Testicular toxicity following chronic codeine administration is via oxidative DNA damage and up-regulation of NO and caspase 3

Mapping Intimacies ◽

10.1101/796110 ◽

2019 ◽

Author(s):

RE Akhigbe ◽

A.F Ajayi

Keyword(s):

Dna Damage ◽

Oxidative Dna Damage ◽

Molecular Mechanisms ◽

Testicular Atrophy ◽

Marked Rise ◽

Oxidative Markers ◽

Inflammatory Parameters ◽

Testicular Weight ◽

Androgen Suppression

AbstractBackgroundCodeine, a 3-methylmorphine, and other related opioids have been implicated in androgen suppression, although the associated mechanisms remain unclear.AimTherefore, the objective of the current study was to elucidate the in vivo molecular mechanisms underlying codeine-induced androgen suppression.MethodsThis study made use of Twenty-one healthy male rabbits, distributed into three groups randomly, control and codeine-treated groups. The control had 1ml of normal saline daily p.o. The codeine-treated groups received either 4mg/kg b.w of codeine or 10mg/kg b.w of codeine p.o. for six weeks. Reproductive hormonal profile, testicular weight, enzymes, oxidative and inflammatory parameters, histological examination and apoptosis marker were evaluated to examine the effects of codeine use.Key findingsOral administration of codeine resulted in testicular atrophy and alterations in testicular histomorphology, elevated testicular enzymes, and suppression of circulatory and intra-testicular testosterone. These changes were associated with a marked rise in oxidative markers, including oxidative DNA damage, inflammatory response, and caspase-dependent apoptosis.SignificanceIn conclusion, chronic codeine use resulted in testicular degeneration and testosterone suppression, which may be attributable to nitric oxide-/oxidativestress-mediated caspase-dependent apoptotic testicular cell death.

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Genotoxicity and Gene Expression in the Rat Lung Tissue following Instillation and Inhalation of Different Variants of Amorphous Silica Nanomaterials (aSiO2 NM)

Nanomaterials ◽

10.3390/nano11061502 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1502

Author(s):

Fátima Brandão ◽

Carla Costa ◽

Maria João Bessa ◽

Elise Dumortier ◽

Florence Debacq-Chainiaux ◽

...

Keyword(s):

Gene Expression ◽

Dna Damage ◽

Amorphous Silica ◽

Oxidative Dna Damage ◽

Intratracheal Instillation ◽

Dna Lesions ◽

Lung Cells ◽

Rat Lung ◽

Inhalation Study

Several reports on amorphous silica nanomaterial (aSiO2 NM) toxicity have been questioning their safety. Herein, we investigated the in vivo pulmonary toxicity of four variants of aSiO2 NM: SiO2_15_Unmod, SiO2_15_Amino, SiO2_7 and SiO2_40. We focused on alterations in lung DNA and protein integrity, and gene expression following single intratracheal instillation in rats. Additionally, a short-term inhalation study (STIS) was carried out for SiO2_7, using TiO2_NM105 as a benchmark NM. In the instillation study, a significant but slight increase in oxidative DNA damage in rats exposed to the highest instilled dose (0.36 mg/rat) of SiO2_15_Amino was observed in the recovery (R) group. Exposure to SiO2_7 or SiO2_40 markedly increased oxidative DNA lesions in rat lung cells of the exposure (E) group at every tested dose. This damage seems to be repaired, since no changes compared to controls were observed in the R groups. In STIS, a significant increase in DNA strand breaks of the lung cells exposed to 0.5 mg/m3 of SiO2_7 or 50 mg/m3 of TiO2_NM105 was observed in both groups. The detected gene expression changes suggest that oxidative stress and/or inflammation pathways are likely implicated in the induction of (oxidative) DNA damage. Overall, all tested aSiO2 NM were not associated with marked in vivo toxicity following instillation or STIS. The genotoxicity findings for SiO2_7 from instillation and STIS are concordant; however, changes in STIS animals were more permanent/difficult to revert.

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Abstract 424: Vascular Smooth Muscle Cell Expression of S100a12 in Vivo Induces Enhanced Oxidative Stress & Vascular Remodeling

Circulation ◽

10.1161/circ.118.suppl_18.s_302-d ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Marion Hofmann Bowman ◽

Jeannine Wilk ◽

Gene Kim ◽

Yanmin Zhang ◽

Jalees Rehman ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Smooth Muscle ◽

