very carefully and corrected the grammatical and typo mistakes. We have added quite
a few very recent citations now.
Reviewer #2: Review Comments For:
Journal: Environmental Science and Pollution Research

Full Title: Ameliorating and pharmacological intervention potential of grape seeds
extract against lead and cadmium induced toxicity
General Comments:
The manuscript reviewed the potential of grape seeds extract against lead and
cadmium induced toxicity. So, I do not recommend the publication of this manuscript in
the actual form.
Specific Comments. The following comments can be considered to improve this paper:
1. Revise all abbreviations in the text. Add the abbreviation and the respective
meaning once in the manuscript, do no repeat it in the manuscript.
Excellent suggestion. We are happy to report that we have revised and added all
abbreviations in our revised manuscript.
2. The motivation for this review in the introduction section of this paper needs to be
more convincing.
Excellent suggestion. We are happy to mention that we have revised introduction
section.
3. Add newer research, most of the articles cited in the paper are not so actual.
Excellent suggestion. We are happy to report that we have added quite a few very
recent citations in our revised manuscript.
4. The review is not a deep study of the actual scenario, the authors should try to
improve the quality paper.
Excellent suggestion. We have tried to improve the manuscript by adding some very
latest studies.
5. To publish this work, the authors should clarify all the previous points. Moreover,
the authors should try to rewrite the manuscript because in this form it is quite
confused.
Reviewer #4:
1-The manuscript lack of novelty.
2-The whole manuscript should be
revised for poor English by the help of native speaker.
3-English editing certificate is required
Reviewer #5: Review Comments
This review discussed an importance topic related to plant extract and metals
regulation, however some improvements and revisions are still required as shown
below;
Thank you very much for your positive assessment.
- The significance and importance of writing this review should be presented clearly in
the introduction. The introduction also should highlight some enough literature on the
recent related works that could be interpreted, particularly, with Section 2.
mistakes. We Furthermore, we are also pleased to mention that we have gone through
the manuscript and revised it very carefully and corrected the grammatical and typo
mistakes.
- The conclusion section should mention the importance and future perspectives as
well.
Excellent point. We are very happy to report that we have added the importance and
future perspective of this study in our revised manuscript.
- Bibliography section should be updated based on the required literature required as

suggested above.
Excellent suggestion. We are happy to report that we have added quite a few very
recent citations in text and in Bibliography of our revised manuscript.
Reviewer #6: Dr. Mohamed M. Abdel-Daim

Respected editor
I read with interest the review article entitled " Ameliorating and pharmacological
intervention potential of grape seeds extract against lead and cadmium induced toxicity
". The presentation of the data is very impressive. The present review accentuates the
ameliorative effects of grape seeds extracts (GSE) and its derivatives against lead and
cadmium-induced toxicity via several mechanisms. Graphical abstracts are illustrative
and descriptive. The review is well-written. Fortunately, this review could be an
important guide for other studies. No points to be addressed to authors.
Reviewer #7: Comments:

General comments:
The writing wording in most parts is weak, unexpressive and disorganized.
mistakes.
2- The authors abbreviate "grape seed extract" to (GSE) in the front of the review, so
they shouldn't repeat this and use the GSE only through the whole review.
Excellent suggestions. We are very happy to report that we have corrected it
throughout the revised manuscript.
3- The abbreviation names of many physiological component, cells, enzymes and

pathways were used without mention their complete names through the whole review.
Excellent suggestions. We are very happy to report that we have corrected it
throughout the revised manuscript.
4- The sources of figures are not included

We are very happy to report that we have made ourselves these figures for this
manuscript.
Introduction
1- Line 34:
large bowel ……., cancer, cataracts, there is a missing word or you mean "large bowel
cancer"
Protective Role of GSE against Metal intoxication and Oxidative stress.
Excellent point. We have made it correct.
2- Line 54
proanthocyanidins in grape seed (GSP) can protect ------------ GSP can protect
3- Line 58
Proanthocyanidins ----------- proanthocyanidins
4- Line 63
vitamins C, and E-------- vitamins C and E
Phenolic Antioxidants in Grapes

5- Table 2 needs to be rearranged by adjusting spaces or writing size and also it needs
to reveal different symbols in more obvious pattern
Bioavailability
6- Line 105
These Procyanidins------- These procyanidins
Effects of GSE on Blood & Effects of GSE on blood Parameters

- Line 113 & 114
"The blood levels of cadmium ranged from about 0.4 to 1.0 ug/l in normal individuals
(Baron and 114 Schweinsberg, 1989)"
should be transferred under the title "Effects of GSE on blood Parameters" and the
normal blood range of Pb should be mentioned also.
- Refine the reviewing of the therapeutic role of GSE in decreasing blood pressure
- Refine the reviewing of the role of GSE in decreasing metal toxicity
Excellent point. We have made all these corrections.
- Starting from line 130 to 140 "Cadmium toxicity increases serum TNF-α level---------
to via different ways i.e. CCL1, CCL2 and TNF-α (Alkhedaide, 140 2015)" should be
transferred under The Anti-inflammatory effect of grape seed extract
Line 141
The Anti-inflammatory effect of grape seed extract--------The Anti-inflammatory effect of
GSE
The Anti-inflammatory effect of grape seed extract
Line 156
- useful prognostic tool for inflammation in which high NLR was found associated-----
was to be found
GSE protecting renal damage
- The two paragraphs under this title need refine writing.

- Line 179
protein analyses----- analysis
Hepatoprotective effects
"GSE has some specific mechanisms of defense against hepatotoxicity induced
through Cd/Pb in rats"
Needs confirmation by references

Protective role of GSE against testicular dysfunction
Grape seeds extract as an anti-obesity agent
Line 214-215 "It can also be a beneficial agent in lung tissue with potential applications
against damages" Should be transferred under a separate title and need confirmation
by references.
Conclusion and Future aspects

