SUPEROXIDE DISMUTASE – EVIDENCE BASED PERSPECTIVES TO ... · SUPEROXIDE DISMUTASE – EVIDENCE...
Transcript of SUPEROXIDE DISMUTASE – EVIDENCE BASED PERSPECTIVES TO ... · SUPEROXIDE DISMUTASE – EVIDENCE...
SUPEROXIDE DISMUTASE – EVIDENCE BASED PERSPECTIVES
TO TARGET THE REDOX DYSREGULATION: UPDATE 2013Dr Navneet Wadhwa *, Dr Hemant Thacker **
*MD (Pharmacology) Deputy General Manager, Medical Services, Alkem (Bergen), Mumbai ** MD (Medicine), FACE. Sr Consultant Physician and Cardiometabolic specialist, Bhatia Hospital, Jaslok Hospital, Breach Candy Hospital Mumbai, India
BACKGROUND
Reactive oxygen species (ROS) including superoxide radicals are attributed for the pathogenesis of various diseases
The reactive intermediate generated by the utilisation of oxygen impairs the functioning of cells and tissues. Superoxide dismutase (SOD) catalyzes the conversion of single electron reduced species of molecular oxygen to hydrogen peroxide and oxygen
There are several classes of SOD that differ in their metal binding ability, distribution in different cell compartments, and sensitivity to various reagents
Removal of ROS by exogenous SODs could be an effective preventive strategy against various diseases. Improvements in SOD formulation overcome the limitation of the exogenous SODs and enhance the therapeutic properties
Views of oxidative stress and redox imbalance have broadened considerably, as these conditions are now often seen as imbalances that have origins in our genes
Transcription factor called nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is referred to as the 'master regulator' of the antioxidant response, modulating the expression of hundreds of genes, including the antioxidant enzymes. Hence, dysregulation of Nrf2-regulated genes provides a logical explanation for the apparent associations between observable oxidative stress and perhaps 200 human diseases involving these various physiological processes
Fig 2: Cumulative numbers of publications retrievable by PubMed.gov on the topics of ''superoxide,'' ''oxidative stress,'' and ''redox signaling.''
Fig 1: Mechanism of oxidative stress induction. An impaired balance between ROS production and antioxidant defences results in the accumulation of oxidative products (adapted from Carillon J et al; Pharm Res. 2013 Nov;30(11):2718-28)
Although superoxide and SOD are closely related to oxidative stress, the usage of the term ''oxidative stress'' in the literature has not tracked with superoxide. The term began to appear in the 1970s, coincident with superoxide and SOD, but didn't seem to catch on until around 1995, at which point it took off with a vengeance, quickly surpassing references to superoxide and SOD. This may be explained by that the broader term ''oxidative stress'' had wide appeal to nearly all disciplines within the biological sciences, as well as to the wider medical community
Cumulative number of papers published since 1968 concerning all aspects of superoxide now exceeds 76,000
The chelating potential of exogenous SODs may partly explain the decrease of oxidative stress and inflammation observed after SODs supplementation. However, SODs half-life is only a few minutes in blood circulation, but more long effects were observed after SODs administration. Moreover, beneficial effects appears after SODs oral supplementation although SODs cannot be absorbed, which suggest that exogenous SODs have an additional influence independent of the antioxidant activity
METHODS
We searched electronic databases (Medline, Pubmed) identify and study peer reviewed case studies, observational studies, case control and cohort studies using the specific MeSH and text 'Superoxide dismutase', 'Oxidative stress' and 'redox dysregulation'. Bibliographies of retrieved papers for additional references were also hand searched and included for analysis.
RESULT
Prof Irwin Fridovich, currently Professor emeritus of Biochemistry at Duke University, North Carolina, USA can rightly be called as the 'father of SOD'; with 51,000 citations in the scientific literature, including 7 papers with >1000 citations, and an H-index of 97
He along with his student Joe M. McCord, discovered 'superoxide dismutase' on April 4, 1968
SOD was introduced to the biochemical community in an oral abstract presented at the 1969 FASEB (Federation of American Societies for Experimental Biology) meeting, followed by highly cited Journal of Biological Chemistry article that provided an assay technique that is even still widely used.
Various causes (smoking, alchohol, radiations,pollution, stress, ageing, unbalanced lifestyle...)
NADPH oxidaseXanthine oxidaseRespiratory chain
O2
_0O2
SODH O2 2
CAT
GPx0OH
0RO2
ROOH
0RO
H O2
Oxidative damage(DNA, proteins, lipids)
Various diseases
120000
100000
80000
60000
40000
20000
0
Cum
ulat
ive
publ
icat
ions Oxidative stress
Superoxide
RedoxSignaling
1960 1970 1980 1990 2000 2010Year
The first paper which identified superoxide dismutase was published in the year 1969, ever since a total of 53,986 research papers have been published till date, of which 4147 research papers have been published only in last one year.
