Environmental Toxicology最新文献

Paraquat (PQ) is a noxious herbicide which adversely affects the vital organs including male reproductive system. Sudachitin (SCN) is a naturally occurring flavonoid that demonstrates a wide range of biological potentials. The current study was designed to investigate the alleviative potential of SCN to avert PQ-induced testicular toxicity in rats. Forty-eight male rats (Rattus norvegicus) were apportioned into four groups including control, PQ (5 mg/kg), PQ + SCN (5 mg/kg + 30 mg/kg), and SCN (30 mg/kg) only treated group. Our findings elucidated that PQ treatment reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2) and its antioxidant genes as well as the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSR) and glutathione peroxidase (GPx), while elevating the levels of reactive oxygen species (ROS), and malondialdehyde (MDA). Furthermore, PQ intoxication upregulated the expressions of Keap-1 while downregulating the expression of 3-beta hydroxysteroid dehydrogenase (3β-HSD), 17-beta hydroxysteroid dehydrogenase (17β-HSD), and steroidogenic acute regulatory protein (StAR). Moreover, sperm anomalies were increased following the exposure to PQ. Besides, PQ exposure decreased the levels of plasma testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) while increasing the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), interleukin-1beta (IL-1β), and cyclooxygenase-2 (COX-2). Additionally, PQ treatment escalated the expressions of cysteinyl aspartate-specific proteases-3 (Caspase-3) and Bcl-2-associated X-protein (Bax) while downregulating the expressions of B-cell lymphoma-2 (Bcl-2). Furthermore, PQ exposure disrupted the normal architecture of testicular tissues. However, SCN treatment remarkably protected the testicular tissues via regulating the aforementioned disruptions owing to its antioxidant, anti-inflammatory, and androgenic potential.

Phenethyl isothiocyanate (PEITC), a natural product, exists in biological activities, including anticancer activity in many human cancer cells. No information shows that PEITC affects DNA damage in human retinoblastoma (RB) cells in vitro. In this study, the aim of experiments was to determine whether PEITC decreased total viable cell number or not by inducing protein expressions involved in DNA damage and repair in Y79 RB cells in vitro. Total cell viability was measured by PI exclusion assay, and PEITC reduced the total Y79 viable cell numbers in a dose-dependent manner. DNA condensation and DNA impairment were conducted by DAPI staining and comet assays, respectively, in Y79 cells. The findings show that PEITC induced DNA condensation dose-dependently based on the brighter fluorescence of cell nuclei stained by DAPI staining. PEITC-induced DNA damage showed a more extended DNA migration smears than that of the control, which was performed by a comet assay. Western blotting was performed to measure the protein expressions involved in DNA damage and repair, which showed that PEITC at 2.5-10 μM increased NRF2, HO-1, SOD (Mn), and catalase; however, it decreased SOD (Cu/Zn) except 10 μM PEITC treatment, and decreased glutathione, which were associated with oxidative stress. Furthermore, PEITC increased DNA-PK, MDC1, H₂A.X^pSer139, ATM^pSer1981, p53, p53^pSer15, PARP, HSP70, and HSP90, but decreased TOPIIα, TOPIIβ, and MDM2^pSer166 that were associated with DNA damage and repair mechanism in Y79 cells. The examination from confocal laser microscopy shows that PEITC increased H₂A.X^pSer139 and p53^pSer15, and decreased glutathione and TOPIIα in Y79 cells. In conclusion, the cytotoxic effects of PEITC on reducing the number of viable cells may be due to the induction of DNA damage and the alteration of DNA repair proteins in Y79 cells in vitro.

Oxyresveratrol (OxyR) exerts biological and pharmacological effects in a variety of tumor cells, including antioxidant action, antitumor activity, and proapoptotic effects. However, the regulation of targeted signaling pathways by OxyR and the mechanism underlying these effects in human renal cell carcinoma (RCC) have been less studied. We observed that OxyR at noncytotoxic doses did not affect the growth of human RCC cells or normal kidney HK2 cells. OxyR inhibited ACHN and Caki-1 cell migration and invasion through targeting matrix metalloproteinase 1 (MMP1) expression. Analysis of clinical databases showed that high MMP1 expression is associated with lower overall survival (OS) in these cancers (p < 0.01). OxyR significantly inhibited the mRNA and protein expression of Sp1. Furthermore, luciferase assay results showed that OxyR inhibited Sp1 transcriptional activity. Additionally, OxyR preferentially suppressed the activation of ERK and PKCα. Treatment with U0126 (MEK inhibitor) or G06976 (PKCα inhibitor) clearly decreased Sp1 and MMP1 expression and inhibited RCC cell migration and invasion. In conclusion, OxyR may be a potential antitumor therapy for the inhibition of migration and invasion by controlling p-ERK/Sp1 and p-PKCα/Sp1-mediated MMP1 expression in RCC.

