Exploring the binding mechanism of paraquat to DNA by a combination of spectroscopic, cellular uptake, molecular docking and molecular dynamics simulation methods

Jafari, Faranak; Moradi, Sajad; Nowroozi, Amin; Sadrjavadi, Komail; Hosseinzadeh, Leila; Shahlaei, Mohsen

doi:10.1039/c7nj01645j

Cited by 23 publications

(11 citation statements)

References 41 publications

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“…Computational toxicogenomics has furthered our understanding of paraquat toxicosis, but while studies have established correlations between paraquat and neurodegenerative diseases, the etiology of sporadic forms of age-related diseases and the mechanisms involved are still largely unknown. Recently, Jafari et al (2017) (Jafari et al, 2017) showed that paraquat preferentially binds to A-T rich regions of DNA in the minor groove using fluorescent spectra in MCF-7 cells, demonstrating that paraquat can act via genotoxic mechanisms. Jafari et al (2017) used computational approaches to show that the most likely mode of action of paraquat as a DNA binding agent was via an intercalation of 4-pyridyl rings between AT base pairs.…”

Section: Pesticidesmentioning

confidence: 99%

“…Recently, Jafari et al (2017) (Jafari et al, 2017) showed that paraquat preferentially binds to A-T rich regions of DNA in the minor groove using fluorescent spectra in MCF-7 cells, demonstrating that paraquat can act via genotoxic mechanisms. Jafari et al (2017) used computational approaches to show that the most likely mode of action of paraquat as a DNA binding agent was via an intercalation of 4-pyridyl rings between AT base pairs. In addition to direct effects on the DNA, transcriptional machinery and gene expression can me modulated by paraquat.…”

Section: Pesticidesmentioning

confidence: 99%

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Elucidating Conserved Transcriptional Networks Underlying Pesticide Exposure and Parkinson's Disease: A Focus on Chemicals of Epidemiological Relevance

et al. 2019

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While a number of genetic mutations are associated with Parkinson's disease (PD), it is also widely acknowledged that the environment plays a significant role in the etiology of neurodegenerative diseases. Epidemiological evidence suggests that occupational exposure to pesticides (e.g., dieldrin, paraquat, rotenone, maneb, and ziram) is associated with a higher risk of developing PD in susceptible populations. Within dopaminergic neurons, environmental chemicals can have an array of adverse effects resulting in cell death, such as aberrant redox cycling and oxidative damage, mitochondrial dysfunction, unfolded protein response, ubiquitin-proteome system dysfunction, neuroinflammation, and metabolic disruption. More recently, our understanding of how pesticides affect cells of the central nervous system has been strengthened by computational biology. New insight has been gained about transcriptional and proteomic networks, and the metabolic pathways perturbed by pesticides. These networks and cell signaling pathways constitute potential therapeutic targets for intervention to slow or mitigate neurodegenerative diseases. Here we review the epidemiological evidence that supports a role for specific pesticides in the etiology of PD and identify molecular profiles amongst these pesticides that may contribute to the disease. Using the Comparative Toxicogenomics Database, these transcripts were compared to those regulated by the PD-associated neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). While many transcripts are already established as those related to PD (alpha-synuclein, caspases, leucine rich repeat kinase 2, and parkin2), lesser studied targets have emerged as “pesticide/PD-associated transcripts” [e.g., phosphatidylinositol glycan anchor biosynthesis class C (Pigc), allograft inflammatory factor 1 (Aif1), TIMP metallopeptidase inhibitor 3, and DNA damage inducible transcript 4]. We also compared pesticide-regulated genes to a recent meta-analysis of genome-wide association studies in PD which revealed new genetic mutant alleles; the pesticides under review regulated the expression of many of these genes (e.g., ELOVL fatty acid elongase 7, ATPase H+ transporting V0 subunit a1, and bridging integrator 3). The significance is that these proteins may contribute to pesticide-related increases in PD risk. This review collates information on transcriptome responses to PD-associated pesticides to develop a mechanistic framework for quantifying PD risk with exposures.

