Exposure to coal mining can lead to imbalanced levels of inorganic elements and DNA damage in individuals living near open-pit mining sites.

Coal mining activities are considered harmful to living organisms. These activities release compounds to the environment, such as polycyclic aromatic hydrocarbons (PAHs), metals, and oxides, which can cause oxidative damage to DNA. In this study, we compared the DNA damage and the chemical composition of peripherical blood of 150 individuals exposed to coal mining residues and 120 non-exposed individuals. Analysis of coal particles revealed the presence of elements such as copper (Cu), aluminum (Al), chrome (Cr), silicon (Si) and iron (Fe). The exposed individuals in our study had significant concentrations of Al, sulfur (S), Cr, Fe, and Cu in their blood, as well as hypokalemia. Results from the enzyme-modified comet assay (FPG enzyme) suggest that exposure to coal mining residues caused oxidative DNA damage, particularly purine damage. Furthermore, particles with a diameter of <2.5 µm indicate that direct inhalation could promote these physiological alterations. Finally, a systems biology analysis was performed to investigate the effects of these elements on DNA damage and oxidative stress pathways. Interestingly, Cu, Cr, Fe, and K are key nodes that intensely modulate these pathways. Our results suggest that understanding the imbalance of inorganic elements caused by exposure to coal mining residues is crucial to understanding their effect on human health.

Cytokinesis-block micronucleus cytome (CBMN-CYT) assay biomarkers and telomere length analysis in relation to inorganic elements in individuals exposed to welding fumes.

During the welding activities many compounds are released, several of these cause oxidative stress and inflammation and some are considered carcinogenic, in fact the International Agency for Research on Cancer established that welding fumes are carcinogenic to humans. The aim of the present study was to analyze the cytotoxic and genotoxic potential of exposure to welding fumes and to determine concentrations of metals in blood and urine of occupationally exposed workers. We included 98 welders and 100 non-exposed individuals. Our results show significant increase in the frequency of micronuclei (MN), nucleoplasmic bridges (NPB), nuclear buds (NBUD) and necrotic cells (NECR) in cytokinesis-block micronucleus cytome (CBMN-Cyt) assay, as well as in the telomere length (TL) of the exposed individuals with respect to the non-exposed group. In the analysis of the concentrations of inorganic elements using PIXE method, were found higher concentrations of Cr, Fe and Cu in the urine, and Cr, Fe, Mg, Al, S, and Mn in the blood in the exposed group compared to the non-exposed group. A significant correlation was observed between MN and age and between NPB and years of exposure. Additionally, we found a significant correlation for TL in relation to MN, NPB, age and years of exposure in the exposed group. Interestingly, a significant correlation between MN and the increase in the concentration of Mg, S, Fe and Cu in blood samples of the exposed group, and between MN and Cr, Fe, Ni and Cu in urine. Thus, our findings may be associated with oxidative and inflammatory damage processes generated by the components contained in welding fumes, suggesting a high occupational risk in welding workers.

Cytotoxic and genotoxic effects in mechanics occupationally exposed to diesel engine exhaust.

Diesel engine exhaust (DEE), which is the product of diesel combustion, is considered carcinogenic in humans. It comprises toxic gases, polycyclic aromatic hydrocarbons (PAHs) and particulate matter which can reach the pulmonary parenchyma and trigger various diseases, including cancer. The aim of the present study was to evaluate the potential cytotoxic and genotoxic effects of DEE exposure on peripheral blood and buccal epithelial cells in mechanics occupationally exposed to DEE. We recruited 120 exposed mechanics and 100 non-exposed control individuals. Significant differences were observed between the two groups in terms of percentage of tail DNA and damage index (DI) in the alkaline comet assay; levels of biomarkers by cytokinesis-block micronucleus cytome (CBMN-Cyt) assay; frequency of micronucleus (MN), nucleoplasmic bridge (NPB), nuclear bud (NBUD) and apoptotic cells (APOP) and levels of biomarkers for micronucleus, karyorrhexis (KRX), karyolysis (KRL) and condensed chromatin (CC) by the buccal micronucleus cytome (BM-Cyt) assay. A significant and positive correlation was found between the frequency of MN in lymphocytes and buccal cells in the exposed group. Also, there was a significant correlation between age and percentage of tail DNA and DI in the comet assay, APOP and MN in the CBMN-Cyt assay and NBUD and MN in the BM-Cyt assay. Additionally, we found a positive and significant correlation of MN frequency in lymphocytes and buccal cells and age and MN frequency in lymphocytes with the time of service (years). Regarding lifestyle-related factors, a significant correlation was observed between meat and vitamin consumption and NBUD formation on CBMN-Cyt and between meat consumption and MN formation on CBMN-Cyt. Of the BM-Cyt biomarkers, there was a correlation between alcohol consumption and NBUD formation and between binucleated cell (BN), pyknosis (PYC), CC and KRL occurrence and family cancer history. These results are the first data in Colombia on the cytotoxic and genotoxic effects induced by continuous exposure to DEE and thus showed the usefulness of biomarkers of the comet, CBMN-Cyt and BM-Cyt assays for human biomonitoring and evaluation of cancer risk in the exposed populations.