The conclusion focuses on the effect of GSE as an antimicrobial agent although this
effect has not been reviewed in detail and only cited in a transient manner in the
introduction.
Excellent point. We are very happy to report that we have added the importance and
future perspective of this study in our revised manuscript.
Reviewer #8:
The review has lack of novelty. The review should be updated to includes many papers
from 2019 and 2020
The whole manuscript should be revised for poor English by the help of native speaker.
English editing certificate is required.
mistakes. We have added quite a few very recent citations now.
The review should be updated by adding recent publications covering the biomedical
applications of grape seed extract and its most potent active constituent, resveratrol.
The following references are recommended:
Environ Sci Pollut Res Int. 2020 Feb;27(6):6505-6514. doi: 10.1007/s11356-019-
07344-8.
Environ Toxicol Pharmacol. 2019 Jul;69:44-50. doi: 10.1016/j.etap.2019.03.016.
Front Pharmacol. 2018 Nov 21;9:1268. doi: 10.3389/fphar.2018.01268.
Oxid Med Cell Longev. 2018 Mar 18;2018:4147320. doi: 10.1155/2018/4147320.
Oxid Med Cell Longev. 2019 Jan 8;2019:8278454. doi: 10.1155/2019/8278454.
Oxid Med Cell Longev. 2019 Feb 12;2019:9783429. doi: 10.1155/2019/9783429.
Excellent suggestions. We are very happy to report that we have added all these
citations now.
Hazard effects of cadmium and lead on animal and plant cells should be updated. The
following refences are recommended:
Sci Total Environ. 2020 Aug 1;728:138832. doi: 10.1016/j.scitotenv.2020.138832.
Environ Sci Pollut Res Int. 2019 Aug;26(24):25167-25177. doi: 10.1007/s11356-019-
05783-x.
Sci Total Environ. 2020 Mar 1;706:136013. doi: 10.1016/j.scitotenv.2019.136013.
Int J Environ Res Public Health. 2020 May 29;17(11):3850. doi:
10.3390/ijerph17113850.
Front Plant Sci. 2020 Oct 23;11:547133. doi: 10.3389/fpls.2020.547133.
citations now.
Hazard effects of lead on animal and plant cells should be updated. The following
refences are recommended:
Antioxidants (Basel). 2020 Oct 19;9(10):1014. doi: 10.3390/antiox9101014.
Environ Sci Pollut Res Int. 2020 Sep;27(27):33723-33731. doi: 10.1007/s11356-020-
09643-x.
Sci Total Environ. 2020 Jan 20;701:134879. doi: 10.1016/j.scitotenv.2019.134879.
citations now.
Additional Information:
Question Response
§Are you submitting to a Special Issue? No
Authors' Response to Reviewers' Comments Click here to access/download;Authors' Response to Reviewers'
Comments;Rebuttal Letter final.doc
GC UNIVERSITY LAHORE
DEPARTMENT OF ZOOLOGY
Dr. Shaukat Ali,

Assistant Professor,
Department of Zoology,
Government College University, Lahore, Pakistan
Emails: shaukatali134@yahoo.com. Ph: +92-305-4190596
Tuesday, March 09, 2021.
Responses to Reviewers for Ref. Ms. No. ESPR-D-20-13196
Title: Ameliorating and pharmacological intervention potential of grape seeds

extract against lead and cadmium induced toxicity
Dear and respected. Prof. Dr. Mohamed M. Abdel-Daim
Editor-in-Chief

Thank you for the opportunity to submit a revised version of the manuscript. As requested, we
provide here a rebuttal to the reviewers’ comments. Please note that we have made required
changes (highlighted in red in revised manuscript).
Thanks again for your consideration.

Reviewer #1:
In this article, the authors reviewed the pharmacological potential of grape seeds extract against
lead and cadmium induced toxicity. The novelty of this manuscript is very poor. Authors cited
only 1 paper from 2019 and no paper from 2020. The quality of English is very poor, extensive
English editing is necessary. The information provided in this manuscript does not flow
logically. The manuscript will require a complete review following language editing.
Excellent suggestions. We are very happy to report that we have corrected all mistakes. We
have rewritten some sections of revised manuscript. Furthermore, we are also pleased to
mention that we have gone through the manuscript and revised it very carefully and corrected
the grammatical and typo mistakes. We have added quite a few very recent citations now.
Reviewer #2: Review Comments For:
Journal: Environmental Science and Pollution Research

Full Title: Ameliorating and pharmacological intervention potential of grape seeds extract
General Comments:
The manuscript reviewed the potential of grape seeds extract against lead and cadmium induced
toxicity. So, I do not recommend the publication of this manuscript in the actual form.
Specific Comments. The following comments can be considered to improve this paper:
1. Revise all abbreviations in the text. Add the abbreviation and the respective meaning once in
the manuscript, do no repeat it in the manuscript.
Excellent suggestion. We are happy to report that we have revised and added all abbreviations
in our revised manuscript.
2. The motivation for this review in the introduction section of this paper needs to be more
convincing.
Excellent suggestion. We are happy to mention that we have revised introduction section.
3. Add newer research, most of the articles cited in the paper are not so actual.
Excellent suggestion. We are happy to report that we have added quite a few very recent
citations in our revised manuscript.
4. The review is not a deep study of the actual scenario, the authors should try to improve the
quality paper.
Excellent suggestion. We have tried to improve the manuscript by adding some very latest
studies.
5. To publish this work, the authors should clarify all the previous points. Moreover, the
authors should try to rewrite the manuscript because in this form it is quite confused.
Reviewer #4:
1-The manuscript lack of novelty.
2-The whole manuscript should be
revised for poor English by the help of native speaker.
3-English editing certificate is required
Reviewer #5: Review Comments
This review discussed an importance topic related to plant extract and metals regulation,
however some improvements and revisions are still required as shown below;
- The significance and importance of writing this review should be presented clearly in the
introduction. The introduction also should highlight some enough literature on the recent related
works that could be interpreted, particularly, with Section 2.
Furthermore, we are also pleased to mention that we have gone through the manuscript and
revised it very carefully and corrected the grammatical and typo mistakes.
- The conclusion section should mention the importance and future perspectives as well.
Excellent point. We are very happy to report that we have added the importance and future
perspective of this study in our revised manuscript.
- Bibliography section should be updated based on the required literature required as suggested
above.
Excellent suggestion. We are happy to report that we have added quite a few very recent
citations in text and in Bibliography of our revised manuscript.
Reviewer #6: Dr. Mohamed M. Abdel-Daim

Respected editor
I read with interest the review article entitled " Ameliorating and pharmacological intervention
potential of grape seeds extract against lead and cadmium induced toxicity ". The presentation of
the data is very impressive. The present review accentuates the ameliorative effects of grape
seeds extracts (GSE) and its derivatives against lead and cadmium-induced toxicity via several
mechanisms. Graphical abstracts are illustrative and descriptive. The review is well-written.
Fortunately, this review could be an important guide for other studies. No points to be addressed
to authors.
Reviewer #7: Comments:

General comments:
The writing wording in most parts is weak, unexpressive and disorganized.
revised it very carefully and corrected the grammatical and typo mistakes.
2- The authors abbreviate "grape seed extract" to (GSE) in the front of the review, so they
shouldn't repeat this and use the GSE only through the whole review.
Excellent suggestions. We are very happy to report that we have corrected it throughout the
revised manuscript.
3- The abbreviation names of many physiological component, cells, enzymes and pathways were
used without mention their complete names through the whole review.
Excellent suggestions. We are very happy to report that we have corrected it throughout the
revised manuscript.
4- The sources of figures are not included

We are very happy to report that we have made ourselves these figures for this manuscript.
Introduction
1- Line 34:
large bowel ……., cancer, cataracts, there is a missing word or you mean "large bowel cancer"
Protective Role of GSE against Metal intoxication and Oxidative stress.
2- Line 54
proanthocyanidins in grape seed (GSP) can protect ------------ GSP can protect
3- Line 58
Proanthocyanidins ----------- proanthocyanidins
4- Line 63
vitamins C, and E-------- vitamins C and E
Phenolic Antioxidants in Grapes

5- Table 2 needs to be rearranged by adjusting spaces or writing size and also it needs to reveal
different symbols in more obvious pattern
Bioavailability
6- Line 105
These Procyanidins------- These procyanidins
Effects of GSE on Blood & Effects of GSE on blood Parameters

- Line 113 & 114
"The blood levels of cadmium ranged from about 0.4 to 1.0 ug/l in normal individuals (Baron
and 114 Schweinsberg, 1989)"
should be transferred under the title "Effects of GSE on blood Parameters" and the normal blood
range of Pb should be mentioned also.
- Refine the reviewing of the therapeutic role of GSE in decreasing blood pressure
- Refine the reviewing of the role of GSE in decreasing metal toxicity
- Starting from line 130 to 140 "Cadmium toxicity increases serum TNF-α level--------- to via
different ways i.e. CCL1, CCL2 and TNF-α (Alkhedaide, 140 2015)" should be transferred under
Line 141
The Anti-inflammatory effect of grape seed extract--------The Anti-inflammatory effect of GSE
Line 156
- useful prognostic tool for inflammation in which high NLR was found associated----- was to
be found
GSE protecting renal damage
- The two paragraphs under this title need refine writing.

- Line 179
protein analyses----- analysis
Hepatoprotective effects
"GSE has some specific mechanisms of defense against hepatotoxicity induced through Cd/Pb
in rats"

Protective role of GSE against testicular dysfunction
Grape seeds extract as an anti-obesity agent
Line 214-215 "It can also be a beneficial agent in lung tissue with potential applications against
damages" Should be transferred under a separate title and need confirmation by references.
Conclusion and Future aspects

The conclusion focuses on the effect of GSE as an antimicrobial agent although this effect has
not been reviewed in detail and only cited in a transient manner in the introduction.
Excellent point. We are very happy to report that we have added the importance and future
perspective of this study in our revised manuscript.
Reviewer #8:
The review has lack of novelty. The review should be updated to includes many papers from
2019 and 2020
The whole manuscript should be revised for poor English by the help of native speaker. English
editing certificate is required.
revised it very carefully and corrected the grammatical and typo mistakes. We have added
quite a few very recent citations now.
The review should be updated by adding recent publications covering the biomedical
applications of grape seed extract and its most potent active constituent, resveratrol. The
following references are recommended:
Environ Sci Pollut Res Int. 2020 Feb;27(6):6505-6514. doi: 10.1007/s11356-019-07344-8.
Environ Toxicol Pharmacol. 2019 Jul;69:44-50. doi: 10.1016/j.etap.2019.03.016.
Front Pharmacol. 2018 Nov 21;9:1268. doi: 10.3389/fphar.2018.01268.
Oxid Med Cell Longev. 2018 Mar 18;2018:4147320. doi: 10.1155/2018/4147320.
Oxid Med Cell Longev. 2019 Jan 8;2019:8278454. doi: 10.1155/2019/8278454.
Oxid Med Cell Longev. 2019 Feb 12;2019:9783429. doi: 10.1155/2019/9783429.
Excellent suggestions. We are very happy to report that we have added all these citations now.
Hazard effects of cadmium and lead on animal and plant cells should be updated. The following
refences are recommended:
Sci Total Environ. 2020 Aug 1;728:138832. doi: 10.1016/j.scitotenv.2020.138832.
Environ Sci Pollut Res Int. 2019 Aug;26(24):25167-25177. doi: 10.1007/s11356-019-05783-x.
Sci Total Environ. 2020 Mar 1;706:136013. doi: 10.1016/j.scitotenv.2019.136013.
Int J Environ Res Public Health. 2020 May 29;17(11):3850. doi: 10.3390/ijerph17113850.
Front Plant Sci. 2020 Oct 23;11:547133. doi: 10.3389/fpls.2020.547133.
Hazard effects of lead on animal and plant cells should be updated. The following refences are
recommended:
Antioxidants (Basel). 2020 Oct 19;9(10):1014. doi: 10.3390/antiox9101014.
Environ Sci Pollut Res Int. 2020 Sep;27(27):33723-33731. doi: 10.1007/s11356-020-09643-x.
Sci Total Environ. 2020 Jan 20;701:134879. doi: 10.1016/j.scitotenv.2019.134879.
Best wishes.
Dr. Shaukat Ali

Cover Letter
GC University Lahore
Department of Zoology
Dr. Shaukat Ali

Assistant Professor,
Department of Zoology,
Government College University
Email: dr.shaukatali@gcu.edu.pk. Ph: +923054190596
Dear Editor In-Chief,
Title: Ameliorating and pharmacological intervention potential of grape seeds extract

We have written a classical review manuscript which describing that Being very toxic heavy
metals like cadmium and lead have no precise, secure and efficient therapeutic administration of
their toxicity. It is revealed in the scientific literature that experimentally induced metal toxicity
in animals is lowered by several medicinal plants and natural products. The present review
attempts to assemble experimental data on the ameliorative effects of grape seeds extracts (GSE)
and its derivatives against lead and cadmium-induced toxicity. Several mechanisms are involved
in GSE ameliorating effect against cadmium and lead toxicity like antioxidant effect, Reduction
of apoptotic cells, prevention of DNA fragmentation, regulating the expression of pro-apoptotic
protein level (Bax-α), increase in anti-apoptotic protein (Bcl-273) and hindering apoptotic
signaling.
Manuscript Click here to access/download;Manuscript;Revised Main
Manuscript.docx
Click here to view linked References
1 Ameliorating and pharmacological intervention

