-
1.
New formaldehyde-free adhesives for wood manufacturing: In vitro evaluation of potential toxicity of fine dust collected during wood sawing using a new experimental model to simulate occupational inhalation exposure.
Cavallo, D, Fresegna, AM, Ciervo, A, Ursini, CL, Maiello, R, Del Frate, V, Ferrante, R, Mabilia, R, Pizzo, B, Grossi, B, et al
Toxicology. 2022;:153085
Abstract
Formaldehyde mainly emitted from wood adhesives, finishing materials, paint for furniture represents, together with wood dust, a potential carcinogenic risk for wood workers. Aims of this multidisciplinary study are to investigate the possibility of replacing urea-formaldehyde (UF) adhesives in the wood industry with organic and/or inorganic-based glues to obtain a final less toxic product and to evaluate the potential toxicity of wood glued with such new adhesives. For this purpose we selected poplar wood to test an organic new adhesive HBP (Hemp Based Protein), a mixture of hemp flour and cross-linker PAE (polyaminoamide epichlorohydrin), and spruce wood to test an inorganic adhesive geopolymer K-PSS (potassium-polysiloxosialate) plus polyvinyl acetate. For the poplar wood, we also used a commercial panel glued with UF for comparison. We reproduced occupational inhalation exposure during sawing activities of mentioned woods, collected and characterized the wood dusts emitted during sawing and evaluated in vitro their potential cyto-genotoxic and inflammatory effects. We used human lung cells (A549) exposed for 24 h to 20 and 100 μg/mL of collected PM2.5 wood dust. We found that both the new adhesives wood dusts induced a slightly higher apoptotic effect than untreated natural wood dusts particularly in spruce wood. Only geopolymer K-PSS wood dust induced membrane damage at the highest concentration and direct and oxidative DNA damage that could be explained by the different chemical composition and the lower particle sizes in respect to organic HBP adhesive wood dust. We found slight induction of IL-6 release, not influenced by K-PSS treatment, at the highest concentration in spruce wood. For poplar wood, IL-6 and IL-8 induction was found particularly for untreated and UF-treated wood at the highest concentration, where hemp adhesive treatment induced lower inflammation while at lower concentration similar slight cytokine induction was found for all tested wood dusts. This preliminary study shows that natural adhesives used to replace UF adhesives represent an interesting alternative, particularly the organic hemp-based adhesive showing very low toxicity.
-
2.
Endosomal trafficking and DNA damage checkpoint kinases dictate survival to replication stress by regulating amino acid uptake and protein synthesis.
Ajazi, A, Bruhn, C, Shubassi, G, Lucca, C, Ferrari, E, Cattaneo, A, Bachi, A, Manfrini, N, Biffo, S, Martini, E, et al
Developmental cell. 2021;(18):2607-2622.e6
Abstract
Atg6Beclin 1 mediates autophagy and endosomal trafficking. We investigated how Atg6 influences replication stress. Combining genetic, genomic, metabolomic, and proteomic approaches, we found that the Vps34-Vps15-Atg6Beclin 1-Vps38UVRAG-phosphatydilinositol-3 phosphate (PtdIns(3)P) axis sensitizes cells to replication stress by favoring the degradation of plasma membrane amino acid (AA) transporters via endosomal trafficking and ESCRT proteins, while the PtdIns(3)P phosphatases Ymr1 and Inp53 promote survival to replication stress by reversing this process. An impaired AA uptake triggers activation of Gcn2, which attenuates protein synthesis by phosphorylating eIF2α. Mec1Atr-Rad53Chk1/Chk2 activation during replication stress further hinders translation efficiency by counteracting eIF2α dephosphorylation through Glc7PP1. AA shortage-induced hyperphosphorylation of eIF2α inhibits the synthesis of 65 stress response proteins, thus resulting in cell sensitization to replication stress, while TORC1 promotes cell survival. Our findings reveal an integrated network mediated by endosomal trafficking, translational control pathways, and checkpoint kinases linking AA availability to the response to replication stress.
-
3.
An insight into understanding the coupling between homologous recombination mediated DNA repair and chromatin remodeling mechanisms in plant genome: an update.
