Long-term exposure to NP and OP, as common synthetic endocrine-disrupting chemicals (EDCs) in surface water environments in China, is closely associated with the development of chronic kidney disease (CKD). However, their potential targets and toxicological mechanisms for inducing CKD remain unknown. This study utilizes network toxicology and molecular docking techniques to explore the potential toxic targets and molecular mechanisms of CKD induction by NP and OP. We identify 49 core targets of NP and OP action in CKD using the Comparative Toxicogenomics Database (CTD) and GeneCards databases. Using the STRING database and Cytoscape software, we identify five hub genes: MAPK3, TNF, BCL2, ESR1, and FOS. We construct a nomogram model based on the CKD dataset GSE66494, utilizing these five hub genes. Calibration and ROC curves demonstrate that the model has good diagnostic value for CKD, and the DCA curve indicates that the model has high clinical utility. Single-gene GSEA enrichment analysis identifies five hub genes that influence the development of CKD through multiple biological pathways, revealing that several immune-regulatory signaling pathways are activated. The CIBERSORT algorithm identifies eight types of immune cell infiltration levels that change significantly during CKD development, and correlation analyses suggest that the five hub genes are strongly associated with multiple immune cell infiltrations. The molecular docking results suggested that ESR1, MAPK3, and TNF had the lowest binding energies and high binding affinities with NP and OP. The results of molecular dynamics simulations similarly confirmed the stability of the interactions between ESR1, MAPK3 and TNF proteins with NP and OP. The results of this study provide a theoretical basis for understanding the potential toxicity targets and mechanisms of NP- and OP-induced CKD and promote the application of network toxicology and molecular docking techniques in the study of environmental pollutants.

4-tert-Octylphenol (OP), an endocrine disrupting chemical is widely used in the production of industrial products. Prenatal exposure to endocrine-disrupting chemicals negatively affects the brain. However, the influence of OP exposure during neurodevelopment in adult offspring remains unclear. Thus, in the present study, we investigated the effects of maternal OP exposure on brain development in adult offspring by analyzing primary glial cell cultures and mice. Our findings revealed that OP exposure led to a specific increase in the mRNA expression of the ionized calcium-binding adapter molecule 1 (Iba-1) and the proportion of amoeboid microglia in the primary glial cell culture and adult offspring mice. Exposure to OP increased the transcriptional activation of Iba-1 and estrogen response element, which were counteracted by estrogen receptor antagonists ICI 182,780. Moreover, OP exposure increased the nuclear localization of the estrogen receptor. Remarkably, OP exposure decreased the mRNA expression levels of proinflammatory cytokines and genes associated with immune response in the brains of the offspring. OP exposure upregulated actin filament-related genes and altered cytoskeletal gene expression, as demonstrated by microarray analysis. The morphological changes in microglia did not result in an inflammatory response following lipopolysaccharide treatment. Taken together, the effects of OP exposure during neurodevelopment persist into adulthood, resulting in microglial dysfunction mediated by estrogen receptor signaling pathways in the brains of adult offspring mice.

Alkylphenols are byproducts of anthropogenic activities that widely contaminate waters, soils and air; among them, the most represented are 4-nonylphenol (4-NP) and 4-octylphenol (4-OP). These compounds tend to bioaccumulate in animal and plant tissues and also represent a risk to human health. Indeed, humans are constantly exposed to alkylphenols through ingestion of contaminated water and food, inhalation and dermal absorption. In the present work, we characterized the cytotoxic ability of 4-OP towards several human cell lines, representing the potential main targets in the human body, also comparing its effect with that of 4-NP and of a mixture of both 4-OP and 4-NP in a range of concentrations between 1 and 100 μM. Viability assays demonstrated that each cell type had a peculiar sensitivity to 4-OP and that, in some cases, a combination of the two alkylphenols displayed a higher cytotoxic activity with respect to the single compound. Then, we focused our attention on a liver cell line (HepG2) in which we observed that 4-OP increased cell death and also caused interference with protective physiological cell processes, such as the unfolded protein response, autophagy and the antioxidant response. Finally, our experimental data were compared and correlated with ADMET properties originating from an in silico analysis. Altogether, our findings highlight a possible contribution of this pollutant to deregulation of the normal homeostasis in human liver cells.