2 potential of grape seeds extract against lead and
3 cadmium induced toxicity
4 Rida Khan1, Shaukat Ali2, *, Shumaila Mumtaz2, Lubna Kanwal2, Samaira Mumtaz2 and
5 Tooba Nauroze2
1
6 Department of Zoology, The University of Azad Jammu and Kashmir, Muzaffarabad, Pakistan
2
7 Department of Zoology, Government College University, Lahore, Pakistan
*
8 Corresponding author: Applied Entomology and Medical Toxicology Laboratory, Department of
9 Zoology, Government College University, Lahore, Pakistan. Phone: +92-3054190596, Email:
10 dr.shuakatali@gcu.edu.pk.
11 Abstract
12 Being very toxic heavy metals like cadmium and lead have no precise, secure and efficient
13 therapeutic administration of their toxicity. It is revealed in the scientific literature that
14 experimentally induced metal toxicity in animals is lowered by several medicinal plants and
15 natural products. The present review attempts to assemble experimental data on the ameliorative
16 effects of grape seed extracts (GSE) and their derivatives against lead and cadmium-induced
17 toxicity. Several mechanisms are involved in GSE ameliorating the effect against cadmium and
18 lead toxicity like antioxidant effect, reduction of apoptotic cells, prevention of DNA
19 fragmentation, regulating the expression of pro-apoptotic protein level (Bax-α), increase in anti-
20 apoptotic protein (Bcl-2), and hindering apoptotic signaling.
21 Keywords: grape seeds, GSE, antioxidant, lead, cadmium, chemopreventive,

22 Introduction
23 Metals and metal compounds intervene with features of a variety of organs and structures such as
24 the central nervous system (CNS) the hematopoietic system, kidneys, and liver (Abdel-Daim et al.
25 2020; El-Kott et al. 2020). Toxic heavy metals have interaction with the vital cation functions,
26 cause inhibition of the enzyme, and generate oxidative stress (Amadi et al. 2019; Saleh et al. 2020;
27 Mirkov 2020). Heavy metals may directly or indirectly damage growth (Jalmi et al., 2018). Heavy
28 metals induced-phytotoxicity leads to oxidative stress by generating harmful reactive oxygen
29 species (ROS) or modification of the antioxidant defense system (Saleh et al. 2020; Samar et al.
30 2020). GSE can replace the enzyme cofactors and transcription factors, it can also contribute to
31 equally balance cellular transport, DNA damage and protein oxidation thus improves inhibited
32 growth (Sardar et al. 2013; Shahid et al. 2014; Jalmi et al. 2018). Grape seed extract, which is one
33 of the most powerful natural antioxidants, is usually used to remove the free radicals in our body
34 and enhance our immunity. It is called “Vitamin for the skin” due to its effect in improving the
35 elasticity and luster of the skin, as well as anti-aging. It may also decrease the serum lipid and
36 cholesterol, thus helps to maintain a healthy cardiovascular system. We can process grape seeds
37 to get GSE (Abd El Kader et al. 2011). GSE has a high value of flavonoids, proanthocyanidins and
38 polyphenols which are powerful antioxidants (Khazri et al. 2016; Ahmed and Fatani 2007). The
39 body is protected against different diseases like atherosclerosis, gastric ulcer, large bowel cancer,
40 cataracts, and diabetes with the help of all of these compounds. For various tissues such as human
41 lung tissue, breast tissue, and stomach gastric mucosa, the grapes proanthocyanidins (PAC) are
42 effective antioxidants and have cytotoxic effects against all of them (Raina et al. 2007; El-Kott et
43 al. 2020). Commercial preparation of bioflavonoid and proanthocyanidins in medicinal and
44 pharmacological use depends on their antioxidant properties. GSE also possesses some
45 antibacterial, anticancer, anti-inflammatory, anti-viral properties along with potent immune
46 stimulant actions (Adhikari et al.2018). GSE is a phytochemical extensively investigated in recent
47 years acts as a very good source of natural antioxidants and is widely utilized in pharmaceutical,
48 cosmetics, food, and beverage industries (Baydar et al. 2007; Leifert et al. 2008). Natural extracts
49 of GSE and their products are good dietary flavonoid sources, which are potent antioxidant
50 compounds (Ahmed and Fatani 2007). Cadmium and lead are known to harm the liver, kidney,
51 bones, reproductive system, and other vital organs as toxic metals (Amadi et al. 2019; Maqbool et
52 al. 2020). The antioxidant and therapeutic role of GSE may be utilized to lessen the effects on the
53 human health of chemical agents shortly as a toxicity-limiting agent.
54 Protective Role of GSE against metal intoxication and oxidative stress
55 Cd/Pb may accumulate in tissues and cause oxidative stress by two mechanisms i.e. reacting with
56 the sulfhydryl groups of various proteins and by depleting glutathione (Mirkov et al.2020; Khazri
57 et al. 2016). It is assumed that antioxidants administration should be vital therapeutic progress.
58 Grape seed constitutes the major proportion of proanthocyanidins. These Proanthocyanidins are
59 also known as condensed tannins. These proanthocyanidins are the oligomers of flavan-3-ol units
60 i.e. (+)-catechin and (−)-epicatechin, all containing several phenolic compounds and water-soluble
61 molecules (Bagchi et al. 2002; Raina et al. 2007). Recent studies have revealed that
62 proanthocyanidins in GSE have a prophylactic effect against oxidative damage and metal toxicity
63 by scavenging reactive oxygen species or free radicals (Bagchi et al. 2000; X Gong 2020), thus a
64 variety of diseases such as myocardial infarction, atherosclerosis, drug-induced liver or kidney
65 damage can be effectively prevented (Spranger et al. 2008). Both hydrophobic and hydrophilic
66 residues are present in proanthocyanidins that can interact with phospholipid head groups of
67 membranes (Manoharan and Prab 2014; El Ayed et al. 2017). Some studies have unambiguously
68 demonstrated that GSE has significant potential and prospects for scavenging free radicals in both
69 experimental models of in vivo and in vitro (Leifert et al. 2008, Bagchi et al. 2014). A recent study
70 exemplifies that grape seeds PAC extracts are advanced scavengers of superoxide anions and
71 reactive free radicals in comparison to the β-carotene, vitamins C and E (Bagchi et al. 2000).
72 Studies also point that some types of flavonoids have cytoprotective effects e.g. resveratrol
73 (Lagouge et al. 2006) and quercetin (Nieman et al. 2010), both of these naturally occurring
74 compounds can boost the aerobic capacity and mitochondrial function of muscle tissue. These
75 flavonoids and proanthocyanidins can also restrain enzyme activities of phospholipase A2,
76 cyclooxygenase, and lipoxygenase thus give protection against metallic toxicants (Salah et al.
77 1995). One of the key mechanisms of lead/ cadmium which induced intoxication is oxidative
78 stress. The summary of causes, associated signs, route of entry, and observable health effects
79 resultant fromheavy metals lead and cadmium is given in figure 1 and table 1.
Figure 1. Mechanism of toxicity of cadmium and lead on various human body organs
80 Table 1. Summary of causes, associated signs, route of entry, and observable health effects
81 resultant fromheavy metals lead (Pb) and cadmium (Cd).
Health
Metals Sources Symptoms Entry routes References
hazards
Abdominal
pain, Nausea,
Hematologic The
Combustio Thirst,
al and respiratory,
n of fuel Diarrhea,
neurological gastrointestin (Waggas, 2012;
and solid Constipation,
disorders, al tract, Zhai et al. 2015;
Lead waste, Shock, Lead
renal and drinking Alawi et al.
ammunitio encephalopath
liver damage, water, 2018).
n, welding, y, Paralysis,
reproductive consumer
cigarette Muscular
dysfunction products
smoking weakness,
pigments. Headache
Pottery, Dysfunction
batteries, in kidney,
Respiratory
chemical lungs, (Jan et al.
emphysema,
Cadmiu reagents cardiovascula Inhalation 2015;Baiomy201
interstitial
m recycling, r and Ingestion 6; Alkhedaide
fibrosis,
industrial pulmonary 2016).
pneumonia
processing system
functions
82
83 Phenolic antioxidants in grapes
84 A variety of bioactive components like phenolic antioxidants including anthocyanins, catechins,
85 phenolic acids, resveratrol, and procyanidins are believed to be related to the beneficial effects of
86 grape and their food products (Vislocky and Fernandez 2010;;; Prasain et al. 2011). About 100 g
87 of fresh grapes have 63–182 mg of the phenolic compounds out of which (65–76%) are constituted
88 by flavonoids in red grapes (Hogan et al. 2009).
89 Grapes carry phenolic compounds usually in the skin or seeds (Careri et al. 2003). In seeds,
90 Procyanidins are in large amounts while resveratrol, anthocyanins, and catechins are bulk in the
91 skin parts (Kammerer et al. 2004). Commercially grape extracts are prepared with waste byproduct
92 i.e. grape pomace, produced in the lucrative wine-making industry (Eyiz et al.2020). This
93 byproduct of commercially prepared GSE adds up annually in large amounts to cause waste-
94 management issues (Bustamante et al. 2008). Approximately 20% of the estimated grape pomace
95 is produced by the harvested grapes but discarded as manure, organic fertilizers, and animal feed
96 as its uses are limited (Hogan et al. 2010). This grape skin and seed have phenolic acids i.e., gallic
97 acid, ferulic acid, caffeic acid, syringic acid, and p-coumaric acid in a considerable amount. Even
98 though resveratrol is one of the most prominent bioactive components in grapes,s skin but its
99 concentration is very low usually 0.21 mg/g of the grape seed extract as analyzed through HPLC
100 analysis (Kammerer et al. 2004; Zhang et al. 2013;). The designated studies on the therapeutic
101 effects of grape seeds extract against metal toxicity are given in table 2.
102
103
104
105
106
107
108 Table 2: Designated studies on the therapeutic effects of GSE against metal toxicity
109
Grape seed Administere Animal Duration Target The proposed References
components d Form Model site underlying
therapeutic
mechanism
20 mg/kg of Male 15 days Down regulating p53 (Eleawa et
BW orally Wistar rats Tests &Bax and al. 2014).
orally upregulating
treated Gonadotropin Bcl2
with CdCl2 gene
10 µg/ml Zebrafish 72 hrs Prevented renal (Hu et al.
exposed to Kidneys collagen deposition, 2017).
1.5 mg/L oxidative stress and
CdCl2 in inflammation via
Resveratrol
water for regulating Nrf-2.