Banerjee, S, Roy, S
Cell cycle (Georgetown, Tex.). 2021;(18):1760-1784
-
-
Free full text
-
Abstract
Plants, with their obligatory immobility, are vastly exposed to a wide range of environmental agents and also various endogenous processes, which frequently cause damage to DNA and impose genotoxic stress. These factors subsequently increase genome instability, thus affecting plant growth and productivity. Therefore, to survive under frequent and extreme environmental stress conditions, plants have developed highly efficient and powerful defense mechanisms to repair the damages in the genome for maintaining genome stability. Such multi-dimensional signaling response, activated in presence of damage in the DNA, is collectively known as DNA Damage Response (DDR). DDR plays a crucial role in the remarkably efficient detection, signaling, and repair of damages in the genome for maintaining plant genome stability and normal growth responses. Like other highly advanced eukaryotic systems, chromatin dynamics play a key role in regulating cell cycle progression in plants through remarkable orchestration of environmental and developmental signals. The regulation of chromatin architecture and nucleosomal organization in DDR is mainly modulated by the ATP dependent chromatin remodelers (ACRs), chromatin modifiers, and histone chaperones. ACRs are mainly responsible for transcriptional regulation of several homologous recombination (HR) repair genes in plants under genotoxic stress. The HR-based repair of DNA damage has been considered as the most error-free mechanism of repair and represents one of the essential sources of genetic diversity and new allelic combinations in plants. The initiation of DDR signaling and DNA damage repair pathway requires recruitment of epigenetic modifiers for remodeling of the damaged chromatin while accumulating evidence has shown that chromatin remodeling and DDR share part of the similar signaling pathway through the altered epigenetic status of the associated chromatin region. In this review, we have integrated information to provide an overview on the association between chromatin remodeling mediated regulation of chromatin structure stability and DDR signaling in plants, with emphasis on the scope of the utilization of the available knowledge for the improvement of plant health and productivity.Abbreviation: ADH: Alcohol Dehydrogenase; AGO2: Argonaute 2; ARP: Actin-Related Protein; ASF:1- Anti-Silencing Function-1; ATM: Ataxia Telangiectasia Mutated; ATR: ATM and Rad3- Related; AtSWI3c: Arabidopsis thaliana Switch 3c; ATXR5: Arabidopsis Trithorax-Related5; ATXR6: Arabidopsis Trithorax-Related6; BER: Base Excision Repair; BRCA1: Breast Cancer Associated 1; BRM: BRAHMA; BRU1: BRUSHY1; CAF:1- Chromatin Assembly Factor-1; CHD: Chromodomain Helicase DNA; CHR5: Chromatin Remodeling Protein 5; CHR11/17: Chromatin Remodeling Protein 11/17; CIPK11- CBL- Interacting Protein Kinase 11; CLF: Curly Leaf; CMT3: Chromomethylase 3; COR15A: Cold Regulated 15A; COR47: Cold Regulated 47; CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats; DDM1: Decreased DNA Methylation1; DRR: DNA Repair and Recombination; DSBs: Double-Strand Breaks; DDR: DNA Damage Response; EXO1: Exonuclease 1; FAS1/2: Fasciata1/2; FACT Facilitates Chromatin Transcription; FT: Flowering Locus T; GMI1: Gamma-Irradiation And Mitomycin C Induced 1; HAC1: Histone Acetyltransferase of the CBP Family 1; HAM1: Histone Acetyltransferase of the MYST Family 1; HAM2: Histone Acetyltransferase of the MYST Family 2; HAF1: Histone Acetyltransferase of the TAF Family 1; HAT: Histone Acetyl Transferase; HDA1: Histone Deacetylase 1; HDA6: Histone Deacetylase 6; HIRA Histone Regulatory Homolog A; HR- Homologous recombination; HAS: Helicase SANT Associated; HSS: HAND-SLANT-SLIDE; ICE1: Inducer of CBF Expression 1; INO80: Inositol Requiring Mutant 80; ISW1: Imitation Switch 1; KIN1/2: Kinase 1 /2; MET1: Methyltransferase 1; MET2: Methyltransferase 2; MINU MINUSCULE; MMS: Methyl Methane Sulfonate; MMS21: Methyl Methane Sulfonate Sensitivity 21; MRN: MRE11, RAD50 and NBS1; MSI1: Multicopy Suppressor Of Ira1; NAP1: Nucleosome Assembly Protein 1; NRP1/NRP2: NAP1-Related Protein; NER: Nucleotide Excision Repair; NHEJ Non-Homologous End Joining; PARP1: Poly-ADP Ribose Polymerase; PIE1: Photoperiod Independent Early Flowering 1; PIKK Phosphoinositide 3-Kinase-Like Kinase; PKL: PICKLE; PKR1/2: PICKLE Related 1/2; RAD: Radiation Sensitive Mutant; RD22: Responsive To Desiccation 22; RD29A: Responsive To Desiccation 29A; ROS: Reactive Oxygen Species; ROS1: Repressor of Silencing 1; RPA1E: Replication Protein A 1E; SANT Swi3, Ada2, N-Cor and TFIIIB; SEP3: SEPALLATA3; SCC3: Sister Chromatid Cohesion Protein 3; SMC1: Structural Maintenance of Chromosomes Protein 1; SMC3: Structural Maintenance of Chromosomes Protein 3; SOG1: Suppressor of Gamma Response 1; SWC6: SWR1 Complex Subunit 6; SWR1: SWI2/SNF2-Related 1; SYD: SPLAYED; SMC5: Structural Maintenance of Chromosome 5; SWI/SNF: Switch/Sucrose Non-Fermentable; TALENs: Transcription Activators Like Effector Nucleases; TRRAP Transformation/Transactivation Domain-Associated Protein; ZFNs: Zinc Finger Nucleases.
-
4.
Investigating the Effect of Fresh Frozen Plasma and Albumin on DNA Damage and Oxidative Stress Biomarkers in Poisoning Cases by Organophosphates.
Afzali, S, Karami, M, Kheyripour, N, Ranjbar, A
Drug research. 2021;(1):10-16
Abstract
The efficacy of albumin and fresh frozen plasma (FFP) and their effects on biomarkers of oxidative stress has been evaluated. In a randomized clinical control trial, 33 poisoned patients by Organophosphate (OP) were enrolled in the research and divided into three groups. The first group underwent conventional treatments by atropine and pralidoxime (control group); the second and third groups, in addition to traditional treatments, received albumin and FFP. Cholinesterase (ChE) enzyme activity, total antioxidant capacity (TAC), serum thiol groups (TTG), malonyl aldehyde (MDA) and DNA damage were measured in all treatment and control groups. Patients were matched in terms of demographic characteristics at the beginning of the study. ChE activity was increased in all three groups during treatment, which was more noticeable in the FFP group and was statistically significant in both albumin and FFP group compared to the control group (p<0.05). TAC increased, and TTG decreased in FFP and albumin groups compared to the control group; no significant difference was observed. MDA decreased in albumin and FFP and was significantly different in the FFP group compared to the control group (p<0.05). The amount of DNA damage in FFP and albumin groups decreased, and there was a significant difference compared to the control group (p<0.05). According to the results of this study, due to the decrease of oxidative damage parameters and the increase of antioxidant parameters in albumin and specially FFP groups, FFP may be considered as an adjunctive treatment for OP poisoning.
-
5.
The impact of oxidative stress damage induced by the environmental stressors on COVID-19.
Bakadia, BM, Boni, BOO, Ahmed, AAQ, Yang, G
Life sciences. 2021;:118653
-
-
Free full text
-
Abstract
The ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a substantial stressor that is greatly impacting environmental sustainability. Besides, the different pre-existing environmental stressors and coronavirus disease-2019 (COVID-19)-related stressors are further worsening the effects of the viral disease by inducing the generation of oxidative stress. The generated oxidative stress results in nucleic acid damage associated with viral mutations, that could potentially reduce the effectiveness of COVID-19 management, including the vaccine approach. The current review is aimed to overview the impact of the oxidative stress damage induced by various environmental stressors on COVID-19. The available data regarding the COVID-19-related stressors and the effects of oxidative stress damage induced by the chronic stress, exposure to free radicals, and malnutrition are also analyzed to showcase the promising options, which could be investigated further for sustainable control of the pandemic.