Nonylphenol (NP) and octylphenol (OP) are environmental contaminants with potential endocrine disrupting effects. However, there is limited research on the mechanisms and intervention of combined NP and OP exposure-induced neurotoxicity. This study aims to explore the cytotoxicity of combined NP and OP exposure and evaluate the potential of Lycium barbarum polysaccharides (LBP) in mitigating the aforementioned toxicity. In present study, LBP (62.5, 125 and 250 µg/mL) were applied to intervene rat adrenal pheochromocytoma (PC-12) cells treated with combined NP and OP (NP: OP = 4:1, w/w; 1, 2, 4 and 8 µg/mL). The results showed that NP and OP induced oxidative stress, disrupted the 5-hydroxytryptamine (5-HT) and cholinergic systems in PC-12 cells. Additionally, they activated the p38 protein kinase (p38) and suppressed the expression of silent information regulation type 1 (SIRT1), monoamine oxidase A (MAOA), phosphorylated cyclic-AMP response binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin-related kinase receptor type B (p-TrkB). However, N-acetyl-L-cysteine (NAC) treatment counteracted the changes of signalling molecule p38, SIRT1/MAOA and CREB/BDNF/TrkB pathways-related proteins induced by NP and OP. LBP pretreatment ameliorated combined NP and OP exposure-induced oxidative stress and neurotransmitter imbalances. Furthermore, the application of LBP and administration of a p38 inhibitor both reversed the alterations in the signaling molecule p38, as well as the proteins associated to the SIRT1/MAOA and CREB/BDNF/TrkB pathways. These results implied that LBP may have neuroprotective effects via p38-mediated SIRT1/MAOA and CREB/BDNF/TrkB pathways.

Alkylphenols ethoxylates are industrial surfactants, and the release in the environmental matrices produces degraded products, of which nonylphenol (NP) and octylphenol (OP) were the most common. They can be classified as endocrine disruptors since the estrogenic potential is widely recognized, but some others toxic aspects are in discussion. This study aimed to evaluate the toxicity of NP, OP, and mixtures of both through cellular, biochemical and genetic biomarkers in fish gonadal cell line RTG-2 exposed to nominal concentrations of 0.05; 0.5; 5; 50, and 100 μg mL^-1 of each chemical and their mixtures of 0.05, 0.5; 5 μg mL^-1 concentrations. After 24 h, the cells were collected for cytotoxic (neutral red - NR; crystal violet - CV, resazurin assay - RA and lactate-dehydrogenase - LDH), antioxidant system (glutathione-s-transferase - GST; superoxide-dismutase - SOD; glutathione-peroxidase - GPx and malondialdehyde - MDA) and genotoxic assays (alkaline comet assay and Fpg-modified alkaline comet assay). The chemicals and their mixtures were cytotoxic at 50 and 100 μg mL^-1, in general aspect, but LDH showed cytotoxicity since 0.05 μg mL^-1. The GST and SOD showed an activity increase trend in most tested groups, while GPx decreased at 5 μg mL^-1 of the mixture. The MDA increase in all groups resulted in lipid peroxidation. The reactive oxygen species caused DNA damage for all groups. The tested chemicals and concentrations have been found in the freshwater systems. They can induce cell toxicity in several parameters that could impair the gonadal tissues considering the RTG-2 responses.

Emergence of parasites resistant to praziquantel, the only therapeutic agent, and its ineffectiveness as a prophylactic agent (inactive against the migratory/juvenile Schistosoma mansoni), makes the development of new antischistosomal drugs urgent. The parasite's mitochondrion is an attractive target for drug development because this organelle is essential for survival throughout the parasite's life cycle. We investigated the effects of 116 compounds against Schistosoma mansoni cercariae motility that have been reported to affect mitochondria-related processes in other organisms. Next, eight compounds plus two controls (mefloquine and praziquantel) were selected and assayed against motility of schistosomula (in vitro) and adults (ex vivo). Prophylactic and therapeutic assays were performed using infected mouse models. Inhibition of oxygen consumption rate (OCR) was assayed using Seahorse XFe24 Analyzer. All selected compounds showed excellent prophylactic activity, reducing the worm burden in the lungs to less than 15% that obtained in the vehicle control. Notably, ascofuranone showed the highest activity with a 98% reduction of the worm burden, suggesting the potential for development of ascofuranone as a prophylactic agent. The worm burden of infected mice with S. mansoni at the adult stage was reduced by more than 50% in mice treated with mefloquine, nitazoxanide, amiodarone, ascofuranone, pyrvinium pamoate, or plumbagin. Moreover, adult mitochondrial OCR was severely inhibited by ascofuranone, atovaquone, and nitazoxanide, while pyrvinium pamoate inhibited both mitochondrial and non-mitochondrial OCRs. These results demonstrate that the mitochondria of S. mansoni are feasible target for drug development.

