A paradoxical relationship between Resveratrol and copper (II) with respect to degradation of DNA and RNA

Subramaniam, Siddharth; Vohra, Iqbal; Iyer, Aishwarya; Nair, Naveen Kumar; Mittra, Indraneel

doi:10.12688/f1000research.7202.2

Cited by 11 publications

(11 citation statements)

References 18 publications

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“…Light metals, such as Zn, are not active when combined with resveratrol (unpublished data). The DNA degrading activity of R-Cu is maintained even when the molar concentration of Cu is reduced more than 10,000 fold with respect to that of R [24]. We have also shown that R-Cu is active in vivo, and can degrade the DNA component of cfCh thereby inactivating it even when the molar ratio of R:Cu is kept at 1: − 10 000 [20,25].…”

Section: Preparation Of Cfch Inactivating Agents Their Sources Dosamentioning

confidence: 68%

Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice

et al. 2020

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We have earlier reported that cell-free chromatin (cfCh) particles that are released from dying cells, or those that circulate blood, can readily enter into healthy cells, illegitimately integrate into their genomes and induce dsDNA breaks, apoptosis and intense activation of inflammatory cytokines. We hypothesized that sepsis is caused by cfCh released from dying host cells following microbial infection leading to bystander host cell apoptosis and inflammation which are perpetuated in a vicious cycle with release of more cfCh from dying host cells. To test this hypothesis we used three cfCh inactivating agents namely 1) anti-histone antibody complexed nanoparticles which inactivate cfCh by binding to histones; 2) DNase I which inactivates cfCh by degrading its DNA component, and 3) a novel pro-oxidant combination of Resveratrol and Copper which, like DNase I, inactivates cfCh by degrading its DNA component. Female C57 BL/6 mice, 6-8 weeks old, were administered a single i.p. injection of LPS at a dose of 10 mg/Kg or 20 mg/Kg with or without concurrent treatment with the above cfCh inactivating agents. Administration of cfCh inactivating agents concurrently with LPS resulted in prevention of following pathological parameters: 1) release of cfCh in extra-cellular spaces of brain, lung and heart and in circulation; 2) release of inflammatory cytokines in circulation; 3) activation of DNA damage, apoptosis and inflammation in cells of thymus, spleen and in PBMCs; 4) DNA damage, apoptosis and inflammation in cells of lung, liver, heart, brain, kidney and small intestine; 5) liver and kidney dysfunction and elevation of serum lactate; 6) coagulopathy, fibrinolysis and thrombocytopenia; 7) lethality. We conclude that cfCh that are released from dying host cells in response to bacterial endotoxin represents a global instigator of sepsis. cfCh inactivation may provide a novel approach to management of sepsis in humans.

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Section: Preparation Of Cfch Inactivating Agents Their Sources Dosamentioning

confidence: 68%

Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice

et al. 2020

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“…It has been reported that resveratrol acts as a pro-oxidant in presence of copper 10 which is another widely researched nutraceutical 11 . Resveratrol can reduce copper (II) to copper (I) thereby generating highly unstable free-radicals 10 which can degrade cell-free chromatin 7, 12-14 and can lead to prevention of endotoxin sepsis in mice 7 . The pro-oxidant activity of resveratrol-copper is maintained even when the molar concentration of copper is reduced 10,000 fold 7, 12-14 .…”

Section: Introductionmentioning

confidence: 99%

“…Resveratrol can reduce copper (II) to copper (I) thereby generating highly unstable free-radicals 10 which can degrade cell-free chromatin 7, 12-14 and can lead to prevention of endotoxin sepsis in mice 7 . The pro-oxidant activity of resveratrol-copper is maintained even when the molar concentration of copper is reduced 10,000 fold 7, 12-14 . Doses of resveratrol and copper taken by the patients included in this analysis were nearly 50 times and 2000 times less, respectively, than those currently recommended as health supplements 15, 16 .…”

Section: Introductionmentioning

confidence: 99%

Resveratrol and Copper for treatment of severe COVID-19: an observational study (RESCU 002)

