scholarly journals Relocalized redox-active lysosomal iron is an important mediator of oxidative-stress-induced DNA damage

2004 ◽  
Vol 378 (3) ◽  
pp. 1039-1045 ◽  
Author(s):  
Tino KURZ ◽  
Alan LEAKE ◽  
Thomas von ZGLINICKI ◽  
Ulf T. BRUNK
Keyword(s):  
Dna Damage ◽  
Free Radical ◽  
Oxidative Damage ◽  
Nuclear Dna ◽  
Membrane Integrity ◽  
Lysosomal Hydrolases ◽  
Free Radical Biol ◽  
Active Iron ◽  
Vacuolar Compartment ◽  
Redox Active

Oxidative damage to nuclear DNA is known to involve site-specific Fenton-type chemistry catalysed by redox-active iron or copper in the immediate vicinity of DNA. However, the presence of transition metals in the nucleus has not been shown convincingly. Recently, it was proposed that a major part of the cellular pool of loose iron is confined within the acidic vacuolar compartment [Yu, Persson, Eaton and Brunk (2003) Free Radical Biol. Med. 34, 1243–1252; Persson, Yu, Tirosh, Eaton and Brunk (2003) Free Radical Biol. Med. 34, 1295–1305]. Consequently, rupture of secondary lysosomes, as well as subsequent relocation of labile iron to the nucleus, could be an important intermediary step in the generation of oxidative damage to DNA. To test this concept we employed the potent iron chelator DFO (desferrioxamine) conjugated with starch to form an HMM-DFO (high-molecular-mass DFO complex). The HMM-DFO complex will enter cells only via fluid-phase endocytosis and remain within the acidic vacuolar compartment, thereby chelating redox-active iron exclusively inside the endosomal/lysosomal compartment. Both free DFO and HMM-DFO equally protected lysosomal-membrane integrity against H2O2-induced oxidative disruption. More importantly, both forms of DFO prevented H2O2-induced strand breaks in nuclear DNA, including telomeres. To exclude the possibility that lysosomal hydrolases, rather than iron, caused the observed DNA damage, limited lysosomal rupture was induced using the lysosomotropic detergent O-methyl-serine dodecylamine hydrochloride; subsequently, hardly any DNA damage was found. These observations suggest that rapid oxidative damage to cellular DNA is minimal in the absence of redox-active iron and that oxidant-mediated DNA damage, observed in normal cells, is mainly derived from intralysosomal iron translocated to the nucleus after lysosomal rupture.

scholarly journals Role of compartmentalized redox-active iron in hydrogen peroxide-induced DNA damage and apoptosis

2005 ◽  
Vol 387 (3) ◽  
pp. 703-710 ◽  
Author(s):  
Margarita TENOPOULOU ◽  
Paschalis-Thomas DOULIAS ◽  
Alexandra BARBOUTI ◽  
Ulf BRUNK ◽  
Dimitrios GALARIS
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Nuclear Dna ◽  
Fluid Phase ◽  
Jurkat Cells ◽  
Acetoxymethyl Ester ◽  
Lysosomal Membranes ◽  
Active Iron ◽  
Redox Active

Jurkat cells in culture were exposed to oxidative stress in the form of continuously generated hydrogen peroxide, obtained by the addition of glucose oxidase to the medium. This treatment induced a rapid, dose-dependent increase in the ICIP (intracellular calcein-chelatable iron pool). Early destabilization of lysosomal membranes and subsequent nuclear DNA strand breaks were also observed, as evaluated by the Acridine Orange relocation test and the comet assay respectively. Somewhat later, these effects were followed by a lowered mitochondrial membrane potential, with release of cytochrome c and apoptosis-inducing factor. These events were all prevented if cells were pretreated with the potent iron chelator DFO (desferrioxamine) for a period of time (2–3 h) long enough to allow the drug to reach the lysosomal compartment following fluid-phase endocytosis. The hydrophilic calcein, a cleavage product of calcein acetoxymethyl ester following the action of cytosolic esterases, obviously does not penetrate intact lysosomal membranes, thus explaining why ICIP increased dramatically following lysosomal rupture. The rapid decrease in ICIP after addition of DFO to the medium suggests draining of cytosolic iron to the medium, rather than penetration of DFO through the plasma membrane. Most importantly, these observations directly connect oxidative stress and resultant DNA damage with lysosomal rupture and the release of redox-active iron into the cytosol and, apparently, the nucleus.