Nonylphenol (NP), a chemical compound widely used in industry, is the result of the nonylphenol ethoxylate decomposition and it is known as an estrogen-like compound. Numerous studies and researches have shown that it has many destructive functions of various organs such as the brain. This toxicant causes oxidative stress in the cortex and hippocampus cells, which are two essential regions to preserve memory and learning in the brain.

This review examines recent findings to better understanding the mechanisms of NP neurotoxicity. We used Scopus, Google Scholar, and PubMed databases to find articles focused on the destructive effects of NP on the oxidative stress pathway and its defense mechanisms.

NP has potential human health hazards associated with gestational, peri- and postnatal exposure. NP can disrupt brain homeostasis in different ways, such as activation of inflammatory factors in brain especially in hippocampus and cortex, disruption of the cell cycle, changes in neuron, dendrites and synapses morphology, disruption of extra and intracellular calcium ion balance and also memory and learning disorders.

Nutrient utilization and reshaping of metabolism in cancer cells is a well-known driver of malignant transformation. Less clear is the influence of the local microenvironment on metastasis formation and choice of the final organ to invade. Here we show that the level of the amino acid serine in the cytosol affects the migratory properties of lung adenocarcinoma (LUAD) cells. Inhibition of serine or glycine uptake from the extracellular milieu, as well as knockdown of the cytosolic one-carbon metabolism enzyme serine hydroxymethyltransferase (SHMT1), abolishes migration. Using rescue experiments with a brain extracellular extract, and direct measurements, we demonstrate that cytosolic serine starvation controls cell movement by increasing reactive oxygen species formation and decreasing ATP levels, thereby promoting activation of the AMP sensor kinase (AMPK) by phosphorylation. Activation of AMPK induces remodeling of the cytoskeleton and finally controls cell motility. These results highlight that cytosolic serine metabolism plays a key role in controlling motility, suggesting that cells are able to dynamically exploit the compartmentalization of this metabolism to adapt their metabolic needs to different cell functions (movement vs. proliferation). We propose a model to explain the relevance of serine/glycine metabolism in the preferential colonization of the brain by LUAD cells and suggest that the inhibition of serine/glycine uptake and/or cytosolic SHMT1 might represent a successful strategy to limit the formation of brain metastasis from primary tumors, a major cause of death in these patients.

Octylphenol (OP) is a widely distributed endocrine disrupting chemical (EDC), and can be commonly found in various and diverse environmental media. Previous studies have reported that OP exposure could cause many adverse effects on aquatic animals. However, knowledge concerning the impact of OP on lipid metabolism in amphibians was still limited. In our study, Rana chensinensis tadpoles were exposed to different OP concentrations (0, 10^-8, 10^-7 and 10^-6 mol/L) from the Gosner stage (Gs) 25-38. The RNA-seq analysis of tadpole intestines was explored by RNA-seq, and six differentially expressed genes (DEGs) related to the fat digestion and absorption were validated by RT-qPCR. Moreover, we used 16s amplicon sequencing to evaluate effects of OP on intestinal microbiome in tadpoles, further determining the variations of lipid metabolism. Our results revealed that OP exposure influenced gene expression levels related to fat digestion and absorption and led to alteration of structure and composition of intestinal microbiome. At the phylum level, the Firmicutes/Bacteroidetes ratio was gradually decreased in OP exposure groups, which disrupted lipid metabolism. According to the results of intestinal microbial functional prediction, OP exposure interfered with metabolic function and increased risk of disease. These data provide us with powerful resources to assess the effects of OP on lipid metabolism by integrating RNAseq and 16s amplicon sequencing analysis of intestinal tract and intestinal microbiome.