72 h
20 mg/kg of Rats 4 weeks
BW treated
with CdCl2
orally
400 mg/kg of Wistar rats 2 weeks improve the (Highab,
BW treated Liver histopathological 2017|).
with lead lesions
acetate
solution
orally
75 mg/kg of Male mice 2 weeks Attenuated germ cell (Bu et al.
Quercetin
BW orally Testes apoptosis by 2011).

administere suppressing the H2O2
d by CdCl2 production and lipid
peroxidation in
testicular tissue.
150 µg/egg Chick eggs E17.5 Embryo Upregulation of (Hau et al.
injected (with the s meiosis-related 2016).
with 3 µg oocytes proteins and gene
CdCl2 arrested expressions and
during in the restored antioxidant
Proanthocyanidin
incubation meiotic activity

cycle
100 mg/kg of Albino rats 3 months Spleen Down regulating Bax (Alkhedadie
BW/day orally & upregulation of et al. 2016)
administere Ki76
d CdCl2
100 mg/kg of Mice orally 6 weeks Liver protect against (Long et al.
BW/day treated oxidative stress via 2016).
with 0.2% the Nrf2/ARE
lead acetate signaling pathway
110
111 Bioavailability
112 About 60% -70% polyphenols in the form of procyanidins exist in grape seeds in comparison to
113 grape skins. These procyanidins are flavan-3-ol derivatives and colorless in pure state (Zhang et
114 al. 2011;Tabeshpour et al. 2018; Zhao et al. 1999; Prieur et al. 1994). The bioactivities of some
115 phenolic compounds present in grapes are summarized in table 3.
116 Table 3. Bioactivities of some phenolic compounds present in different parts of grapes.
Resource Phenolic compounds Therapeutic potentials References