Antimutagenic and antioxidant properties of the aqueous extracts of organic and conventional grapevine Vitis labrusca cv. Isabella leaves in V79 cells.

Grapes are one of the most commonly consumed fruit, in both fresh and processed forms; however, a significant amount is disposed of in the environment. Searching for a use of this waste, the antigenotoxic, antimutagenic, and antioxidant activities of aqueous extracts from organic and conventional Vitis labrusca leaves were determined using V79 cells as model. The antigenotoxic activity was analyzed by the alkaline comet assay using endonuclease III and formamidopyrimidine DNA glycosylase enzymes. The antimutagenic property was assessed through the micronucleus (MN) formation, and antioxidant activities were assessed using 2',7'-dichlorodihydrofluorescin diacetate (DCFH-DA) assay and 2,2-diphenyl-1-picrylhydrazyl (DPPH(●)) radical scavenging, as well as with superoxide dismutase (SOD) and catalase (CAT) activity assays. In addition, phenolic content and ascorbic acid levels of both extracts were determined. Data showed that both organic and conventional grapevine leaves extracts possessed antigenotoxic and antimutagenic properties. The extract of organic leaves significantly reduced intracellular reactive oxygen species (ROS) levels in V79 cells, and displayed greater ability for DPPH(●) scavenging and higher SOD and CAT activities than extract from conventional leaves. Further, the extract from organic leaves contained higher phenolic and ascorbic acid concentrations. In summary, extracts from organic and conventional grape leaves induced important in vitro biological effects.

Antigenotoxic and antimutagenic effects of diphenyl ditelluride against several known mutagens in Chinese hamster lung fibroblasts.

The present study evaluates antigenotoxic and antimutagenic properties of diphenyl ditelluride (DPDT) against several known mutagens in Chinese hamster lung fibroblasts (V79 cells). DPDT was not cytotoxic and genotoxic at concentrations ranging from 0.01 to 0.1 µM. The pre-treatment for 2h with this organotellurium compound at non-cytotoxic dose range (0.01, 0.05 and 0.1 µM) increased cell survival after challenge with hydrogen peroxide (H2O2), t-butyl hydroperoxide (t-BOOH), methylmethanesulphonate (MMS) or ultraviolet (UV)C radiation. In addition, the pre-treatment with DPDT decreased the DNA damage and Formamidopyrimidine DNA-glycosylase (Fpg)- and Endonuclease III (Endo III) sensitive sites induction by the studied genotoxic agents, as verified by comet assay and modified comet assay, respectively. The pre-treatment also reduced micronucleus frequency, revealing the protector effect of DPDT against MMS and UVC-induced mutagenesis. Our results demonstrate that DPDT-treated cells at concentration range of 0.01-0.1 µM do not change thiobarbituric acid reactive species (TBARS) levels and ROS generation. Moreover, DPDT pre-treatment at this concentration range decreases the ROS induction by H2O2 and t-BOOH treatment indicating antioxidant potential. On the other hand, concentrations higher than 0.1 µM increase TBARS formation and inhibited superoxide dismutase (SOD) activity, suggesting pro-oxidative effect of this compound at high concentrations. Our results suggest that DPDT presents antigenotoxic and antimutagenic properties at concentration range of 0.01-0.1 µM. The protection effect could be attributed to antioxidant capacity of DPDT at this concentration range in V79 cells.