Increased levels of redox-active iron in follicular fluid: A possible cause of free radical - mediated infertility in β-thalassemia major

1996 ◽  
Vol 174 (3) ◽  
pp. 914-918 ◽  
Author(s):  
Benjamin E. Reubinoff ◽  
Ronit Har-El ◽  
Nahum Kitrossky ◽  
Shevach Friedler ◽  
Ruth Levic ◽  
...  
Keyword(s):  
Free Radical ◽  
Follicular Fluid ◽  
Thalassemia Major ◽  
Active Iron ◽  
Redox Active ◽  
Possible Cause

Lysosomal Redox-Active Iron Is Important for Oxidative Stress-Induced DNA Damage

2004 ◽  
Vol 1019 (1) ◽  
pp. 285-288 ◽  
Author(s):  
TINO KURZ ◽  
ALAN LEAKE ◽  
THOMAS ZGLINICKI ◽  
ULF T. BRUNK
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Active Iron ◽  
Redox Active

scholarly journals 215.Analysis of DNA damage induced by pro-oxidant treatment of mammalian spermatozoa in vitro

2004 ◽  
Vol 16 (9) ◽  
pp. 215
Author(s):  
L. E. Bennetts ◽  
R. J. Aitken
Keyword(s):  
Dna Damage ◽  
Oxidative Damage ◽  
Dna Sequences ◽  
Nuclear Dna ◽  
Quantitative Polymerase Chain Reaction ◽  
Mammalian Species ◽  
Dose Range ◽  
Tammar Wallaby ◽  
Sperm Chromatin ◽  
Sperm Dna

Defects in the male genome produced as a consequence of oxidative insult have been associated with decreased fertility levels, an elevated incidence of childhood cancer and dominant genetic disease in the offspring (1). The objective of this study was to determine the relative susceptibility of sperm DNA of different mammalian species to oxidative injury. We applied a highly sensitive quantitative PCR assay (QPCR) to measure gene-specific DNA damage in nuclear and mitochondrial compartments of spermatozoa treated with H2O2. Human, murine and tammar wallaby (Macropus eugenii) spermatozoa were treated with H2O2 (0–5�mM) over a 1�h period. After DNA purification, DNA damage was assessed in a nuclear and a mitochondrial fragment of DNA by quantitative polymerase chain reaction assay (QPCR). DNA damage was detected as a decrease amplification of the target sequences. In murine and human spermatozoa, mitochondrial DNA exhibited greater sensitivity to oxidative damage than nuclear DNA. Doses ranging from 0.25–5�mM H2O2 induced DNA damage of up to 0.65 lesions/10�kb in the mouse, and 1.42 lesions /10�kb in the human. No significant effect on DNA damage was observed over this dose range in the nuclear DNA fragments investigated in these species. In contrast, tammar wallaby spermatozoa were susceptible to DNA damage at the 5�mM H2O2 dose in both nuclear (0.51 lesions/10�kb) and mitochondrial (0.55 lesions/10�kb) genomes. This study is the first to compare DNA damage in specific DNA sequences in spermatozoa of different mammalian species. Nuclear DNA of the metatherian species, the tammar wallaby, was more susceptible to oxidative damage than that of the eutherian species. A major difference between metatherian and eutherian spermatozoa is that, in general, the former possess protamines that are not stabilised by disulfide cross-linkage. These findings therefore suggest that sperm chromatin packaging affects the susceptibility of sperm DNA to oxidative damage. (1) Sawyer and Aitken (2000) Reprod. Med. Rev. 8, 107–126.

Release of free, redox-active iron in the liver and DNA oxidative damage following phenylhydrazine intoxication

1997 ◽  
Vol 53 (11) ◽  
pp. 1743-1751 ◽  
Author(s):  
Marco Ferrali ◽  
Cinzia Signorini ◽  
Lidia Sugherini ◽  
Alfonso Pompella ◽  
Maura Lodovici ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Dna Oxidative Damage ◽  
Active Iron ◽  
Redox Active

scholarly journals Iron-Mediated Lysosomal Membrane Permeabilization in Ethanol-Induced Hepatic Oxidative Damage and Apoptosis: Protective Effects of Quercetin

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Yanyan Li ◽  
Man Chen ◽  
Yanyan Xu ◽  
Xiao Yu ◽  
Ting Xiong ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Protective Effects ◽  
Lysosomal Membrane Permeabilization ◽  
Active Iron ◽  
Redox Active ◽  
Chronic Ethanol Consumption ◽  
Continuous Decomposition ◽  
Alcoholic Liver Diseases

Iron, in its free ferrous states, can catalyze Fenton reaction to produceOH∙, which is recognized as a crucial role in the pathogenesis of alcoholic liver diseases (ALD). As a result of continuous decomposition of iron-containing compounds, lysosomes contain a pool of redox-active iron. To investigate the important role of intralysosomal iron in alcoholic liver injury and the potential protection of quercetin, male C57BL/6J mice fed by Lieber De Carli diets containing ethanol (30% of total calories) were cotreated by quercetin or deferoxamine (DFO) for 15 weeks and ethanol-incubated mice primary hepatocytes were pretreated with FeCl3, DFO, and bafilomycin A1 at their optimal concentrations and exposure times. Chronic ethanol consumption caused an evident increase in lysosomal redox-active iron accompanying sustained oxidative damage. Iron-mediated ROS could trigger lysosomal membrane permeabilization (LMP) and subsequent mitochondria apoptosis. The hepatotoxicity was attenuated by reducing lysosomal iron while being exacerbated by escalating lysosomal iron. Quercetin substantially alleviated the alcoholic liver oxidative damage and apoptosis by decreasing lysosome iron and ameliorating iron-mediated LMP, which provided a new prospective of the use of quercetin against ALD.

