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Pei J, Peng J, Wu M, Zhan X, Wang D, Zhu G, Wang W, An N, Pan X. Analyzing the potential targets and mechanisms of chronic kidney disease induced by common synthetic Endocrine Disrupting Compounds (EDCs) in Chinese surface water environment using network toxicology and molecular docking techniques. THE SCIENCE OF THE TOTAL ENVIRONMENT 2025; 958:177980. [PMID: 39657341 DOI: 10.1016/j.scitotenv.2024.177980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 11/20/2024] [Accepted: 12/05/2024] [Indexed: 12/12/2024]
Abstract
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.
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Affiliation(s)
- Jun Pei
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550000, China.
| | - Jinpu Peng
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550000, China
| | - Moudong Wu
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550000, China
| | - Xiong Zhan
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550000, China
| | - Dan Wang
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550000, China
| | - Guohua Zhu
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550000, China
| | - Wei Wang
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550000, China
| | - Nini An
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550000, China
| | - Xingyu Pan
- Department of Pediatric surgrey, Guizhou Provincial People's Hospital, Guiyang 550000, China.
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2
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Lee SH, Shin HS, So YH, Lee DH, An BS, Lee GS, Jung EM. Maternal exposure to 4-tert-octylphenol causes alterations in the morphology and function of microglia in the offspring mouse brain. JOURNAL OF HAZARDOUS MATERIALS 2024; 480:136258. [PMID: 39471617 DOI: 10.1016/j.jhazmat.2024.136258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/01/2024] [Accepted: 10/21/2024] [Indexed: 11/01/2024]
Abstract
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.
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Affiliation(s)
- Seung Hyun Lee
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea; Institute for Future Earth, Pusan National University, Busan, Republic of Korea
| | - Hyun Seung Shin
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea; Institute for Future Earth, Pusan National University, Busan, Republic of Korea
| | - Yun Hee So
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea; Institute for Future Earth, Pusan National University, Busan, Republic of Korea
| | - Dong Hun Lee
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea; Institute for Future Earth, Pusan National University, Busan, Republic of Korea
| | - Beum-Soo An
- Department of Biomaterials Science, College of Natural Resources & Life Science, Pusan National University, Miryang, Republic of Korea
| | - Geun-Shik Lee
- Department of Veterinary Medicine, Kangwon National University, Chuncheon, Republic of Korea
| | - Eui-Man Jung
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea; Institute for Future Earth, Pusan National University, Busan, Republic of Korea.
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3
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Romanelli AM, Montefusco A, Sposito S, Scafuri B, Caputo I, Paolella G. In Vitro Investigation of Biological and Toxic Effects of 4-Octylphenol on Human Cells. Int J Mol Sci 2024; 25:13032. [PMID: 39684746 DOI: 10.3390/ijms252313032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/27/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
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.
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Affiliation(s)
| | - Antonio Montefusco
- Department of Chemistry and Biology, University of Salerno, 84084 Fisciano, Italy
| | - Silvia Sposito
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84084 Fisciano, Italy
| | - Bernardina Scafuri
- Department of Chemistry and Biology, University of Salerno, 84084 Fisciano, Italy
| | - Ivana Caputo
- Department of Chemistry and Biology, University of Salerno, 84084 Fisciano, Italy
- European Laboratory for the Investigation of Food-Induced Diseases (ELFID), University of Salerno, 84084 Fisciano, Italy
| | - Gaetana Paolella
- Department of Chemistry and Biology, University of Salerno, 84084 Fisciano, Italy
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Lin CY, Lee HL, Wang C, Sung FC, Su TC. Positive Association Between Serum Concentration of 4-Tertiary-octylphenol and Oxidation of DNA and Lipid in Adolescents and Young Adults. EXPOSURE AND HEALTH 2024; 16:1311-1320. [DOI: 10.1007/s12403-024-00628-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/14/2023] [Accepted: 01/08/2024] [Indexed: 01/04/2025]
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Xu L, Liu H, Rang Y, Zhou L, Wang X, Li Y, Liu C. Lycium barbarum polysaccharides attenuate nonylphenol and octylphenol-induced oxidative stress and neurotransmitter disorders in PC-12 cells. Toxicology 2024; 505:153808. [PMID: 38642822 DOI: 10.1016/j.tox.2024.153808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/05/2024] [Accepted: 04/16/2024] [Indexed: 04/22/2024]
Abstract
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.