Cytotoxicity and genotoxicity of orthodontic bands with or without silver soldered joints.

Stainless steel bands, with or without silver soldered joints, are routinely used in orthodontics. However, little is known about the toxic biological effects of these appliances. The aims of this study were to evaluate the cytotoxic, cytostatic, genotoxic and DNA damage-inducing effects of non-soldered bands (NSB) and silver soldered bands (SSB) on the HepG2 and HOK cell lines and to quantify the amount of ions released by the bands. The 24-h metallic eluates of NSBs and SSBs were quantified by atomic absorption spectrophotometry. An MTT reduction assay was performed to evaluate the cytotoxicity, alkaline and modified comet assays were employed to measure genotoxicity and oxidative DNA damage effects, and cytokinesis-block micronucleus cytome (CBMN-Cyt) assays were used to verify DNA damage, cytostasis and cytotoxicity. Ag, Cd, Cr, Cu and Zn were detected in SSB medium samples, and Fe and Ni were detected in both the SSB and NSB medium samples. The SSB group induced stronger cytotoxic effects than the NSB group in both evaluated cell lines. NSB and SSB induced genotoxicity as evaluated by comet assays; stronger effects were observed in the SSB group. Both groups induced similar increases in the number of oxidative DNA lesions, as detected by the FPG and Endo III enzymes. Nucleoplasmic bridges, biomarkers of DNA misrepair and/or telomere end fusions, were significantly elevated in the SSB group. The SSB eluates showed higher amounts of Ni and Fe than NSB, and all the quantified ions were detected in SSB eluates, including Cd. The SSB eluates were more cytotoxic and genotoxic than the NSB samples. Based on these results, we propose that other brands, materials and techniques should be further investigated for the future manufacture of orthodontic appliances.

Chemical characterization of Callingcard Vine (Entada polystachya (L.) DC. var. polystachya) aqueous seed extract and evaluation of its cytotoxic, genotoxic and mutagenic properties.

Callingcard Vine (Entada polystachya (L.) DC. var. polystachya - Fabaceae) is a common plant in coastal thickets from western Mexico through Central America to Colombia and Brazil, especially in Amazon biome. It has been popularly used as a urinary burning reliever and diuretic. However, the plant chemical constituents are poorly understood and Entada spp. genotoxic potential have not been previously investigated. In the present study we determined the chemical composition of the aqueous E. polystachya crude seed extract (EPCSE) and evaluated the cytotoxic, genotoxic and mutagenic properties of EPCSE in Salmonella typhimurium and Chinese hamster fibroblast (V79) cells. Cytotoxic activity was also evaluated in tumor cell lines (HT29, MCF7 and U87) and non-malignant cells (MRC5). The chemical analysis by High Resolution Mass Spectrometry (HRMS) of EPCSE indicated the presence of saponin and chalcone. The results of the MTT and clonal survival assays suggest that EPCSE is cytotoxic to V79 cells. Survival analysis showed higher IC50 in non-tumor compared with tumor cell lines. EPCSE showed induction of DNA strand breaks as revealed by the alkaline comet assay and micronucleus test. Using the modified comet assay, it was possible to detect the induction of oxidative DNA base damage by EPCSE in V79 cells. Consistently, the extract induced increase lipid peroxidation (TBARS), superoxide dismutase (SOD) and catalase (CAT) activities in V79 cells. In addition, EPCSE induced mutations in S. typhimurium TA98 and TA100 strains, confirming a mutagenic potential. Taken together, our results suggest that EPCSE is cytotoxic and genotoxic to V79 cells and mutagenic to S. typhimurium. These properties can be related to the pro-oxidant ability of the extract and induction of DNA lesions. Additionally, EPCSE could inhibit the growth of tumor cells, especially human colorectal adenocarcinoma (HT29) cell line, and can constitute a possible source of antitumor natural agents.

Antioxidant and Anticancer Potential of the New Cu(II) Complexes Bearing Imine-Phenolate Ligands with Pendant Amine N-Donor Groups.