Contribution of redox-active iron and copper to oxidative damage in Alzheimer disease

2004 ◽  
Vol 3 (3) ◽  
pp. 319-326 ◽  
Author(s):  
Rudy J Castellani ◽  
Kazuhiro Honda ◽  
Xiongwei Zhu ◽  
Adam D Cash ◽  
Akihiko Nunomura ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Oxidative Damage ◽  
Active Iron ◽  
Redox Active

scholarly journals Protective role of Clitoria ternatea L. flower extract on methylglyoxal-induced protein glycation and oxidative damage to DNA

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Poramin Chayaratanasin ◽  
Sirichai Adisakwattana ◽  
Thavaree Thilavech
Keyword(s):  
Dna Damage ◽  
Free Radical ◽  
Oxidative Damage ◽  
Protein Oxidation ◽  
Oxidative Dna Damage ◽  
Protein Carbonyl ◽  
Protein Glycation ◽  
Dependent Manner ◽  
Clitoria Ternatea ◽  
Flower Extract

Abstract Background Methylglyoxal (MG) is a highly reactive dicarbonyl precursor for the formation of advanced glycation end products (AGEs) associated with age-related diseases, including diabetes and its complications. Clitoria ternatea L. flower has been reported to possess antioxidant and antiglycating properties. Evidence indicates that the extract of Clitoria ternatea L. flower inhibits fructose-induced protein glycation and oxidative damage to bovine serum albumin (BSA). However, there is no evidence to support the inhibitory effect of CTE against MG-mediated protein glycation and oxidative damage to protein and DNA. Therefore, the aim of the present study was to investigate whether C. ternatea flower extract (CTE) prevents MG-induced protein glycation and oxidative DNA damage. Methods The formation of fluorescent AGEs in BSA was evaluated using spectrofluorometer. The protein carbonyl and thiol group content were used for detecting protein oxidation. DNA strand breakage in a glycation model comprising of MG, lysine and Cu2+ or a free radical generator 2,2′-azobis(2-methylpropionamidine) dihydrochloride (AAPH) systems was investigated using gel electrophoresis. Generation of superoxide anions and hydroxyl radicals in the MG/lysine system was assessed by the cytochrome c reduction assay and thiobarbituric acid reactive substances assay, respectively. High performance liquid chromatography (HPLC) was used to measure the MG-trapping ability. Results In the BSA/MG system, CTE (0.25–1 mg/mL) significantly inhibited the formation of fluorescent AGEs and protein oxidation by reducing protein carbonyl content as well as preventing the protein thiol depletion. The concentration of CTE at 0.125–1 mg/mL prevented oxidative DNA cleavage in MG/lysine and AAPH systems associated with the inhibition of superoxide anion and hydroxyl radical formation. It also directly trapped MG in a concentration-dependent manner, ranging from 15 to 43%. Conclusions The study findings suggest that the direct carbonyl trapping ability and the free radical scavenging activity of CTE are the underlying mechanisms responsible for the prevention of protein glycation and oxidative DNA damage.

Curcumin-containing Silver Nanoparticles prevent carbon tetrachlorideinduced hepatotoxicity in mice

2020 ◽  
Vol 23 ◽  
Author(s):  
Hossam Ebaid ◽  
Mohamed Habila ◽  
Iftekhar Hassan ◽  
Jameel Al-Tamimi ◽  
Mohamed S. Omar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Silver Nanoparticles ◽  
Nuclear Dna ◽  
Liquid Paraffin ◽  
Tail Length ◽  
Hepatic Tissue ◽  
Tissue Destruction ◽  
Group 2 ◽  
The Impact

Background: Hepatotoxicity remains an important clinical challenge. Hepatotoxicity observed in response to toxins and hazardous chemicals may be alleviated by delivery of the curcumin in silver nanoparticles (AgNPs-curcumin). In this study, we examined the impact of AgNPs-curcumin in a mouse model of carbon tetrachloride (CCl4)-induced hepatic injury. Methods: Male C57BL/6 mice were divided into three groups (n=8 per group). Mice in group 1 were treated with vehicle control alone, while mice in Group 2 received a single intraperitoneal injection of 1 ml/kg CCl4 in liquid paraffin (1:1 v/v). Mice in group 3 were treated with 2.5 mg/kg AgNPs-curcumin twice per week for three weeks after the CCl4 challenge. Results: Administration of CCL4 resulted in oxidative dysregulation, including significant reductions in reduced glutathione and concomitant elevations in the level of malondialdehyde (MDA). CCL4 challenge also resulted in elevated levels of serum aspartate transaminase (AST) and alanine transaminase (ALT); these findings were associated with the destruction of hepatic tissues. Treatment with AgNPs-curcumin prevented oxidative imbalance, hepatic dysfunction, and tissue destruction. A comet assay revealed that CCl4 challenge resulted in significant DNA damage as documented by a 70% increase in nuclear DNA tail-length; treatment with AgNPs-curcumin inhibited the CCL4-mediated increase in nuclear DNA tail-length by 34%. Conclusion: Administration of AgNPs-curcumin resulted in significant antioxidant activity in vivo. This agent has the potential to prevent the hepatic tissue destruction and DNA damage that results from direct exposure to CCL4.

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