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Affiliation(s)
- Linjing Xu
- College of Food Science, South China Agricultural University, Guangzhou 510642, China; The Key Laboratory of Food Quality and Safety of Guangdong Province, Guangzhou 510642, China
| | - Huan Liu
- College of Life Sciences, Hubei Normal University, Huangshi 435000, China
| | - Yifeng Rang
- College of Food Science, South China Agricultural University, Guangzhou 510642, China; The Key Laboratory of Food Quality and Safety of Guangdong Province, Guangzhou 510642, China
| | - Lizi Zhou
- College of Food Science, South China Agricultural University, Guangzhou 510642, China; The Key Laboratory of Food Quality and Safety of Guangdong Province, Guangzhou 510642, China
| | - Xukai Wang
- College of Food Science, South China Agricultural University, Guangzhou 510642, China; The Key Laboratory of Food Quality and Safety of Guangdong Province, Guangzhou 510642, China
| | - Yinhuan Li
- College of Food Science, South China Agricultural University, Guangzhou 510642, China; The Key Laboratory of Food Quality and Safety of Guangdong Province, Guangzhou 510642, China
| | - Chunhong Liu
- College of Food Science, South China Agricultural University, Guangzhou 510642, China; The Key Laboratory of Food Quality and Safety of Guangdong Province, Guangzhou 510642, China.
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de Almeida W, Matei JC, Akiyama Kitamura RS, Gomes MP, Leme DM, Silva de Assis HC, Vicari T, Cestari MM. Alkylphenols cause cytotoxicity and genotoxicity induced by oxidative stress in RTG-2 cell line. CHEMOSPHERE 2023; 313:137387. [PMID: 36436576 DOI: 10.1016/j.chemosphere.2022.137387] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 06/16/2023]
Abstract
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.
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Affiliation(s)
- William de Almeida
- Ecology and Conservation Program, Federal University of Paraná, Brazil; Genetics Department, Federal University of Paraná, Brazil.
| | | | - Rafael Shinji Akiyama Kitamura
- Ecology and Conservation Program, Federal University of Paraná, Brazil; Pharmacology Department, Federal University of Paraná, Brazil; Botany Department, Federal University of Paraná, Brazil
| | | | | | | | - Taynah Vicari
- Ecology and Conservation Program, Federal University of Paraná, Brazil; Genetics Department, Federal University of Paraná, Brazil
| | - Marta Margarete Cestari
- Ecology and Conservation Program, Federal University of Paraná, Brazil; Genetics Department, Federal University of Paraná, Brazil
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7
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Endocrine-Disrupting Chemicals and Their Adverse Effects on the Endoplasmic Reticulum. Int J Mol Sci 2022; 23:ijms23031581. [PMID: 35163501 PMCID: PMC8836273 DOI: 10.3390/ijms23031581] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/19/2022] [Accepted: 01/27/2022] [Indexed: 02/01/2023] Open
Abstract
There is growing concern regarding the health and safety issues of endocrine-disrupting chemicals (EDCs). Long-term exposure to EDCs has serious adverse health effects through both hormone-direct and hormone-indirect ways. Accordingly, some EDCs can be a pathogen and an inducer to the susceptibility of disease, even if they have a very low affinity on the estrogen receptor, or no estrogenic effect. Endoplasmic reticulum (ER) stress recently attracted attention in this research area. Because ER and ER stress could be key regulators of the EDC’s adverse effects, such as the malfunction of the organ, as well as the death, apoptosis, and proliferation of a cell. In this review, we focused on finding evidence which shows that EDCs could be a trigger for ER stress and provide specific examples of EDCs, which are known to cause ER stress currently.
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Mitochondria as a potential target for the development of prophylactic and therapeutic drugs against Schistosoma mansoni infection. Antimicrob Agents Chemother 2021; 65:e0041821. [PMID: 34339272 DOI: 10.1128/aac.00418-21] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
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.