Bladder cancer (BC), the predominant urological malignancy in men, exhibits complex molecular underpinnings contributing to its progression. This investigation aims to elucidate the expression dynamics of calcium-binding protein 39 (CAB39) in both healthy and cancerous tissues and to explore its functional role in the epithelial–mesenchymal transition (EMT) within human bladder cancer contexts. Utilizing immunohistochemistry and quantitative reverse transcription analyses, we assessed CAB39 expression across BC specimens and cell lines. Further, we implemented wound healing, cell invasion, and CCK-8 proliferation assays in CAB39-knockdown cell lines, alongside a nude mouse xenograft model, to gauge the impact of diminished CAB39 expression on the invasive, migratory, and proliferative capacities of BC cells. Our gene set enrichment analysis probed into the repertoire of genes augmented by increased CAB39 expression in BC cells, with subsequent validation via western blotting. Our findings reveal a pronounced overexpression of CAB39 in both BC tissues and cellular models, inversely correlated with disease prognosis. Remarkably, the oncogenic trajectory of bladder cancer was mitigated upon the establishment of shRNA-mediated CAB39 knockdown in vitro and in vivo, effectively reversing the cancer's invasive and metastatic behaviors and curbing tumorigenesis in xenograft models. Hence, CAB39 emerges as a critical biomarker for bladder cancer progression, significantly implicated in facilitating EMT via the upregulation of neural cadherin (N-cadherin) and the suppression of epithelial cadherin through NF-κB signaling pathways. CU-T12-9 effectively overturned the downregulation of p65-NF-kB and N-cadherin, key elements involved in EMT and cell motility, induced by CAB39 knockdown. This study underscores CAB39's pivotal role in bladder cancer pathophysiology and its potential as a therapeutic target.

This study explores the molecular interplay between systemic lupus erythematosus (SLE) and osteoporosis (OP), aiming to uncover shared gene signatures and pathways for better treatment approaches. Leveraging microarray data from the Gene Expression Omnibus (GEO) database, we employed weighted gene coexpression network analysis to identify coexpression modules in SLE and OP, with subsequent protein–protein interaction analysis clarifying the connections among shared genes. Key genes were pinpointed using CytoHubba and random forest algorithms, validated across independent GEO datasets, and further analyzed through gene set enrichment analysis (GSEA) and immune infiltration studies. We discovered two highly correlated modules in SLE and OP, isolating 30 shared genes and identifying GBP1, SOCS1, IFI16, and XAF1 as central to both conditions. Notably, XAF1 and GBP1 mRNA levels were significantly elevated in the peripheral blood of SLE patients compared with healthy and RA counterparts, underscoring their potential as biomarkers. GSEA and immune infiltration analyses indicated pronounced immune and inflammatory responses, especially in interferon signaling pathways, implicating these core-shared gene networks in the diseases' pathogenesis. The findings highlight the involvement of GBP1, SOCS1, IFI16, and XAF1 in SLE with concurrent OP and suggest that targeting immune and inflammatory responses, particularly through interferon pathways, may offer therapeutic promise for these intertwined conditions.

Osteosarcoma, known for its rapid progression and high metastatic potential, poses significant challenges in adolescent oncology. This study delves into the roles of lipid metabolism and acetylation genes in the disease's pathogenesis. Utilizing gene set variation analysis, we examined 14 lipid metabolism-related pathways in osteosarcoma patients, identifying significant variances in three pathways between metastatic and primary cases. Additionally, differences in four acetylation genes between these groups were observed. A comprehensive analysis pinpointed 62 lipid metabolism-related genes, with 39 exhibiting significant correlations with acetylation genes, termed lipid metabolism acetylation (LMA) genes. Employing machine learning techniques like Lasso+RSF and GBM, we developed a predictive model for overall survival based on LMA genes. This model, with an average c-index of 0.771, focuses on three key genes: CYP2C8, PAFAH2, and ACOX3, whose prognostic value was confirmed through survival and receiver operating characteristic curve analyses. Quantitative RT-PCR results indicated higher expression levels of ACOX3 and PAFAH2 in OS cells (143B, HOS, MG63) than in osteoblasts (hFOB1.19), while CYP2C8 was lower in OS cells. Furthermore, drug sensitivity analysis through the pRRophetic algorithm suggested potential targeted therapies, revealing drugs with differential sensitivity based on LMA scores and varied treatment responses related to the expression of core genes. This study not only highlights the crucial role of lipid metabolism and acetylation in osteosarcoma but also offers a foundation for personalized treatment strategies, marking a notable advancement in combating this severe form of adolescent cancer.

Various studies have demonstrated that ubiquitin D (UBD) is overexpressed in different cancer types and may serve as a potential prognostic factor. However, additional research is necessary to establish the prognostic significance and possible role of UBD in glioma. Transcriptomic expression data from The Cancer Genome Atlas database (TCGA) and Chinese Glioma Genome Atlas (CGGA) were analyzed to identify UBD expression differences in tumor and normal tissues. The relative levels of UBD in glioma and normal tissues were determined using qRT-PCR and WB. Logistic regression analysis was performed to investigate the association between UBD expression and clinicopathological characteristics of glioma patients. To evaluate the diagnostic and prognostic predictive values of UBD, we used Kaplan-Meier survival curves, Cox regression analysis, diagnostic receiver operating characteristic (ROC) curves, and nomogram model. We also conducted wound healing assays, transwell assays, EdU assays, and colony formation assays to verify the UBD function. Gene ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, as well as gene set enrichment analysis (GSEA), were employed to determine the functions of UBD. Finally, we performed the western blot assays to assess changes in EMT markers as well as p-PI3K, p-AKT, and p-mTOR expressions. Our study revealed a remarkable increase of UBD expression in glioma samples. Cox regression analysis demonstrated that high expression of UBD mRNA was an independent prognostic factor for overall survival (OS) in TCGA. ROC curve analysis showed that UBD expression levels could differentiate glioma from adjacent normal tissues accurately. Additionally, knockdown of UBD reduced the migration, invasion, and proliferation ability of glioma cells while UBD overexpression had the opposite effect. GSEA showed that the expression of UBD involved with various pathways including epithelial-mesenchymal transition (EMT), PI3K-AKT-mTOR signaling, P53 pathway, angiogenesis, inflammatory response, KRAS signaling, hypoxia, as well as TGF-β signaling. Furthermore, our findings suggest that UBD accelerates the activation of EMT and PI3K/AKT/mTOR pathway.