Till date, 1060 clinical trials have been published, of which 610 have been conducted under randomized controlled setting. 279 case reports, 27 meta-analysis have been published. 3797 papers from India have been published of which 52 are been clinical trials.
Table 1. Superoxide Dismutase- Published Strength of Evidence *
Number of published evidences since 1969
More than 50,000 papers till date, of which 1000 clinical studies have been published, approx 60% of them have been conducted under randomised controlled clinical trial setting (the highest level of evidence)
Hence, concept is well researched ever since first paper was published, consistently for more than 4 decades back, starting in 1969 with publication of first research work
A lmost, every 1 in 10 paper published over last 5 years on SOD has been from India. Hence, substantial Indian data exists
In 2013 alone, till Aug 2013, approx 8000 papers have been published
Figure 4. Superoxide Dismutase- Recent Publications **Analysis as of Aug 2013
Figure 5. Superoxide Dismutase from Melon- Recent Publications**Analysis as of Aug 2013
B ernard Babior in 1973 discovered that phagocytosing polymorphonuclear leukocytes produced superoxide during the respiratory burst through the NADPH oxidase, as a bactericidal agent, which led to the understanding of the cause of chronic granulomatous disease, as a genetic defect in the NADPH oxidase. This opened the door to recognizing the useful contributions of superoxide production
Specific protective effects have been observed against irradiation, carcinogenesis, apoptosis and neurodegeneration. SODs administration alleviate inflammatory, infectious, respiratory, metabolic and cardiovascular diseases and genitourinary and fertility disorders. Role of SODs has been particularly described for modulation of various diseases including, hypertension, diabetes, familial amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, vitiligo, Oral Submucous Fibrosis, Oral Leukoplakia, dengue fever Down's syndrome, osteoarthritis, and ageing. For example- Down syndrome patients display an increased Cu/Zn-SOD/GPx and CAT activity ratio
Figure 6. Extramel® M coating guarantees SOD bioactivity
A n increase in endogenous antioxidant enzymes after exogenous SODs administration has been demonstrated in several published reports. The induction of endogenous antioxidant defence with a decrease in oxidative stress, explain all the effects observed and could be an important element to explain the cause effect relationship.
CONCLUSION
SODs enzymatic pathway is a well researched concept encompassing the entire spectrum from healthy to various disease states
SOD as an exogenous source is an emerging therapeutic option with wide therapeutic applications
The precise role of the free radicals and the need to counter the high oxidative stress to alleviate the diseased states in now better understood, which has the potential to transform the benefits of translational medicine
The quantum and the level of evidence for SOD is accelerating rapidly
Bibliography
1. McCord JM and Fridovich I. Superoxide dismutase: an enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244: 6049–6055, 1969
2. McCord JM, Fridovich I (1969). "Superoxide Dismutase, An Enzymic Function for Erythrocuprein (Hemocuprein)". Journal of Biological Chemistry 244 (22): 6049–6055
3. Fridovich I (1998). "The trail to superoxide dismutase". Protein Science 7: 2688–2690
4. Carillon J, et al; Pharm Res. 2013 Nov;30(11):2718-28
5. McCord JM, Fridovich I; Antioxid Redox Signal. 2013 Sep 11
6. Milesi MA; Nutr J. 2009 Sep 15;8:40
7. Noor R et al; Med Sci Monit, 2002; 8(9): RA210-215
8. McCord JM. The evolution of free radicals and oxidative stress.Am J Med. 2000;108:652–9.
9. Kadrnka F. Results of a multicenter orgotein study in radiation induced and interstitial cystitis. Eur J Rheumatol Inflamm.1981;4(2):237–43
10. Baret A et al; Pharmacokinetics and anti-inflammatory properties in the rat of superoxide dismutase (CuSODs and MnSOD) from various species. Biochem Pharmacol.1984;33(17):2755–60.
*Analysis as of Aug 2013
Research publication
53986
Review articles
2397
Clinical Trials
1060
Randomised Trials
610
Meta analysis
27
12000
10000
8000
6000
4000
2000
0
7790
740
2013 2012 2011 2010 2009
10617
1066 739
7457
6164
566 593
7176
Overall publications
Indian publications
18
16
14
12
10
8
6
4
2
0
5
2013 2012 2011 2010 2009
14 1416 16
SO
D p
lasm
a co
ncen
trat
ion
(U/m
L)
400
360
320
280
240
200Control
+37.5%
®SOD by Bionov
Fig 3: SOD B® Original mechanism of action
In the cell:
EndogenousSODGpxCAT
Oxidative stress and inflammation
Beneficial effects in several situationsNo intestinal absorption
Year
No.
of
publ
icat
ions
Year
No.
of
publ
icat
ions