free radical scavenging (Baxter 2008;
antiproliferation Dinicola et al. 2012;;
anti-aging Bermen et al. 2017).
Juice, stem, cancer chemoprevention
pomace, Resveratrol
and skin raise plasma nitrous oxide
level (Jin 2008; Kaur, et al.
regulates lipid metabolism 2009)
neuro-protective action
(Rodriguez-Vaquero
antibacterial
Skin, leaf, et al. 2007;
Quercetin raising plasma nitrous oxide
and stem Appeldoorn et al.
level
2009).
Gallic acid free radical scavenger
anticancer free radical (Halliwell 1996; Faria
Skin and scavenging antibacterial
Proanthocyanidins et al. 2006;;
Seed anti-inflammation
(catechin&epicatechins) Alkedaide, 2015).
protection against membrane
oxidation
Flavonol free radical scavenging (Cosme et al. 2020).
vasorelaxation free radical
scavenger antibacterial
anthocyanin (Mattivi et al. 2006).
antioxidant inducing
apoptosis
117
118 Effects of GSE on blood
119 GSE contains powerful vasodilating effects on the blood pressure of individuals with metabolic
120 syndrome. This recommends that GSE could be exercised as a nutraceutical in a lifestyle
121 modification program for patients with metabolic syndrome (Sivaprakasapillai et al. 2009).
122 According to currently available literature grape seed extract appears to lower systolic blood
123 pressure and heart rate considerably without affecting serum lipid or blood glucose. (Feringa et al.
124 2011). GSE can boost the antioxidant properties of cells and reduced lipid peroxidation induced
125 by free radicals in the blood (Enginar et al. 2007).
126 Effects of GSE on blood parameters
127 The blood levels of cadmium and lead ranged from about 0.4 to 1.0 ug/l and 10 mcg/dL
128 respectively in normal adult individuals ( Alli, 2015; Wang et al. 2019). In erythrocytes, lead
129 and cadmium-induced toxicities significantly enhance the lipid peroxidation markers while
130 enzymatic and non-enzymatic markers activity is decreased. On the other hand, pharmacological
131 pretreatment with GSE significantly prohibited the drop-off in the antioxidant and membrane-
132 bound ATPase activities. Structural changes in erythrocytes conformation are also cited in the
133 literature. This review disclosed that GSE can offer prime defense against lead/cadmium-induced
134 ROS generation and lipid peroxidation, which probably mirrors that these grape flavonoids can
135 give protection to erythrocytes and lymphocytes against Cd/Pb intoxication to some extent
136 (Nazima et al. 2016).
137 The anti-inflammatory effect of GSE
138 Cadmium toxicity increases serum TNF-α level in the experimental animals, while GSE has shown
139 a significant reduction in animals that were co-treated with both CdCl2 and GSE. These data are
140 nicely fit the data presented previously in which the grape seed extract exerts an anti-inflammatory
141 effect via different pathways leukocyte cell production, proliferation, inflammatory mediators’
142 induction, and anti-oxidant reaction. Grape Seed Extract (GSE) displays ameliorating effects
143 against Cd-induced inflammation that is confirmed by the reduction of Neutrophils/Lymphocytes
144 ratio, enhanced antioxidant activity via increased leukocytic counts, and reduction of serum TNF-
145 α level. The published data suggest that Grape Seed Extract (GSE) enhances the immune response
146 and might exert its anti-inflammatory effects via different ways i.e. TBARS, CCL1, CCL2, and
147 TNF-α (Alkhedaide 2015).
148 The mechanism by which Cd/Pb toxicity operates is just like any other heavy metal toxicity i.e.
149 generating reactive oxygen species (ROS) in large amounts which accompany tissue damages and
150 physiological stress (Chatterjee et al. 2014; Choong et al. 2014). In the same context, inflammatory
151 mediators stimulate the production of ROS which in turn causes DNA impairment, mitophagy as
152 well as autophagy (Kraaij et al. 2014, Leavy 2014). Several studies have demonstrated that
153 cadmium exposure induces inflammation in different target organs such as lungs, kidneys and
154 cardiovascular system (Kataranovski et al. 2009; Gessner et al. 2012). Moreover, inflammation is
155 identified as an immune reaction caused by infections, toxicity, or injury which might lead to
156 further risk progressions such as tumorigenesis or chronic disease (Grivennikov et al. 2010).
157 Therefore, measurement of the inflammatory degree in the case of cadmium toxicity might be a
158 useful tool for monitoring both severities of exposure and treatment of the physiological defect
159 caused by that exposure. However, there are several parameters used for estimation the degree of
160 inflammation such as leukocyte counts, serum cytokines, and Neutrophils/Lymphocytes ratio
161 (NLR) (Jaishankar et al. 2014). Recently, this ratio became a useful prognostic tool for
162 inflammation in which high NLR was found associated with increased serum levels of some
163 inflammatory cytokines (Grivennikov et al. 2010). GSE prevents eicosanoid generating enzymes,
164 inflammatory excretion, and the mitogen-activated protein kinase (MAPK) pathway (Karami et al.
165 2018).
166 GSE protecting renal damage
167 Acute renal failure (ARF) is a life-threatening disease with a high mortality rate. The two prime
168 mechanisms i.e. oxidative stress and inflammation. GSE supplementation attenuates MDA levels
169 and enhances NO, GSH, GPx and CAT activity in the diabetic rats in comparison to those who
170 were not supplemented by GSE (Amin etal, 2018). Though, we found enormous literature on the
171 pharmacological effectiveness of GSE for ARF treatment. Several Published works have shown
172 that cadmium toxicity induces renal damage and was associated with progressive renal defects
173 (Järup, 2002; Godt et al. 2006; Chen 2013). Acute overexposure to cadmium irritates the
174 pulmonary system while passive accumulation occurring due to chronic exposure leads to renal
175 tubule damage in the kidneys (Nogue et al. 2004; Al-Malki, 2013; Sochorova et al, 2020 ).
176 The levels of blood urea nitrogen, serum creatinine and urine, lipid peroxidation, protein
177 carbonylation, enzymatic, and non-enzymatic antioxidants, NF-κB p65, NO, TNF-α, IL-6,
178 apoptotic (caspase-3, caspase-9, Bax, Bcl-2), membrane-bound ATPases, and Nrf2 (HO-1, keap1,
179 γ-GCS, and μ-GST) markers are elevated in Cd/Pb-treated rats. Chemoprevention with GSE
180 treatment decreases the amount of iNOS, NF-κB, TNF-α, caspase-3, and Bax and increases the
181 levels of Bcl-2 protein expression. Similarly, mRNA and protein analysis substantiated that GSE
182 treatment notably normalizes the renal expression of Nrf2/Keap1 and its downstream regulatory
183 proteins in the Cd-treated rats (Nazima et al. 2014).
184
185 Cardioprotective effect of grape seed extract
186 Leifert et al. (2008) described the mechanism by which GSE ameliorates metal-induced toxicity
187 as chiefly credited to its anti-oxidative nature as GSE scavenges the free radicals by blocking the
188 lipid peroxidation. This inhibitory activity of GSE on lipid peroxidation can be reflected firstly by
189 decline of the myocardial MDA and GSH content contrary to metal treated groups (Charrad et al.
190 2013). Secondly, the normal SOD activity may suggest the augmentation of SOD leading to the
191 promoted enzymatic detoxification of reactive oxygen species (Siti et al. 2015; Razmaraii et al.
192 2016; Sochorova et al. 2020). The cardioprotective effect of grape seed extract is explained in
193 figure 2.
Figure 2. The mechanism of the cardioprotective effect of grape seed extract.
194 Hepatoprotective effects of GSE
195 It may be summarized that GSE has some specific mechanisms of defense against hepatotoxicity
196 induced through Cd/Pb in rats at the mitochondria level. GSE significantly rescued DNA
197 impairment induced by the Cd/Pb intoxication, apoptosis, inflammation, and ultrastructural
198 alterations in the hepatic tissue. GSE also compromised the Cd/Pb induced biochemical and
199 structural changes in liver mitochondria by scavenging free radicals, antioxidant activity, and via
200 metal chelating property. Dietary grapes seed extracts attenuate liver damage in rats induced by
201 lead via an integrated system associated with various mechanisms of miRNA153 and
202 AKT/glycogen synthase kinase 3 beta/ Fyn mediated activation of Nrf 2. GSE attenuates
203 miRNA153 expression and increases nuclear factor erythroid 2-related factor 2 (Nrf 2)
204 translocation and level of its downstream protein, protein kinase B (AKT) phosphorylation in Pb
205 or Cd-induced injury in the liver (Liu et al. 2018; Bashir et al. 2016). The overall mechanism of
206 GSE protection is expressed in figure 3. Improvement of liver function with the effects of GSE
207 (Khoshbaten et al. 2010), minimizing cardiac arrhythmias and reducing infarct size, (Najafi et al.
208 2011) lipid profile (Abedini et al. 2013) and lipid peroxidation (Pourghassem-Gargari et al. 2011)
209 in patients of type II diabetes have been reported too.
210
Figure 3. The protective mechanism of grape seed extract
211 Protective role of GSE against testicular dysfunction
212 Cd accumulation may occur in the testes, where it induces testicular oxidative stress by two
213 mechanisms: By reacting with the sulfhydryl groups of various proteins or by glutathione
214 depletion. Histopathological alterations, immune reactivity, and mRNA expression of
215 steroidogenesis-associated genes through cadmium intoxication can be ameliorated by GSE.
216 Further, in vitro investigation is needed to understand the more beneficial effect of GSE and its
217 bioavailability for testicular dysfunction treatment during CdCl2 toxicity on Leydig cell function.
218
219 Grape seeds extract as an anti-obesity agent