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Section: Pesticidesmentioning

confidence: 99%

Section: Pesticidesmentioning

confidence: 99%

Elucidating Conserved Transcriptional Networks Underlying Pesticide Exposure and Parkinson's Disease: A Focus on Chemicals of Epidemiological Relevance

et al. 2019

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“…Methyl parathion/albumin interaction has crucial importance in the pesticide’s toxic activity [ 32 ] and the reversible binding to bovine serum albumin can be exploited to enhance a pesticide’s performance [ 33 ]. To the best of our knowledge, only an example of a PQ/DNA binding study is reported in the literature [ 34 ] where PQ is proposed to weakly bind the DNA groove. However, the authors do not seem to consider the superimposition of the spectroscopic signals, which strongly affect and limit the investigation.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic Analysis of the Binding of Paraquat and Diquat Herbicides to Biosubstrates

Macii

Detti

Bloise

et al. 2021

IJERPH

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The study of the interaction of persistent organic pollutants with biosubstrates helps to unravel the pathways for toxicity, however, few mechanistic data are present in the literature for these systems. We analyzed the binding of paraquat (PQ) and diquat (DQ) herbicides to natural calf thymus DNA and a DNA G-quadruplex by spectrophotometric titrations, ethidium bromide exchange tests, viscometry, and melting experiments. The interaction with bovine serum albumin (BSA) protein was studied spectrofluorimetrically at different temperatures. The retention of the targets on positive, negative, and neutral micellar aggregates and liposomes was analyzed by ultrafiltration experiments. Despite some favorable features, PQ and DQ only externally bind natural DNA and do not interact with DNA oligonucleotides. Both herbicides bind bovine serum albumin (BSA). PQ binds BSA mainly according to an electrostatics-driven process. However, ultrafiltration data also show that some hydrophobic contribution participates in the features of these systems. The practical problems related to unfavorable spectroscopic signals and inner filter effects are also discussed. Overall, both herbicides show a low affinity for nucleic acids and weak penetration into liposomes; in addition, the equilibrium constants values found for BSA system suggest optimal conditions for transport in the body.

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“…Investigating the interactions between exogenous ligands and biomacromolecules such as DNA and proteins is very important, hence these interactions can interfere with the homeostasis in the function of macromolecules ( 7 ). In this regard, in addition to experimental spectroscopic techniques ( 8 ), the computational molecular modeling approaches are also employed ( 9 10 ). Recently, some studies on the interaction between different ligands and pepsin have been reported.…”

Section: Introductionmentioning

confidence: 99%

Interactions and effects of food additive dye Allura red on pepsin structure and protease activity; experimental and computational supports

et al. 2021

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Background and purpose: Today, color additives such as Allura red (AR) are widely used in different kinds of food products. Pepsin is a globular protein that is secreted as a digestive protease from the main cells in the stomach. Because of the important role of pepsin in protein digestion and because of its importance in digestive diseases the study of the interactions of pepsin with chemical food additives is important. Experimental approach: In this study, the interactions between AR and pepsin were investigated by different computational and experimental approaches such as ultraviolet and fluorescence spectroscopy along with computational molecular modeling. Findings/Results: The experimental results of fluorescence indicated that AR can strongly quench the fluorescence of pepsin through a static quenching. Thermodynamic analysis of the binding phenomena suggests that van der Waals forces and hydrogen bonding played a major role in the complex formation. The results of synchronous fluorescence spectra and furrier transformed infra-red (FTIR) experiments showed that there are no significant structural changes in the protein conformation. Also, examined pepsin protease activity revealed that the activity of pepsin was increased upon ligand binding. In agreement with the experimental results, the computational results showed that hydrogen bonding and van der Waals interactions occurred between AR and binding sites. Conclusion and implications: From the pharmaceutical point of view, this interaction can help us to get a deeper understanding of the effect of this synthetic dye on food digestion.

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Exploring the binding mechanism of paraquat to DNA by a combination of spectroscopic, cellular uptake, molecular docking and molecular dynamics simulation methods

Abstract: The possibility that paraquat may exert its toxicity also by interaction with DNA is studied using a combination of different computational and experimental techniques.

Cited by 23 publications

References 41 publications

Elucidating Conserved Transcriptional Networks Underlying Pesticide Exposure and Parkinson's Disease: A Focus on Chemicals of Epidemiological Relevance

Elucidating Conserved Transcriptional Networks Underlying Pesticide Exposure and Parkinson's Disease: A Focus on Chemicals of Epidemiological Relevance

Spectroscopic Analysis of the Binding of Paraquat and Diquat Herbicides to Biosubstrates

Interactions and effects of food additive dye Allura red on pepsin structure and protease activity; experimental and computational supports

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