The Role of Surface Functionality on Acute Cytotoxicity, ROS Generation and DNA Damage by Cationic Gold Nanoparticles

Apiwat Chompoosor; Krishnendu Saha; Partha S. Ghosh; Dylan J. Macarthy; Oscar R. Miranda; Zheng-Jiang Zhu; Kathleen F. Arcaro; Vincent M. Rotello

doi:10.1002/smll.201000463

EPAC1 Inhibition Protects the Heart from Doxorubicin-Induced Toxicity

10.1101/2021.06.16.448655 ◽

2021 ◽

Author(s):

Marianne Mazevet ◽

Maxance Ribeiro ◽

Anissa Belhadef ◽

Delphine Dayde ◽

Anna Llach ◽

...

Keyword(s):

Dna Damage ◽

Cell Death ◽

Membrane Potential ◽

Dilated Cardiomyopathy ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Membrane ◽

Dna Intercalation ◽

Antitumoral Activity ◽

Ros Generation

Rationale: The widely used chemotherapeutic agent Doxorubicin (Dox) induces cardiotoxicity leading to dilated cardiomyopathy and heart failure. This cardiotoxicity has been related to ROS generation, DNA intercalation, bioenergetic distress and cell death. However, alternative mechanisms are emerging, focusing on signaling pathways. Objective: We investigated the role of Exchange Protein directly Activated by cAMP (EPAC), key factor in cAMP signaling, in Dox-induced cardiotoxicity. Methods and Results: Dox was administrated in vivo (10 +/- 2 mg/kg, i.v.; with analysis at 2, 6 and 15 weeks post injection) in WT and EPAC1 KO C57BL6 mice. Cardiac function was analyzed by echocardiography and intracellular Ca2+ homeostasis by confocal microscopy in isolated ventricular cardiomyocytes. 15 weeks post-injections, Dox-treated WT mice, developed a dilated cardiomyopathy with decreased ejection fraction, increased telediastolic volume and impaired Ca2+ homeostasis, which were totally prevented in the EPAC1 KO mice. The underlying mechanisms were investigated in neonatal and adult rat cardiac myocytes under Dox treatment (1-10 uM). Flow cytometry, Western blot, BRET sensor assay, and RT-qPCR analysis showed that Dox induced DNA damage and cardiomyocyte cell death with apoptotic features rather than necrosis, including Ca2+-CaMKKβ-dependent opening of the Mitochondrial Permeability Transition Pore, dissipation of the Mitochondrial membrane potential, caspase activation, cell size reduction, and DNA fragmentation. Dox also led to an increase in both cAMP concentration and EPAC1 protein level and activity. The pharmacological inhibition of EPAC1 (CE3F4) but not EPAC2 alleviated the whole Dox-induced pattern of alterations including DNA damage, Mitochondrial membrane potential, apoptosis, mitochondrial biogenesis, dynamic, and fission/fusion balance, and respiratory chain activity, suggesting a crucial role of EPAC1 in these processes. Importantly, while preserving cardiomyocyte integrity, EPAC1 inhibition potentiated Dox-induced cell death in several human cancer cell lines. Conclusion: Thus, EPAC1 inhibition could be a valuable therapeutic strategy to limit Dox-induced cardiomyopathy without interfering with its antitumoral activity.

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The Role of Temperature and Lipid Charge on Intake/Uptake of Cationic Gold Nanoparticles into Lipid Bilayers

Small ◽

10.1002/smll.201805046 ◽

2019 ◽

pp. 1805046 ◽

Cited By ~ 12

Author(s):

Fabio Lolicato ◽

Loic Joly ◽

Hector Martinez‐Seara ◽

Giovanna Fragneto ◽

Ernesto Scoppola ◽

...

Keyword(s):

Gold Nanoparticles ◽

Lipid Bilayers ◽

Cationic Gold

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Genotoxicity and Cytotoxicity of Gold Nanoparticles In Vitro: Role of Surface Functionalization and Particle Size

Nanomaterials ◽

10.3390/nano10020271 ◽

2020 ◽

Vol 10 (2) ◽

pp. 271 ◽

Cited By ~ 5

Author(s):

Gerard Vales ◽

Satu Suhonen ◽

Kirsi M. Siivola ◽

Kai M. Savolainen ◽

Julia Catalán ◽

...

Keyword(s):

Dna Damage ◽

Gold Nanoparticles ◽

Comet Assay ◽

Positive Result ◽

Cellular Uptake ◽

Micronucleus Assay ◽

Gold Nps ◽

20 Nm

Several studies suggested that gold nanoparticles (NPs) could be genotoxic in vitro and in vivo. However, gold NPs have currently produced present a wide range of sizes and functionalization, which could affect their interactions with the environment or with biological structures and, thus, modify their toxic effects. In this study, we investigated the role of surface charge in determining the genotoxic potential of gold NPs, as measured by the induction of DNA damage (comet assay) and chromosomal damage (micronucleus assay) in human bronchial epithelial BEAS-2B cells. The cellular uptake of gold NPs was assessed by hyperspectral imaging. Two core sizes (~5 nm and ~20 nm) and three functionalizations representing negative (carboxylate), positive (ammonium), and neutral (poly(ethylene glycol); (PEG)ylated) surface charges were examined. Cationic ammonium gold NPs were clearly more cytotoxic than their anionic and neutral counterparts, but genotoxicity was not simply dependent on functionalization or size, since DNA damage was induced by 20-nm ammonium and PEGylated gold NPs, while micronucleus induction was increased by 5-nm ammonium and 20-nm PEGylated gold NPs. The 5-nm carboxylated gold NPs were not genotoxic, and evidence on the genotoxicity of the 20-nm carboxylated gold NPs was restricted to a positive result at the lowest dose in the micronucleus assay. When interpreting the results, it has to be taken into account that cytotoxicity limited the doses available for the ammonium-functionalized gold NPs and that gold NPs have earlier been described to interfere with the comet assay procedure, possibly resulting in a false positive result. In conclusion, our findings show that the cellular uptake and cytotoxicity of gold NPs are clearly enhanced by positive surface charge, but neither functionalization nor size can single-handedly account for the genotoxic effects of the gold NPs.