Vascular Remodeling ◽

Oxidative Dna Damage ◽

Fold Increase ◽

Brdu Incorporation ◽

Elastic Fibers ◽

Nuclear Staining

S100A12 is a small calcium binding protein that is a signal transduction ligand of the receptor for advance glycation endproducts (RAGE). S100A12, like RAGE, is expressed in the vessel wall of atherosclerotic vasculature, particularly in smooth muscle cells (SMC). While RAGE has been extensively implicated in inflammatory states such as atherosclerosis, the role of S100A12 is less clear. We tested the hypothesis that expression of human S100A12 directly exacerbates vascular inflammation. Several lines of Bl6/J transgenic mice (tg) expressing human S100A12 in SMC under control of the SM22a promoter were generated. Primary aortic SMC from tg and wild type (wt) littermates were isolated and analyzed for (i) proliferation using MTS/Formazan Assay and BrdU incorporation, (ii) oxidative stress using using flow cytometry with MitoSOX antibody, oxidative DNA damage using immunofluorescence microscopy with anti-8-oxo-dG antibody, and NF-kB activation measured by EMSA and (iii) cytokine expression measured by IL-6 ELISA. Furthermore, the aortas from tg and wt mice were examined. Results: Tg but not wt SMC expressed S100A12 protein. Tg SMC had a significant 1.9 to 2.7 fold increase in conversion of MTS into Formazan at 24–96 hours likely reflective of increased metabolic activity since BrdU incorporation into DNA was less in tg compared to wt SMC (4% vs 21% positive BrdU nuclei, p <0.05). Tg SMC showed significantly higher levels of mitochondrial generated ROS, nuclear staining for oxidative DNA damage which was not detected in the nuclei of wt SMC’s, and a 2.5 fold increase in NFkB activity. IL-6 production at baseline was higher in tg SMC’s (615 vs 213 pg/ml, p< 0.05) and increased dramatically after LPS treatment (10 ng/ml) in tg SMC’s (2130 vs 415 pg/ml). Histologic examination of the thoracic aorta at 10 weeks of age revealed increased collagen deposition in the aortic media with fragmentation and disarray of elastic fibers. In vivo ultrasound revealed a progressive dilation of the aortic arch from age 10 weeks to 16 weeks of age (1.27 to 1.60 mm, p<0.05) in tg but not in wt littermate mice (1.30 to 1.33 mm, p=0.1). These data reveal the novel finding that targeted expression of human S100A12 in SMC modulates oxidative stress, inflammation and vascular remodeling.

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Vimentin provides the mechanical resilience required for amoeboid migration and protection of the nucleus

10.1101/720946 ◽

2019 ◽

Cited By ~ 4

Author(s):

Luiza Da Cunha Stankevicins ◽

Marta Urbanska ◽

Daniel AD. Flormann ◽

Emmanuel Terriac ◽

Zahra Mostajeran ◽

...

Keyword(s):

Dna Damage ◽

Dendritic Cells ◽

Cell Migration ◽

Molecular Mechanisms ◽

Cell Cortex ◽

Dna Double Strand Breaks ◽

Nuclear Positioning ◽

Mechanical Stiffness

AbstractDendritic cells use amoeboid migration through constricted passages to reach the lymph nodes, and this homing function is crucial for immune responses. Amoeboid migration requires mechanical resilience, however, the underlying molecular mechanisms for this type of migration remain unknown. Because vimentin intermediate filaments (IFs) and microfilaments regulate adhesion-dependent migration in a bidirectional manner, we analyzed if they exert a similar control on amoeboid migration. Vimentin was required for cellular resilience, via a joint interaction between vimentin IFs and F-actin. Reduced actin mobility in the cell cortex of vimentin-reduced cells indicated that vimentin promotes Factin subunit exchange and dynamics. These mechano-dynamic alterations in vimentin-deficient dendritic cells impaired amoeboid migration in confined environments in vitro and blocked lymph node homing in mouse experiments in vivo. Correct nuclear positioning is important in confined amoeboid migration both to minimize resistance and to avoid DNA damage. Vimentin-deficiency also led to DNA double strand breaks in the compressed dendritic cells, pointing to a role of vimentin in nuclear positioning. Together, these observations show that vimentin IF-microfilament interactions provide both the specific mechano-dynamics required for dendritic cell migration and the protection the genome needs in compressed spaces.Summary statementVimentin — in joint action with actin — mediates the mechanical stiffness of cells required for amoeboid cell migration through confined spaces and protects the nucleus from DNA damage.

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Molecular Mechanisms of Zinc Oxide Nanoparticle-Induced Genotoxicity

Materials ◽

10.3390/ma10121427 ◽

2017 ◽

Vol 10 (12) ◽

pp. 1427 ◽

Cited By ~ 25

Author(s):

Agmal Scherzad ◽

Till Meyer ◽

Norbert Kleinsasser ◽

Stephan Hackenberg

Keyword(s):

Dna Damage ◽

Zinc Oxide ◽

Mammalian Cells ◽

Oxidative Dna Damage ◽

Molecular Mechanisms ◽

Consumer Products ◽

Zno Nps ◽

Cytotoxic Effects

Background: Zinc oxide nanoparticles (ZnO NPs) are among the most frequently applied nanomaterials in consumer products. Evidence exists regarding the cytotoxic effects of ZnO NPs in mammalian cells; however, knowledge about the potential genotoxicity of ZnO NPs is rare, and results presented in the current literature are inconsistent. Objectives: The aim of this review is to summarize the existing data regarding the DNA damage that ZnO NPs induce, and focus on the possible molecular mechanisms underlying genotoxic events. Methods: Electronic literature databases were systematically searched for studies that report on the genotoxicity of ZnO NPs. Results: Several methods and different endpoints demonstrate the genotoxic potential of ZnO NPs. Most publications describe in vitro assessments of the oxidative DNA damage triggered by dissoluted Zn2+ ions. Most genotoxicological investigations of ZnO NPs address acute exposure situations. Conclusion: Existing evidence indicates that ZnO NPs possibly have the potential to damage DNA. However, there is a lack of long-term exposure experiments that clarify the intracellular bioaccumulation of ZnO NPs and the possible mechanisms of DNA repair and cell survival.