Mittra

Souza

Bhadade

et al. 2020

Preprint

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Background To be universally applicable in treatment of severe COVID-19, novel therapies, especially those with little toxicity and low cost, are urgently needed. We report here the use of one such therapeutic combination involving two commonly used nutraceuticals, namely resveratrol and copper in patients with this disease. This study was prompted by pre-clinical reports that sepsis-related cytokine storm and fatality in mice can be prevented by oral administration of small quantities of resveratrol and copper. Since cytokine storm and sepsis are major causes of death in severe COVID-19, we retrospectively analyzed outcomes of patients with this condition who had received resveratrol and copper. Methods & Findings Our analysis comprised of 230 patients with severe COVID-19 requiring inhaled oxygen who were admitted in a single tertiary care hospital in Mumbai between April 1 and May 13 2020. Thirty of these patients received, in addition to standard care, resveratrol and copper at doses of 5.6 mg and 560 ng, respectively, orally, once every 6 hours, until discharge or death. These doses were based on our pre-clinical studies, and were nearly 50 times and 2000 times less, respectively, than those recommended as health supplements. A multivariable-adjusted analysis was used to model the outcome of death in these patients and evaluate factors associated with this event. A binary logistic regression analysis was used, with age, sex, presence of comorbidities and receipt of resveratrol-copper as covariates. Data were updated as of May 30 2020. The number of deaths in resveratrol-copper and standard care only groups were 7/30 (23.3%, 95% CI 8.1%-38.4%) and 89/200 (44.5%, 95% CI 37.6%-51.3%), respectively. In multivariable analysis, age >50 years [odds ratio (OR) 2.558, 95% CI 1.454-4.302, P=0.0011] and female sex (OR 1.939, 95% CI 1.079-3.482, P=0.0267) were significantly associated, while presence of co-morbidities was not significantly associated (OR 0.713, 95% CI 0.405-1.256, P=0.2421) with death. There was a trend towards reduction in death in patients receiving resveratrol-copper (OR 0.413, 95% CI 0.164-1.039, P= 0.0604). Conclusions We provide preliminary results of a novel approach to the treatment of severe COVID-19 using a combination of small amounts of commonly used nutraceuticals, which is non-toxic and inexpensive, and therefore could be widely accessible globally. The nearly two-fold reduction in mortality with resveratrol-copper observed in our study needs to be confirmed in a randomized controlled trial.

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“…Therefore the analysis of the effect of chemicals and drugs on DNA and proteins, in the presence of iron and copper is very important and interesting for many researchers. In contrast to the drugs such as Resveratrol (26), bleomycin (27), chloramphenicol (28), N-acetylcysteine (29) and procarbazine (30), bezafibrate, even at high concentrations, did not cause any breakage in a supercoiled plasmid in the presence of iron or copper. In contrast, bezafibrate could protect supercoiled pUC19 plasmid DNA against damaging hydroxyl radicals generated by Fenton reactions.…”

Section: Discussionmentioning

confidence: 90%

Effect of Bezafibrate on Deoxyribonucleic Acid in the Presence of Iron and Copper

Arman¹

2019

Turk J Diab Obes

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Amaç: Bezafibrat genellikle hiperlipidemi ve diyabetik hastaları tedavi etmek için kullanılır. Kimyasal ve ilaçların demir ve bakır varlığında DNA üzerindeki etkilerinin analizi, tıbbi araştırmalarda çok önem arz etmektedir. Bu nedenle, bu araştırma bezafibratın DNA üzerindeki etkisini demir ve bakır varlığında analiz etmeyi amaçlamıştır. Gereç ve Yöntemler: Süpersarmal pUC19 plazmid DNA bakır, demir ve bakır artı hidrojen peroksit varlığında Bezafibrat'ın farklı derişimleri (2,6-1,3-0,13-0,013 ve 0,0013 mM) ile muamele edildi, ardından agaroz jeli (% 1) elektroforezinde analiz edildi. Bulgular: Bezafibrat derişimlerinin hiçbirinin FeS04 ve CuCl2 varlığında DNA'yı kıramadığı gözlemlendi. Muamele edilen Süpersarmal DNA'nın band yoğunluğu ve parlaklığı kontrol örnekler ile karşılaştırıldığında hiçbir fark görülmedi. Her ne kadar 0,13-0,013 ve 0,0013 mM Bezafibrat DNA'yı hidrojen radikallerine karşı koruyamasa da, ilacın 2,6-1,3 mM'si derişimine bağlı olarak DNA'yı koruyabildiği gözlemlendi. Sonuç: Bizim Çalışmamız bezafibratın DNA fragmantasyonu üzerindeki zararlı etkisinin dolaylı bir şekilde olabileceğini göstermektedir.

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A paradoxical relationship between Resveratrol and copper (II) with respect to degradation of DNA and RNA

Cited by 11 publications

References 18 publications

Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice

Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice

Resveratrol and Copper for treatment of severe COVID-19: an observational study (RESCU 002)

Effect of Bezafibrate on Deoxyribonucleic Acid in the Presence of Iron and Copper

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