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Sharma P, Singh S. Combinatorial Effect of DCA and Let-7a on Triple-Negative MDA-MB-231 Cells: A Metabolic Approach of Treatment. Integr Cancer Ther 2021; 19:1534735420911437. [PMID: 32248711 PMCID: PMC7136934 DOI: 10.1177/1534735420911437] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Dichloroacetate (DCA) is a metabolic modulator that inhibits pyruvate dehydrogenase activity and promotes the influx of pyruvate into the tricarboxylic acid cycle for complete oxidation of glucose. DCA stimulates oxidative phosphorylation (OXPHOS) more than glycolysis by altering the morphology of the mitochondria and supports mitochondrial apoptosis. As a consequence, DCA induces apoptosis in cancer cells and inhibits the proliferation of cancer cells. Recently, the role of miRNAs has been reported in regulating gene expression at the transcriptional level and also in reprogramming energy metabolism. In this article, we indicate that DCA treatment leads to the upregulation of let-7a expression, but DCA-induced cancer cell death is independent of let-7a. We observed that the combined effect of DCA and let-7a induces apoptosis, reduces reactive oxygen species generation and autophagy, and stimulates mitochondrial biogenesis. This was later accompanied by stimulation of OXPHOS in combined treatment and was thus involved in metabolic reprogramming of MDA-MB-231 cells.
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Affiliation(s)
| | - Sandeep Singh
- Central University of Punjab, Bathinda, Punjab, India
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Lotfi M, Hasanpour AH, Moghadamnia AA, Kazemi S. The Investigation into Neurotoxicity Mechanisms of Nonylphenol: A Narrative Review. Curr Neuropharmacol 2021; 19:1345-1353. [PMID: 33213348 PMCID: PMC8719294 DOI: 10.2174/1570159x18666201119160347] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 10/07/2020] [Accepted: 10/14/2020] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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.
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Affiliation(s)
| | | | | | - Sohrab Kazemi
- Address correspondence to this author at the Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran, Tel: +98.9111162119; Fax: +98.1132207918; E-mail:
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Bouzidi A, Magnifico MC, Paiardini A, Macone A, Boumis G, Giardina G, Rinaldo S, Liberati FR, Lauro C, Limatola C, Lanzillotta C, Tramutola A, Perluigi M, Sgarbi G, Solaini G, Baracca A, Paone A, Cutruzzolà F. Cytosolic serine hydroxymethyltransferase controls lung adenocarcinoma cells migratory ability by modulating AMP kinase activity. Cell Death Dis 2020; 11:1012. [PMID: 33243973 PMCID: PMC7691363 DOI: 10.1038/s41419-020-03215-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/06/2020] [Accepted: 11/06/2020] [Indexed: 02/07/2023]
Abstract
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.
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Affiliation(s)
- Amani Bouzidi
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Maria Chiara Magnifico
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", Via Orabona 4, 70121, Bari, Italy
| | - Alessandro Paiardini
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Alberto Macone
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Giovanna Boumis
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Giorgio Giardina
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Serena Rinaldo
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Francesca Romana Liberati
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Clotilde Lauro
- Department of Physiology and Pharmacology V. Erspamer, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Cristina Limatola
- Department of Physiology and Pharmacology V. Erspamer, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Chiara Lanzillotta
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Antonella Tramutola
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Marzia Perluigi
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy
| | - Gianluca Sgarbi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy
| | - Giancarlo Solaini
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy
| | - Alessandra Baracca
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy
| | - Alessio Paone
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy.
| | - Francesca Cutruzzolà
- Department of Biochemical Sciences A. Rossi Fanelli, Laboratory Affiliated to Istituto Pasteur Italia, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy.
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Liu R, Zhang Y, Gao J, Li X. Effects of octylphenol exposure on the lipid metabolism and microbiome of the intestinal tract of Rana chensinensis tadpole by RNAseq and 16s amplicon sequencing. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 197:110650. [PMID: 32315788 DOI: 10.1016/j.ecoenv.2020.110650] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 03/20/2020] [Accepted: 04/14/2020] [Indexed: 06/11/2023]
Abstract
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.
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Affiliation(s)
- Rong Liu
- College of Life Science, Shaanxi Normal University, Xi'an, 710119, China
| | - Yuhui Zhang
- College of Life Science, Shaanxi Normal University, Xi'an, 710119, China
| | - Jinshu Gao
- College of Life Science, Shaanxi Normal University, Xi'an, 710119, China
| | - Xinyi Li
- College of Life Science, Shaanxi Normal University, Xi'an, 710119, China.
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