Cu(II) complexes bearing NNO-donor Schiff base ligands (2a, b) have been synthesized and characterized. The single crystal X-ray analysis of the 2a complex revealed that a mononuclear and a dinuclear complex co-crystallize in the solid state. The electronic structures of the complexes are optimized by Density Functional Theory (DFT) calculations. The monomeric nature of 2a and 2b species is maintained in solution. Antioxidant activities of the ligands (1a, b) and Cu(II) complexes (2a, b) were determined by in vitro assays such as 1,1-diphenyl-2-picrylhydrazyl free radicals (DPPH.) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radicals (ABTS+). Our results demonstrated that 2a showed better antioxidant activity. MTT assays were performed to assess the toxicity of ligands and Cu(II) complexes in V79 cells. The antiproliferative activity of compounds was tested against two human tumor cell lines: MCF-7 (breast adenocarcinoma) and SW620 (colorectal carcinoma) and on MRC-5 (normal lung fibroblast). All compounds showed high cytotoxicity in the all-cell lines but showed no selectivity for tumor cell lines. Antiproliferative activity by clonogenic assay 2b showed a more significant inhibitory effect on the MCF-7 cell lines than on MRC-5. DNA damage for the 2b compound at 10 µM concentration was about three times higher in MCF-7 cells than in MRC-5 cells.

Diphenyl ditelluride anticancer activity and DNA topoisomerase I poisoning in human colon cancer HCT116 cells.

Diphenyl ditelluride (DPDT) is an organotellurium (OT) compound with pharmacological properties, including antioxidant, antigenotoxic and antimutagenic activities when applied at low concentrations. However, DPDT as well as other OT compounds also show cytotoxicity against mammalian cells when treatments occur at higher drug concentrations. Considering that the underlying mechanisms of toxicity of DPDT against tumor cells have been poorly explored, the objective of our study was to investigate the effects of DPDT against both human cancer and non-tumorigenic cells. As a model, we used the colonic HCT116 cancer cells and the MRC5 fibroblasts. Our results showed that DPDT preferentially targets HCT116 cancer cells when compared to MRC5 cells with IC50 values of 2.4 and 10.1 µM, respectively. This effect was accompanied by the induction of apoptosis and a pronounced G2/M cell cycle arrest in HCT116 cells. Furthermore, DPDT induces DNA strand breaks at concentrations below 5 µM in HCT116 cells and promotes the occurrence of DNA double strand breaks mostly during S-phase as measured by γ-H2AX/EdU double staining. Finally, DPDT forms covalent complexes with DNA topoisomerase I, as observed by the TARDIS assay, with a more prominent effect observed in HCT116 than in MRC5 cells. Taken together, our results show that DPDT preferentially targets HCT116 colon cancer cells likely through DNA topoisomerase I poisoning. This makes DPDT an interesting molecule for further development as an anti-proliferative compound in the context of cancer.

Association of buccal micronucleus cytome assay (BMNCyt) biomarkers with inorganic element concentration and genetic polymorphisms in welders.

Welding fumes are classified as carcinogenic to humans. The aim of the present study was to measure buccal micronucleus cytome assay biomarkers and to evaluate their association with inorganic elements and genetic polymorphisms (XRCC1, OGG1, XRCC3, GSTM1, and GSTT1) in welders (n = 98) and control individuals (n = 100). Higher levels of DNA damage and cell death were observed in the exposed group. Also, a significant correlation between the frequency of micronuclei and Na, Si, Cl, Ti, Cr, Zn and Mg concentrations. The formation of micronuclei, binucleated cells, cell death was associated with polymorphisms in repair pathways. The OGG1Ser326Cys and XRCC3 241Thr/Met genotypes were associated with cell death. Individuals with GSTM1 null genotype had a higher frequency of micronuclei. These results demonstrate that the deleterious effects of exposure to welding fumes are exacerbated by lifestyle habits, and genetic polymorphisms can influence DNA damage and cell death.

Analysis of the cytotoxic and genotoxic effects in a population chronically exposed to coal mining residues.