220 GSE had a substantial precautionary effect against obesity, and hence may be practiced as an anti-
221 obesity agent. It can also be a beneficial agent reducing the lipotoxicity in lung tissue of rats
222 exposed to a high fat diet (El Ayed et al. 2017). Grape seeds proanthocyanidins decrease
223 hyperinsulinemia by increasing adiponectin secretion from white adipocytes and enhancing
224 glucose tranporter4 expression in skeletal muscle. They may also inhibit β-cell mass and insulin
225 secretion (Charradi, 2014; Gonzalez-Abuin, 2015).
226 Anticancer effects of grape seed extract
227 The antioxidant potential of GSE has been evaluated more than other identified antioxidants
228 including vitamin C and E (Bagchi 1997). The summary of the anti-cancerous activities of
229 grapephenolic compounds is given in table 4.
230 Cell got unrestricted division potential in the disease of cancer. The conversion of the normal cell
231 towards cancerous phenotype is owed to the prevalence of various faults in normal cell physiology,
232 which leads to abnormal growth advantage to the transforming cell (Hanahan and Weinberg 2000).
233 As these flaws are mainly due to improper signaling cascades involving several molecules, the use
234 of some chemopreventive agents could be an efficient strategy in targeting them for cancer control.
235 The mechanism by which GSE copes with these defects in signaling cascades through its
236 anticancer and/or chemopreventive efficacy is via phosphorylation of MAP-kinases, down-
237 regulation of cyclins, and CDKs, inhibition of PI3K-Akt and NFkB pathways, and initiation of
238 both extrinsic and intrinsic apoptotic pathways (Kaur et al. 2009).
239
240 Table 4: Summary of anti-cancerous activities of phenolic compounds present in grapes
Phenols Study model Effects References

mouse
mammary Inhibition of metastasis in
proanthocyanidins (Mantena et al. 2006).
carcinoma cell breast cancer
line
Activation of an
rat liver clone
antioxidant response (Shih et al. 2007).
9 cells
element
colon cancer induced 2–4 times increase
(Yi et al. 2005).
Anthocyanin cell lines in DNA fragmentation
(HT-29 and repaired and protected
Caco- genomic DNA integrity
(Bagchi et al. 2004).
2)vascular and retard blood vessel
tumor biology growth in some tumors
mice spleen Inhibit ion of DNA
(Fan and Lou 2008).
procyanidin, cells damage induced by H2O2
catechin, or gallic
decreased cell viability and
acid human breast
proliferation at 30 and 60 (Faria et al. 2006).
cancer cell line
μg/mL
cell antiproliferation with
human colon an EC50 value of 54.8 ±
carcinoma HT- 1.3 µmol/L, induced
Flavone & 29 cells differentiation and
(Wenzel et al. 2000).
Flavonoid apoptosis
more effectively induced
HT-29 cells apoptosis than antitumor
agent camptothecin
prostate cancer apoptotic and
(Kuwajerwala et al. 2002).
cell lines antiproliferative effects
Resveratrol human
cyclooxygenase-2
mammary
transcription inhibition (Subbaramaiah et al. 1998).
epithelial cells
Table 5: Some other studies related to pharmacological treatment with GSE
Effect on
Experiment
Extract/Compound Tissue Health Effects
Model
(Organism)
GSE rich in polyphenols does not
significantly reduce outpatient blood
effect on pressure in untreated individuals with
GSE/polyphenols human
blood pressure pre-hypertension and stage I
hypertension
anti-
inflammatory inhibited carrageenan-induced paw
GSE/PAC effect/ reduce edema and ear swelling in mice mice
lipid
peroxidation
antioxidant Improve liver function and relieve
activity/anti- inflammation and oxidative stress in
GSE rats
inflammatory cholestatic ischemia/reperfusion injury
antioxidant
activity/reduce
GSE lipid alleviate the negative effect of X-rays rats
peroxidation
Protection against liver and kidney

damage by regulating, against ischemic
antioxidant Rats, in
GSE/PAC reperfusion injury of the myocardium
activity vitro
and myocardial infarction
GSE and effect on fatty

