In silico attempt to reveal the link between cancer development and combined exposure to the maize herbicides: Glyphosate, nicosulfuron, S-metolachlor and terbuthylazine.

Pesticides are crucial for crop protection and have seen a 50 % increase in use in the last decade. Besides preventing significant crop losses their use has raised health concerns due to consumer exposure through residues in food and water. The toxicity data from individual components is often used to assess overall mixture toxicity, but uncertainty persists in understanding the behaviors of individual chemicals within these mixtures. Assessing the risk of pesticide mixture exposure remains challenging, potentially leading to overestimation or underestimation of toxicity. This study aims to establish a possible link between exposure to a herbicide mixture and genotoxic effects, focusing on cancer development. Our analysis was focused on four herbicides glyphosate, nicosulfuron, S-metolachlor and terbuthylazine. To determine the link between genes associated with cancer development due to exposure to herbicide mixture, a CTD database tools were used. Through the ToppFun tool molecular function and biological process associated with genes common to the disease of interest and selected herbicides were evaluated. And finally, GeneMANIA was used in order to analyze the function and interaction between common genes of herbicide mixture. Among the 7 common genes for herbicide mixture and cancer development coexpression characteristics were dominant at 65.41 %, 22.14 % of annotated genes shared the same pathway and 7.88 % showed co-localization. Among six target genes involved in genetic disease development co-expression was dominant at 87.34 %, colocalization at 8.03 % and shared protein domains at 4.52 %. Comprehensive molecular analyses, encompassing genomics, proteomics, and pathway analysis, are essential to unravel the specific mechanisms involved in the context of the studied mixture and its potential carcinogenic effects.

Involvement of toxic metals and PCBs mixture in the thyroid and male reproductive toxicity: In silico toxicogenomic data mining.

Toxicological research is mostly limited to considering the effects of a single substance, even though the real exposure of people is reflected in their daily exposure to many different chemical substances in low-doses. This in silico toxicogenomic study aims to provide evidence for the selected environmental (organo)metals (lead, cadmium, methyl mercury) + polychlorinated biphenyls mixture involvement in the possible alteration of thyroid, and male reproductive system function, and furthermore to predict the possible toxic mechanisms of the environmental cocktail. The Comparative Toxicogenomic Database, GeneMANIA online software, and ToppGene Suite portal were used as the main tools for toxicogenomic data mining and gene ontology analysis. The results show that 35 annotated common genes between selected chemicals and endocrine system diseases can interact on the co-expression level. Our study highlighted the disruption of the cytokines, the cell's response to oxidative stress, and the influence of the transcription factors as the potential core of toxicological mechanisms of the discussed mixture's effects. The connected toxicological effects of the tested mixture were abnormal sperm cells, a disrupted level of testosterone, and thyroid hormones. The core mechanisms of these effects were inflammation, oxidative stress, disruption of androgen receptor signaling, and the alteration of the FOXO3-Keap-1/NRF2-HMOX1-NQO1 pathway signaling most likely controlled by the co-expression of overlapped genes among used chemicals. This in silico research can be used as a potential core for the determination of biomarkers that can be monitored in future further in vitro and in vivo experiments.

In silico assessment of mixture toxicity mechanisms involved in the pathogenesis of thyroid diseases: The combination of toxic metal(oid)s and decabrominated diphenyl ether.

The current study aimed to assess the connection between the mixture of lead (Pb), cadmium (Cd), arsenic (As), methylmercury (MeHg) and decabrominated diphenyl ether (decaBDE) and thyroid function, by using in silico toxicogenomic data-mining approach. To obtain the linkage between investigated toxic mixture and thyroid diseases (TDs), the Comparative Toxicogenomics Database (CTD) was used, while gene ontology (GO) enrichment analysis was performed by ToppGeneSuite portal. The analysis has shown 10 genes connected to all chemicals present in the mixture and TDs (CAT, GSR, IFNG, IL1B, IL4, IL6, MAPK1, SOD2, TGFB1, TNF), most of which were in co-expression (45.68%), or belonged to the same pathway (30.47%). Top 5 biological processes and molecular functions affected by the investigated mixture emphasized the role of two common mechanisms - oxidative stress and inflammation. Cytokines and inflammatory response was listed as the main molecular pathway that may be triggered by simultaneous exposure to toxic metal(oid)s and decaBDE and connected to TDs. The direct relations between Pb/decaBDE and redox status impairment in thyroid tissue was confirmed by our chemical-phenotype interaction analysis, while the strongest linkage between Pb, As and decaBDE and thyroid disorders was found. The obtained results provide better understanding of molecular mechanisms involved in the thyrotoxicity of the investigated mixture, and can be used to direct further research.

An overview of the safety assessment of medicines currently used in the COVID-19 disease treatment.

On 11th March 2020, the pandemic of the new coronavirus was declared by the World Health Organization. At the moment, there are no new registered medicines that can effectively treat the coronavirus infection. However, a number of ongoing clinical trials are investigating the efficacy and safety of the medicines which have already been registered and used for the treatment of other diseases, in the treatment of the coronavirus infection. The proposed combinations of these medicines could potentially present a safety risk, since most of these medicines have the potential to cause numerous side or toxic effects, even when used in monotherapy. Thus, the aim of this study was to review and evaluate the literature data on the toxicity of the selected individual drugs (ritonavir, lopinavir, remdesivir, chloroquine, and umifenovir) and the available clinical data concerning the possible adverse effects of the selected drug combinations (lopinavir/ritonavir + umifenovir, lopinavir/ritonavir + interferon ß, chloroquine + remdesivir, and chloroquine + azithromycin). The most often reported toxic effects of these medicines such as hepatotoxicity, retinal damage, nephrotoxicity, and cardiotoxicity, together with the fact that the health status of the patients with COVID-19 disease is often complicated by co-existing illnesses and therapy implicate that the decision on the therapeutic strategy should be made with caution.