During coal mining activities, many compounds are released into the environment that can negatively impact human health. Particulate matter, polycyclic aromatic hydrocarbons (PAHs), metals, and oxides are part of the complex mixture that can affect nearby populations. Therefore, we designed this study to evaluate the potential cytotoxic and genotoxic effects in individuals chronically exposed to coal residues from peripheral blood lymphocytes and buccal cells. We recruited 150 individuals who lived more than 20 years in La Loma-Colombia and 120 control individuals from the city of Barranquilla without a history of exposure to coal mining. In the cytokinesis-block micronucleus cytome (CBMN-Cyt) assay, significant differences in the frequency of micronucleus (MN), nucleoplasmic bridge (NPB), nuclear bud (NBUD), and apoptotic cells (APOP) were observed between the two groups. In the buccal micronucleus cytome (BM-Cyt) assay, a significant formation of NBUD, karyorrhexis (KRX), karyolysis (KRL), condensed chromatin (CC), and binucleated (BN) cells was observed in the exposed group. Considering the characteristics of the study group, a significant correlation for CBMN-Cyt was found between NBUD and vitamin consumption, between MN or APOP and meat consumption, and between MN and age. Moreover, a significant correlation for BM-Cyt was found between KRL and vitamin consumption or age, and BN versus alcohol consumption. Using Raman spectroscopy, a significant increase in the concentration of DNA/RNA bases, creatinine, polysaccharides, and fatty acids was detected in the urine of individuals exposed to coal mining compared to the control group. These results contribute to the discussion on the effects of coal mining on nearby populations and the development of diseases due to chronic exposure to these residues.

NAP prevents acute cerebral oxidative stress and protects against long-term brain injury and cognitive impairment in a model of neonatal hypoxia-ischemia.

Hypoxia-ischemia (HI) is a common cause of neonatal brain damage with lifelong morbidities in which current therapies are limited. In this study, we investigated the effect of neuropeptide NAP (NAPVSIPQ) on early cerebral oxidative stress, long-term neurological function and brain injury after neonatal HI. Seven-day-old rat pups were subjected to an HI model by applying a unilateral carotid artery occlusion and systemic hypoxia. The animals were randomly assigned to groups receiving an intraperitoneal injection of NAP (3 µg/g) or vehicle immediately (0 h) and 24 h after HI. Brain DNA damage, lipid peroxidation and reduced glutathione (GSH) content were determined 24 h after the last NAP injection. Cognitive impairment was assessed on postnatal day 60 using the spatial version of the Morris water maze learning task. Next, the animals were euthanized to assess the cerebral hemispheric volume using the Cavalieri principle associated with the counting point method. We observed that NAP prevented the acute HI-induced DNA and lipid membrane damage and also recovered the GSH levels in the injured hemisphere of the HI rat pups. Further, NAP was able to prevent impairments in learning and long-term spatial memory and to significantly reduce brain damage up to 7 weeks following the neonatal HI injury. Our findings demonstrate that NAP confers potent neuroprotection from acute brain oxidative stress, long-term cognitive impairment and brain lesions induced by neonatal HI through, at least in part, the modulation of the glutathione-mediated antioxidant system.

Cystic Fibrosis: Systems Biology Analysis from Homozygous p.Phe508del Variant Patients' Samples Reveals Perturbations in Tissue-Specific Pathways.

Cystic fibrosis (CF) is an autosomal recessive disorder, caused by diverse genetic variants for the CF transmembrane conductance regulator (CFTR) protein. Among these, p.Phe508del is the most prevalent variant. The effects of this variant on the physiology of each tissue remains unknown. This study is aimed at predicting cell signaling pathways present in different tissues of fibrocystic patients, homozygous for p.Phe508del. The study involved analysis of two microarray datasets, E-GEOD-15568 and E-MTAB-360 corresponding to the rectal and bronchial epithelium, respectively, obtained from the ArrayExpress repository. Particularly, differentially expressed genes (DEGs) were predicted, protein-protein interaction (PPI) networks were designed, and centrality and functional interaction networks were analyzed. The study reported that p.Phe508del-mutated CFTR-allele in homozygous state influenced the whole gene expression in each tissue differently. Interestingly, gene ontology (GO) term enrichment analysis revealed that only "neutrophil activation" was shared between both tissues; however, nonshared DEGs were grouped into the same GO term. For further verification, functional interaction networks were generated, wherein no shared nodes were reported between these tissues. These results suggested that the p.Phe508del-mutated CFTR-allele in homozygous state promoted tissue-specific pathways in fibrocystic patients. The generated data might further assist in prediction diagnosis to define biomarkers or devising therapeutic strategies.