-
6.
Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.
Simonetti, G, Mengucci, C, Padella, A, Fonzi, E, Picone, G, Delpino, C, Nanni, J, De Tommaso, R, Franchini, E, Papayannidis, C, et al
Leukemia. 2021;(10):2813-2826
-
-
Free full text
-
Abstract
Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.
-
7.
Cellular pathologies and genotoxic effects arising secondary to heavy metal exposure: A review.
Kocadal, K, Alkas, FB, Battal, D, Saygi, S
Human & experimental toxicology. 2020;(1):3-13
Abstract
Environmental pollution is significant and oftentimes hazardous in the areas, where mining, foundries and smelters and other metallurgical operations are located. Systematic research on the chronic effects of metals started during the past century; nevertheless, it is evident that even today, there are large gaps in knowledge regarding the assessment of the health effects caused by environmental and occupational exposures to these metals. Heavy metals induce the production of reactive oxygen species (ROS) causing oxidative stress, make several repair-inhibiting cellular changes and alter the DNA repair processes. They favour the 'false' repairing of double-strand breaks (DSBs), propagate DNA mutations and induce carcinogenesis. A detailed literature search was performed using the MedLine/PubMed database. Depending on the mechanism of action, arsenicals can act as genotoxins, non-genotoxic agents and carcinogens. Cadmium can bind to proteins, reduce DNA repair, activate protein degradation, up-regulate cytokines and proto-oncogenes (c-fos, c-jun and c-myc), induce the expression of metallothionein, haeme-oxygenases, glutathione transferases, heat-shock proteins, acute-phase reactants and DNA polymerase β at lower concentrations. Inorganic mercury damages oxidative phosphorylation and electron transport pathways at the ubiquinone-cytochrome b5 locus and thus induces ROS production. Abandoned mining areas generate environmentally persistent waste. These specific sites urgently require maximally efficient and cheap remediation. This bears the need for methodologies employing green and sustainable remediation. Phytoremediation is important in that it is a prevalent in situ remediation technique. Its advantages include the use of solar energy, cost-effectiveness, easy operation, reduction in secondary contaminants, the use of biomass for biofuel production and low-cost adsorbents.
-
8.
Use of antioxidant could ameliorate the negative impact of etoposide on human sperm DNA during chemotherapy.
Rabaça, A, Ferreira, C, Bernardino, R, Alves, M, Oliveira, P, Viana, P, Barros, A, Sousa, M, Sá, R
Reproductive biomedicine online. 2020;(6):856-866
Abstract
RESEARCH QUESTION A previous study showed that N-acetylcysteine (NAC), used after in-vitro exposure to the gonadotoxic chemotherapeutic drug etoposide, has the ability to decrease DNA damage in human spermatozoa; however, it showed no benefit when used before exposure. This study aimed to evaluate the impact of the NAC on the preservation of sperm quality during in-vitro exposure to etoposide. DESIGN Twenty semen samples were submitted to four experimental conditions: control, NAC-only incubation, etoposide-only incubation, and concomitant etoposide and NAC incubation. After in-vitro incubation, semen parameters, sperm chromatin condensation, sperm DNA fragmentation, sperm oxidative stress and sperm metabolism were used to evaluate the role of NAC in protecting human spermatozoa from etoposide. RESULTS Etoposide did not affect semen parameters, nor did it cause sperm oxidative damage or alterations in glycolytic profile. However, it induced chromatin decondensation and DNA fragmentation, which were fully prevented by NAC. CONCLUSIONS NAC was able to protect sperm DNA integrity during etoposide treatment in vitro, suggesting that NAC may be useful as an adjuvant agent in preserving male fertility during chemotherapy treatments.
-
9.
Sodium butyrate induces genotoxic stress in function of photoperiod variations and differentially modulates the expression of genes involved in chromatin modification and DNA repair in Petunia hybrida seedlings.