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In vivo repair of alkylating and oxidative DNA damage in the mitochondrial and nuclear genomes of wild-type and glycosylase-deficient Caenorhabditis elegans

DNA Repair ◽

10.1016/j.dnarep.2012.08.002 ◽

2012 ◽

Vol 11 (11) ◽

pp. 857-863 ◽

Cited By ~ 15

Author(s):

Senyene E. Hunter ◽

Margaret A. Gustafson ◽

Kathleen M. Margillo ◽

Sean A. Lee ◽

Ian T. Ryde ◽

...

Keyword(s):

Dna Damage ◽

Caenorhabditis Elegans ◽

Oxidative Dna Damage ◽

Wild Type ◽

Nuclear Genomes

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Acquired temozolomide resistance in MGMT-deficient glioblastoma cells is associated with regulation of DNA repair by DHC2

Brain ◽

10.1093/brain/awz202 ◽

2019 ◽

Vol 142 (8) ◽

pp. 2352-2366 ◽

Cited By ~ 15

Author(s):

Guo-zhong Yi ◽

Guanglong Huang ◽

Manlan Guo ◽

Xi’an Zhang ◽

Hai Wang ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Methyltransferase ◽

Molecular Mechanisms ◽

Progression Free Survival ◽

Recurrent Glioblastoma ◽

Dna Lesions ◽

Dna Repair Proteins

Abstract The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by O6-methylguanine-DNA methyltransferase (MGMT). However, some MGMT-deficient glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DYNC2H1 (DHC2) was expressed more in MGMT-deficient recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT promotor methylated glioblastoma patients. Furthermore, silencing DHC2, both in vitro and in vivo, enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-deficient glioblastoma. Using a combination of subcellular proteomics and in vitro analyses, we showed that DHC2 was involved in nuclear localization of the DNA repair proteins, namely XPC and CBX5, and knockdown of either XPC or CBX5 resulted in increased temozolomide-induced DNA damage. In summary, we identified the nuclear transportation of DNA repair proteins by DHC2 as a critical regulator of acquired temozolomide resistance in MGMT-deficient glioblastoma. Our study offers novel insights for improving therapeutic management of MGMT-deficient glioblastoma.

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In vivo Oxidative DNA Damage and lipid Peroxidation as a Biomarker of Oxidative Stress in Preterm Low-Birthweight Infants

Journal of Tropical Pediatrics ◽

10.1093/tropej/fmr078 ◽

2011 ◽

Vol 58 (4) ◽

pp. 326-328 ◽

Cited By ~ 22

Author(s):

R. Negi ◽

D. Pande ◽

A. Kumar ◽

R. S. Khanna ◽

H. D. Khanna

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Dna Damage ◽

Oxidative Dna Damage ◽

Low Birthweight

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α-Lipoic acid attenuates transplacental nicotine-induced germ cell and oxidative DNA damage in adult mice

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2015-0151 ◽

2016 ◽

Vol 27 (6) ◽

Cited By ~ 4

Author(s):

Santo K. Anto ◽

Naresh Koyada ◽

Sabbir Khan ◽

Gopabandhu Jena

Keyword(s):

Dna Damage ◽

Germ Cell ◽

Lipoic Acid ◽

Oxidative Dna Damage ◽

Sperm Count ◽

Protective Role ◽

Sperm Head ◽

Smoking During Pregnancy ◽

Adult Mice ◽

Testicular Weight

AbstractBackground:Smoking during pregnancy is associated with numerous fetal and developmental complications and reproductive dysfunctions in the offspring. Nicotine is one of the key chemicals of tobacco responsible for addiction. The present study was aimed to investigate the protective role of α-lipoic acid (ALA) during the transplacental nicotine-induced germ cell and DNA damage in the offspring of Swiss mice.Methods:Pregnant mice were treated with nicotine (20 mg/kg/day) in drinking water from 10 to 20 days of gestation period, and ALA (120 mg/kg/day) was administered orally for the same period. Endpoint of evaluation includes general observations at delivery and throughout the study, litter weight and size, sperm count and sperm head morphology, while structural damages and protein expression were assessed by histology and immunohistochemistry, respectively.Results:Maternal nicotine exposure led to decreased growth rate, litter and testicular weight, testosterone level, 3β-HSD expression and sperm count as well as increased sperm head abnormalities, micronucleus frequency and 8-oxo-dG positive cells, and the effects have been restored by ALA supplementation.Conclusions:The present study clearly demonstrated that ALA ameliorates nicotine-associated oxidative stress, DNA damage and testicular toxicity in the offspring by improving steroidogenesis, spermatogenesis and sperm count.

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