Diclofenac Administration after Physical Training Blunts Adaptations of Peripheral Systems and Leads to Losses in Exercise Performance: In Vivo and In Silico Analyses.

Recovery in athletes is hampered by soreness and fatigue. Consequently, nonsteroidal anti-inflammatory drugs are used as an effective strategy to maintain high performance. However, impact of these drugs on adaptations induced by training remains unknown. This study assessed the effects of diclofenac administration (10 mg/kg/day) on rats subjected to an exhaustive test, after six weeks of swimming training. Over the course of 10 days, three repeated swimming bouts were performed, and diclofenac or saline were administered once a day. Trained animals exhibited higher muscle citrate synthase and lower plasma creatinine kinase activities as compared to sedentary animals, wherein diclofenac had no impact. Training increased time to exhaustion, however, diclofenac blunted this effect. It also impaired the increase in plasma and liver interleukin-6 levels. The trained group exhibited augmented catalase, glutathione peroxidase, and glutathione reductase activities, and a higher ratio of reduced-to-oxidized glutathione in the liver. However, diclofenac treatment blunted all these effects. Systems biology analysis revealed a close relationship between diclofenac and liver catalase. These results confirmed that regular exercise induces inflammation and oxidative stress, which are crucial for tissue adaptations. Altogether, diclofenac treatment might be helpful in preventing pain and inflammation, but its use severely affects performance and tissue adaptation.

DNA damage, salivary cortisol levels, and cognitive parameters in a nursing team.

In a cross-sectional study of women in a nursing team at a university hospital in southern Brazil, we studied DNA damage, salivary cortisol levels, and cognition. DNA damage was measured in blood leukocytes with the comet assay and the micronucleus test. Salivary cortisol levels were determined upon waking, 30 min later, and at bedtime. Cognition was evaluated according to the Stroop, Digit span and Word span tests. Cortisol levels on waking up were associated negatively with the number of years the employee worked at the institution and positively with the DNA damage in comet assay. Cognitive scores were lower when the cortisol levels were low at awakening and high at bedtime; and were associated positively with educational level. Cortisol status may influence overall health as well as essential work skills, such as attention.

Cytokinesis-block micronucleus cytome (CBMN-CYT) assay and its relationship with genetic polymorphisms in welders.

Fumes generated in the welding process are composed of micrometric and nanometric particles that form when metal fumes condense. The International Agency for Research on Cancer established that many compounds derived from the welding process are carcinogenic to humans. Still, there are few studies related to the role of genetic polymorphisms. This work aimed to analyze the influence of OGG1 Ser326Cys, XRCC1 Arg280His, XRCC1 Arg194Thr, XRCC1 Arg399Gln, XRCC3 Thr241Met, GSTM1, and GSTT1 gene polymorphisms on DNA damage of 98 subjects occupationally exposed to welding fumes and 100 non exposed individuals. The results showed that individuals exposed to welding fumes with XRCC3 Thr241Thr, XRCC3 Thr241Met, and GSTM1 null genotypes demonstrated a significantly higher micronucleus frequency in lymphocytes. In contrast, individuals with XRCC1 Arg399Gln and XRCC1 Gln399Gln genotypes had significant levels of NPBs. OGG1 326 Ser/Cys, OGG1 326 Cys/Cys, XRCC1 194Arg/Thr, XRCC1 194Thr/Thr, and GSTT1 null genotypes exhibited significantly higher apoptotic values. Also, XRCC1 194Arg/Trp, XRCC1 194Thr/Thr, and GSTM1 null genotype carriers had higher necrotic levels compared to XRCC1 194Arg/Arg and GSTM1 nonnull carriers. Compositional analysis revealed the presence of iron, manganese, silicon as well as particles smaller than 2 µm that adhere to each other and form agglomerates. These results may be associated with a mixture of components, such as nitrogen dioxide, carbon monoxide, and metallic fumes, leading to significant DNA damage and cell death processes. These findings demonstrated the importance of the association between individual susceptibility and DNA damage levels due to occupational exposure to welding fumes; and constitute one of the first studies carried out in exposed workers from Colombia.