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Nanoparticle-Membrane Interactions: The Role of Temperature and Lipid Charge on Intake/Uptake of Cationic Gold Nanoparticles into Lipid Bilayers (Small 23/2019)

Small ◽

10.1002/smll.201970124 ◽

2019 ◽

Vol 15 (23) ◽

pp. 1970124 ◽

Cited By ~ 1

Author(s):

Fabio Lolicato ◽

Loic Joly ◽

Hector Martinez-Seara ◽

Giovanna Fragneto ◽

Ernesto Scoppola ◽

...

Keyword(s):

Gold Nanoparticles ◽

Lipid Bilayers ◽

Membrane Interactions ◽

Cationic Gold

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The Protective Effect of Autophagy on DNA Damage in Mouse Spermatocyte-Derived Cells Exposed to 1800 MHz Radiofrequency Electromagnetic Fields

Cellular Physiology and Biochemistry ◽

10.1159/000491660 ◽

2018 ◽

Vol 48 (1) ◽

pp. 29-41 ◽

Cited By ~ 4

Author(s):

Renyan Li ◽

Mingfu Ma ◽

Lianbing Li ◽

Letian Zhao ◽

Tianfeng Zhang ◽

...

Keyword(s):

Dna Damage ◽

Western Blot ◽

Signaling Pathway ◽

Electromagnetic Fields ◽

Ros Generation ◽

Molecular Signaling ◽

Radiofrequency Electromagnetic Fields ◽

Transmission Electron ◽

Amp Activated Protein Kinase

Background/Aims: The effects of exposure to radiofrequency electromagnetic fields (RF-EMFs) on the male reproductive system have raised public concern and studies have shown that exposure to RF-EMFs can induce DNA damage and autophagy. However, there are no related reports on the role of autophagy in DNA damage in spermatocytes, especially after exposure to RF-EMFs. The aim of the present study was to determine the mechanism and role of autophagy induced by RF-EMFs in spermatozoa cells. Methods: Mouse spermatocyte-derived cells (GC-2) were exposed to RF-EMFs 4 W/kg for 24 h. The level of reactive oxygen species (ROS) was determined by ROS assay kit. Comet assay was utilized to detect DNA damage. Autophagy was detected by three indicators: LC3II/LC3I, autophagic vacuoles, and GFP-LC3 dots, which were measured by western blot, transmission electron microscopy, and transfection with GFP-LC3, respectively. The expression of the molecular signaling pathway AMP-activated protein kinase (AMPK)/mTOR was determined by western blot. Results: The results showed that RF-EMFs induced autophagy and DNA damage in GC-2 cells via ROS generation, and the autophagy signaling pathway AMPK/mTOR was activated by ROS generation. Furthermore, following inhibition of autophagy by knockdown of AMPKα, increased DNA damage was observed in GC-2 cells following RF-EMFs exposure, and overexpression of AMPKα promoted autophagy and attenuated DNA damage. Conclusions: These findings demonstrated that the autophagy which was induced by RF-EMFs via the AMPK/mTOR signaling pathway could prevent DNA damage in spermatozoa cells.

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Curcumin protects DNA damage in a chronically arsenic-exposed population of West Bengal

Human & Experimental Toxicology ◽

10.1177/0960327109359020 ◽

2010 ◽

Vol 29 (6) ◽

pp. 513-524 ◽

Cited By ~ 59

Author(s):

Jaydip Biswas ◽

Dona Sinha ◽

Sutapa Mukherjee ◽

Soumi Roy ◽

Maqsood Siddiqi ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Dna Damage ◽

West Bengal ◽

Health Hazard ◽

Human Lymphocytes ◽

Protein Carbonyl ◽

Ros Generation ◽

Exposed Population

Groundwater arsenic contamination has been a health hazard for West Bengal, India. Oxidative stress to DNA is recognized as an underlying mechanism of arsenic carcinogenicity. A phytochemical, curcumin, from turmeric appears to be potent antioxidant and antimutagenic agent. DNA damage prevention with curcumin could be an effective strategy to combat arsenic toxicity. This field trial in Chakdah block of West Bengal evaluated the role of curcumin against the genotoxic effects of arsenic. DNA damage in human lymphocytes was assessed by comet assay and fluorescence-activated DNA unwinding assay. Curcumin was analyzed in blood by high performance liquid chromatography (HPLC). Arsenic induced oxidative stress and elucidation of the antagonistic role of curcumin was done by observation on reactive oxygen species (ROS) generation, lipid peroxidation and protein carbonyl. Antioxidant enzymes like catalase, superoxide dismutase, glutathione reductase, glutathioneS-transferase, glutathione peroxidase and non-enzymatic glutathione were also analyzed. The blood samples of the endemic regions showed severe DNA damage with increased levels of ROS and lipid peroxidation. The antioxidants were found with depleted activity. Three months curcumin intervention reduced the DNA damage, retarded ROS generation and lipid peroxidation and raised the level of antioxidant activity. Thus curcumin may have some protective role against the DNA damage caused by arsenic.

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