Pagano, A, L'Andolina, C, Sabatini, ME, de Sousa Araújo, S, Balestrazzi, A, Macovei, A
Planta. 2020;(5):102
Abstract
Sodium butyrate applied to Petunia hybrida seeds under a long-day photoperiod has a negative impact (reduced seedling length, decreased production of photosynthetic pigments, and accumulation of DNA damage) on early seedling development, whereas its administration under dark/light conditions (complete dark conditions for 5 days followed by exposure to long-day photoperiod for 5 days) bypasses some of the adverse effects. Genotoxic stress impairs plant development. To circumvent DNA damage, plants activate DNA repair pathways in concert with chromatin dynamics. These are essential during seed germination and seedling establishment, and may be influenced by photoperiod variations. To assess this interplay, an experimental design was developed in Petunia hybrida, a relevant horticultural crop and model species. Seeds were treated with different doses of sodium butyrate (NaB, 1 mM and 5 mM) as a stress agent applied under different light/dark conditions throughout a time period of 10 days. Phenotypic (germination percentage and speed, seedling length, and photosynthetic pigments) and molecular (DNA damage and gene expression profiles) analyses were performed to monitor the response to the imposed conditions. Seed germination was not affected by the treatments. Seedling development was hampered by increasing NaB concentrations applied under a long-day photoperiod (L) as reflected by the decreased seedling length accompanied by increased DNA damage. When seedlings were grown under dark conditions for 5 days and then exposed to long-day photoperiod for the remaining 5 days (D/L), the damaging effects of NaB were circumvented. NaB exposure under L conditions resulted in enhanced expression of HAT/HDAC (HISTONE ACETYLTRANSFERASES/HISTONE DEACTEYLASES) genes along with repression of genes involved in DNA repair. Differently, under D/L conditions, the expression of DNA repair genes was increased by NaB treatment and this was associated with lower levels of DNA damage. The observed DNA damage and gene expression profiles suggest the involvement of chromatin modification- and DNA repair-associated pathways in response to NaB and dark/light exposure during seedling development.
-
10.
Prevention by L-carnitine of DNA damage induced by 3-hydroxy-3-methylglutaric and 3-methylglutaric acids and experimental evidence of lipid and DNA damage in patients with 3-hydroxy-3-methylglutaric aciduria.
Delgado, CA, Balbueno Guerreiro, GB, Diaz Jacques, CE, de Moura Coelho, D, Sitta, A, Manfredini, V, Wajner, M, Vargas, CR
Archives of biochemistry and biophysics. 2019;:16-22
Abstract
3-hydroxy-3-methylglutaric aciduria (HMGA) is an inherited disorder of the leucine catabolic pathway in which occurs a deficiency of the 3-hydroxy-3-methylglutaryl-CoA lyase enzyme. Therefore, the organic acids 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA), mainly, accumulate in tissues of affected patients. Lately, much attention has been focused on free radicals as mediators of tissue damage in human diseases, causing lipid peroxidation, protein oxidation and DNA damage. The treatment of this disease is based in a restricted protein ingest and supplementation with l-carnitine (LC), an antioxidant and detoxifying agent. In the present work, we investigated the in vitro oxidative damage to DNA induced by the accumulation of organic acids and oxidative stress parameters in vivo of patients with 3-HMG, as well as the effect of the recommended therapy. The in vitro DNA damage was analyzed by the alkaline comet assay in leukocytes incubated with HMG and MGA (1 mM, 2.5 mM and 5 mM) and co-incubated with LC (90 μM and 150 μM). The in vivo urinary 15-F2t-isoprostane levels and urinary oxidized guanine species were measured by ELISA kits in patient's urine before and after the treatment with LC. HMG and MGA induced a DNA damage index (DI) significantly higher than that of the control group. The DI was significantly reduced in the presence of LC. It was also verified a significant increase of oxidized guanine species and urinary isoprostane levels, biomarker of oxidative DNA damage and lipid peroxidation respectively, in patients before treatment. After the treatment and supplementation with LC, patients presented significantly lower levels of those biomarkers. Analyzing the data together, we can conclude that HMGA patients present oxidative lipid and DNA damage, which is induced by HMG and MGA, and the antioxidant therapy with LC can prevent that kind of injuries.