Cellular Mechanisms Triggered by the Cotreatment of Resveratrol and Doxorubicin in Breast Cancer: A Translational In Vitro-In Silico Model.

Doxorubicin (Doxo) is the most effective chemotherapeutic agent for the treatment of breast cancer. However, resistance to Doxo is common. Adjuvant compounds capable of modulating mechanisms involved in Doxo resistance may potentiate the effectiveness of the drug. Resveratrol (Rsv) has been tested as an adjuvant in mammary malignancies. However, the cellular and molecular mechanisms underlying the effects of cotreatment with Doxo and Rsv in breast cancer are poorly understood. Here, we combined in vitro and in silico analysis to characterize these mechanisms. In vitro, we employed a clinically relevant experimental design consisting of acute (24 h) treatment followed by 15 days of analysis. Acute Rsv potentiated the long-lasting effect of Doxo through the induction of apoptosis and senescence. Cells that survived to the cotreatment triggered high levels of autophagy. Autophagy inhibition during its peak of activation but not concomitant with Doxo+Rsv increased the long-term toxicity of the cotreatment. To uncover key proteins potentially associated with in vitro effects, an in silico multistep strategy was implemented. Chemical-protein networks were predicted based on constitutive gene expression of MCF7 cells and interatomic data from breast cancer. Topological analysis, KM survival analysis, and a quantitative model based on the connectivity between apoptosis, senescence, and autophagy were performed. We found seven putative genes predicted to be modulated by Rsv in the context of Doxo treatment: CCND1, CDH1, ESR1, HSP90AA1, MAPK3, PTPN11, and RPS6KB1. Six out of these seven genes have been experimentally proven to be modulated by Rsv in cancer cells, with 4 of the 6 genes in MCF7 cells. In conclusion, acute Rsv potentiated the long-term toxicity of Doxo in breast cancer potentially through the modulation of genes and mechanisms involved in Doxo resistance. Rational autophagy inhibition potentiated the effects of Rsv+Doxo, a strategy that should be further tested in animal models.

COVID-19 Pandemic - A Narrative Review of the Potential Roles of Chloroquine and Hydroxychloroquine.

BACKGROUND: Chloroquine (CQ) and hydroxychloroquine (HCQ) are old drugs used against malaria, rheumatism, inflammation in the joints, lupus, among others. These drugs showed positive results in preliminary scientific research for treatment of the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Since the studies with CQ and HCQ are initial with small patient populations, it is not yet known whether there are adverse effects from the use of CQ and HCQ for patients infected with the coronavirus. OBJECTIVES: The aim of this study was to evaluate the evidence regarding the efficacy and safety of CQ and HCQ used against viral infection caused by SARS-CoV-2. STUDY DESIGN: This is a narrative review of the traditional prescriptions of CQ and HCQ efficacy and adverse effects as well as their employment for coronavirus disease 2019 (COVID-19). SETTING: In vitro and clinical studies comparing the antiviral efficacy and adverse effect profile of CQ and HCQ against COVID-19 in adult patients were evaluated. METHODS: A systemic search of reviews, including in vitro and clinical trial studies in English focusing on CQ and HCQ effects and adverse effects against COVID-19 in the adult patient population from PubMed was performed. It included studies reporting chloroquine and hydroxychloroquine effects and adverse effects against COVID-19. RESULTS: A total of 42 articles published between 2004 and April 2020 were reviewed for therapeutic use of CQ and HCQ. Both these drugs showed a significant in vitro potential against coronavirus. Many studies for clinical use of CQ and HCQ showed that patients presented adverse reactions on high doses. LIMITATIONS: Clinical studies have some methodology shortcomings, such as lack of information about the treatment and small number of experimental patients, leading to a misinterpretation of the data. Besides, there are few clinical studies with a limited sample size. Moreover, most of them did not present control groups, and some patients had died during these protocols. DISCUSSION: Despite both CQ and HCQ in vitro antiviral evidence, clinically, both drugs, either alone or combined with other medications, may increase the risk of cardiac arrhythmias, leading to cardiac arrest and sudden death. Besides, a lot of uncertainty still remains, such as starting administration period, dose prescribed, length of treatment, patients' condition, concomitant drug use, among others. CONCLUSION: From the studies reviewed, it is not possible to state the precise efficacy and safety of CQ and HCQ use in the treatment of COVID-19 at any time in the course of the disease. Future studies are warranted.