affected the fatty acid profile in the liver chickens
pomegranate oil acid profile
antioxidant
No effect on health could be
activity/effect
GSE recommended as an addition to the broilers
on ileal
broiler diet
microflora
antioxidant prevent lipid oxidation and improve
GSE activity/reduce antioxidant activity In vitro
lipid oxidation
anti-
hypertensive
via the attenuation of JNK and p38
GSSE and anti- rats
kinases activity
oxidative
stress effects
241
242 Conclusion and future aspects
243 In the end, we can conclude that the natural origin, structural varieties, and their ready availability
244 make GSE a noticeable biological agent with promising chemotherapeutic and chemoprevention
245 effects. GSE is a substitute for clinical due to its antioxidant, anti-inflammatory, neuroprotective,
246 cardioprotective, nephroprotective, and antiapoptotic properties However, more research and
247 investigation should be added to the literature about the ingredients in the GSE because its special
248 pharmacodynamic properties could be originating from these components. Phytochemicals present
249 in grape seeds effectively kill cancerous cells by selectively targeting them. This review attempts
250 to evaluate the anti-inflammatory, antioxidant, antiproliferative, antiapoptotic and antigenotoxic
251 potential of Grape seeds. The continuing public interest and the growing availability of GSE on the
252 market require an overview of available in vitro experimental studies in human cells.
253 Ethical Approval
254 “Not applicable”
255 Consent to Participate
257 Consent to Publish
259 Authors Contributions
260 Conceptualization: Rida Khan, Shaukat Ali, Shumaila Mumtaz, Supervision: Shaukat Ali,
261 Writing Original draft: Shaukat Ali, Lubna Kanwal, Samaira Mumtaz and Tooba Nauroze,
262 Review and Editing: Rida Khan, Shaukat Ali, Shumaila Mumtaz
263 Funding: There is no funding for this study.

264 Competing Interests: Authors declare no any kind of financial and authorship conflict of
265 interest.
266 Availability of data and materials: Most of the data generated or analyzed during this
267 study are included in this published article.
268
269 Abbreviations
ALT alanine aminotransferase-tissue damage biomarker
ARE antioxidant response element
ARF Acute renal failure
AST Aspartate aminotransferase-tissue damage biomarker
BW body weight
CAT catalase-biomarker for oxidative stress
CCL chemokine ligand
CdCl2 cadmium chloride
CRC colorectal cancer cells
GPx glucose peroxidase
GPx Glutathione peroxidase
GSE grape seed extract
GSH glutathione redox biomarker
GSH Glutathione
GSPE grape seed proanthocyanidin extract
GSSE grape seed and skin extract
HDL high density lipoprotein
HFD high-fat diet
HPLC High Performance Liquid Chromatography
IL Interleukin
LDH lactate dehydrogenase-tissue damage biomarker
LDL low density lipoprotein

MAPK mitogen-activated protein kinase
MDA malondialdehyde lipid peroxidation marker
MDA Malondialdehyde
MPO myeloperoxidase-biomarker for cardiovascular disease risk
NO Nitric oxide
Nrf2 nuclear erythroid 2-related factor 2
PAC Proanthocyanidine
ROS reactive oxygen species
SOD superoxide dismutase-biomarker for oxidative stress
TBARS thiobarbituric acid reactive substances-biomarker of oxidative stress
TNF tumor necrosis factor
270
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Environmental Science and Pollution Research

Ameliorating and pharmacological intervention potential of grape seeds extract against

Manuscript Number: ESPR-D-20-13196R1

Article Type: Review Article

Corresponding Author: Shaukat Ali, Ph.D

Corresponding Author Secondary

Corresponding Author's Institution: Government College University Lahore

Corresponding Author's Secondary

First Author: Rida Khan

First Author Secondary Information:

Order of Authors: Rida Khan

Shaukat Ali, Ph.D

Order of Authors Secondary Information:

Response to Reviewers: Responses to Reviewers for Ref. Ms. No. ESPR-D-20-13196

Dear and respected. Prof. Dr. Mohamed M. Abdel-Daim

Reviewer #2: Review Comments For:

Journal: Environmental Science and Pollution Research

Reviewer #5: Review Comments

- Bibliography section should be updated based on the required literature required as

Reviewer #6: Dr. Mohamed M. Abdel-Daim

Reviewer #7: Comments:

3- The abbreviation names of many physiological component, cells, enzymes and

4- The sources of figures are not included

Phenolic Antioxidants in Grapes

Effects of GSE on Blood & Effects of GSE on blood Parameters

- The two paragraphs under this title need refine writing.

Needs confirmation by references

Conclusion and Future aspects

§Are you submitting to a Special Issue? No

Dr. Shaukat Ali,

Tuesday, March 09, 2021.

Responses to Reviewers for Ref. Ms. No. ESPR-D-20-13196

Title: Ameliorating and pharmacological intervention potential of grape seeds

Dear and respected. Prof. Dr. Mohamed M. Abdel-Daim

Environmental Science and Pollution Research

Thanks again for your consideration.

Reviewer #2: Review Comments For:

Journal: Environmental Science and Pollution Research

Reviewer #5: Review Comments

Reviewer #6: Dr. Mohamed M. Abdel-Daim

Reviewer #7: Comments:

4- The sources of figures are not included

Phenolic Antioxidants in Grapes

Effects of GSE on Blood & Effects of GSE on blood Parameters

- The two paragraphs under this title need refine writing.

Needs confirmation by references

Conclusion and Future aspects

Dr. Shaukat Ali

Dr. Shaukat Ali

Dear Editor In-Chief,

Environmental Science and Pollution Research

Title: Ameliorating and pharmacological intervention potential of grape seeds extract

of apoptotic cells, prevention of DNA fragmentation, regulating the expression of pro-apoptotic

1 Ameliorating and pharmacological intervention

9 Zoology, Government College University, Lahore, Pakistan. Phone: +92-3054190596, Email:

13 therapeutic administration of their toxicity. It is revealed in the scientific literature that

20 apoptotic protein (Bcl-2), and hindering apoptotic signaling.

21 Keywords: grape seeds, GSE, antioxidant, lead, cadmium, chemopreventive,

28 metals induced-phytotoxicity leads to oxidative stress by generating harmful reactive oxygen

43 al. 2020). Commercial preparation of bioflavonoid and proanthocyanidins in medicinal and

46 stimulant actions (Adhikari et al.2018). GSE is a phytochemical extensively investigated in recent

53 human health of chemical agents shortly as a toxicity-limiting agent.