DNA repair and metabolic gene polymorphisms affect genetic damage due to diesel engine exhaust exposure.

Diesel engine exhaust (DEE) is a complex mixture of toxic gases, halogenated aromatic hydrocarbons, alkyl polycyclic aromatic hydrocarbons, polycyclic aromatic hydrocarbons, benzene derivatives, metals and diesel exhaust particles (DEPs) generated from the incomplete combustion of diesel fuel. Many of the compounds in this mixture can cause oxidative damage to DNA and are considered carcinogenic for humans. Further, chronic DEE exposure increases risks of cardiovascular and pulmonary diseases. Despite these pervasive health risks, there is limited and inconsistent information regarding genetic factors conferring susceptibility or resistance to DEE genotoxicity. The present study evaluated the effects of polymorphisms in two base excision repair (BER) genes (OGG1 Ser326Cys and XRCC1 Arg280His), one homologous recombination (HRR) gene (XRCC3 Thr241Met) and two xenobiotic metabolism genes (GSTM1 and GSTT1) on the genotoxicity profiles among 123 mechanics exposed to workplace DEE. Polymorphisms were determined by PCR-RFLP. In comet assay, individuals with the GSTT1 null genotype demonstrated significantly greater % tail DNA in lymphocytes than those with non-null genotype. In contrast, these null individuals exhibited significantly lower frequencies of binucleated (BN) cells and nuclear buds (NBUDs) in buccal cells than non-null individuals. Heterozygous hOGG1 326 individuals (hOGG1 326 Ser/Cys) exhibited higher buccal cell NBUD frequency than hOGG1 326 Ser/Ser individuals. Individuals carrying the XRCC3 241 Met/Met polymorphism also showed significantly higher buccal cell NBUD frequencies than those carrying the XRCC3 241 Thr/Thr polymorphism. We found a high flow of particulate matter with a diameter of < 2.5 µm (PM2.5) in the workplace. The most abundant metals in DEPs were iron, copper, silicon and manganese as detected by transmission electron microscopy-energy-dispersive X-ray spectroscopy (TEM-EDX). Scanning electron microscopy (SEM-EDS) revealed particles with diameters smaller than PM2.5, including nanoparticles forming aggregates and agglomerates. Our results demonstrate the genotoxic effects of DEE and the critical influence of genetic susceptibility conferred by DNA repair and metabolic gene polymorphisms that shed light into the understanding of underlying mechanisms.

Diphenyl Ditelluride: Redox-Modulating and Antiproliferative Properties.

Tellurium is a rare element that has been regarded as a toxic, nonessential element, and its biological role is not clearly established. In addition, the biological effects of elemental tellurium and some of its organic and inorganic derivatives have been studied, leading to a set of interesting and promising applications. Diphenyl ditelluride (DPDT), an organic tellurium derivate, showed antioxidant, antigenotoxic, antimutagenic, and anticancer properties. The antioxidant and prooxidant properties of DPDT are complex and depend on experimental conditions, which may explain the contradictory reports of these properties. In addition, DPDT may exert its effects through different pathways, including distinct ones to those responsible for chemotherapy resistance phenotypes: transcription factors, membrane receptors, adhesion, structural molecules, cell cycle regulatory components, and apoptosis pathways. This review aims to present recent advances in our understanding of the biological effects, therapeutic potential, and safety of DPDT treatment. Moreover, original results demonstrating the cytotoxic effects of DPDT in different mammalian cell lines and systems biology analysis are included, and emerging approaches for possible future applications are inferred.