Xiaoting Jin

Protective efficacy of vitamins C and E on p,p'-DDT-induced cytotoxicity via the ROS-mediated mitochondrial pathway and NF-κB/FasL pathway.

Dichlorodiphenoxytrichloroethane (DDT) is a known persistent organic pollutant and liver damage toxicant. However, there has been little emphasis on the mechanism underlying liver damage toxicity of DDT and the relevant effective inhibitors. Hence, the present study was conducted to explore the protective effects of vitamin C (VC) and vitamin E (VE) on the cytotoxicity of DDT in HL-7702 cells and elaborate the specific molecular mechanisms. The results demonstrated that p,p′-DDT exposure at over 10 µM depleted cell viability of HL-7702 cells and led to cell apoptotic. p,p′-DDT treatment elevated the level of reactive oxygen species (ROS) generation, induced mitochondrial membrane potential, and released cytochrome c into the cytosol, with subsequent elevations of Bax and p53, along with suppression of Bcl-2. In addition, the activations of caspase-3 and -8 were triggered. Furthermore, p,p′-DDT promoted the expressions of NF-κB and FasL. When the cells were exposed to the NF-κB inhibitor (PDTC), the up-regulated expression of FasL was attenuated. Strikingly, these alterations caused by DDT treatment were prevented or reversed by the addition of VC or VE, and the protective effects of co-treatment with VC and VE were higher than the single supplement with p,p′-DDT. Taken together, these findings provide novel experimental evidences supporting that VC or/and VE could reduce p,p′-DDT-induced cytotoxicity of HL-7702 cells via the ROS-mediated mitochondrial pathway and NF-κB/FasL pathway.

Amelioration of particulate matter-induced oxidative damage by vitamin c and quercetin in human bronchial epithelial cells

Exposure to fine particulate matter (PM2.5) has a close association with respiratory damage. Vitamin c and quercetin have been documented to possess antioxidant and anti-inflammation properties. However, their potential protective effects against PM2.5-induced respiratory damage have not been evaluated yet. Hence, the study was aimed to investigate their protective effects and delineate the possible mechanisms. The results indicated that PM2.5 depleted the cell viability of 16HBE cells, elevated reactive oxygen species (ROS) generation, and inhibited mitochondrial genes expressions, including fusion proteins Mfn1 and OPA1, along with biogenesis markers SIRT1 and p53R2. Additionally, the damage of mitochondrial morphology was observed upon PM2.5 exposure using both JC-1 and MitoTracker Red staining. Expressions of mitochondrial respiratory chain genes including NDUFS2 and UQCRI1 were also attenuated by PM2.5 exposure. Furthermore, PM2.5 promoted the mRNA levels of NADPH oxidase and inflammation cytokines. However, the addition of vitamin c or quercetin strikingly antagonized the PM2.5-induced toxic effects. Collectively, these findings suggest that vitamin c and quercetin have repressive roles in respiratory oxidative damage incurred by PM2.5, which provide the theoretical basis about intervention and control of food nutrients on PM2.5-induced human adverse health.

p, p′-Dichlorodiphenyldichloroethylene Induces Colorectal Adenocarcinoma Cell Proliferation through Oxidative Stress

p, p′-Dichlorodiphenyldichloroethylene (DDE), the major metabolite of Dichlorodiphenyltrichloroethane (DDT), is an organochlorine pollutant and associated with cancer progression. The present study investigated the possible effects of p,p′-DDE on colorectal cancer and the involved molecular mechanism. The results indicated that exposure to low concentrations of p,p′-DDE from 10−10 to 10−7 M for 96 h markedly enhanced proliferations of human colorectal adenocarcinoma cell lines. Moreover, p,p′-DDE exposure could activate Wnt/β-catenin and Hedgehog/Gli1 signaling cascades, and the expression level of c-Myc and cyclin D1 was significantly increased. Consistently, p,p′-DDE-induced cell proliferation along with upregulated c-Myc and cyclin D1 were impeded by β-catenin siRNA or Gli1 siRNA. In addition, p,p′-DDE was able to activate NADPH oxidase, generate reactive oxygen species (ROS) and reduce GSH content, superoxide dismutase (SOD) and calatase (CAT) activities. Treatment with antioxidants prevented p,p′-DDE-induced cell proliferation and signaling pathways of Wnt/β-catenin and Hedgehog/Gli1. These results indicated that p,p′-DDE promoted colorectal cancer cell proliferation through Wnt/β-catenin and Hedgehog/Gli1 signalings mediated by oxidative stress. The finding suggests an association between p,p′-DDE exposure and the risk of colorectal cancer progression.

Bisphenol a exposure promotes the migration of NCM460 cells via estrogen receptor-mediated integrin β1/MMP-9 pathway.

Bisphenol A (BPA) is a widely used industrial chemical and also an environmental endocrine disruptor (EED), which serves as a monomer in the manufacture of polycarbonate plastics. BPA enters human body mainly through oral intake, and has been reported as being linked to oncogenesis in many tissues. However, the association of BPA intake with gastrointestinal cancer, such as colon cancer, has received less attention. The present study was conducted to investigate the effects of BPA on the migration of normal colon epithelial cells (NCM460 cells) and further elucidate the underlying mechanisms. Our data showed that 1 × 10−8 M (equivalent to environmental concentration) of BPA potently promoted the migration of NCM460 cells. Interestingly, BPA treatment induced an increase of integrin β1 expression, and the functional blocking of integrin β1 abolished the migration‐promoting effects of BPA. Moreover, the results showed that it was estrogen receptor β but not estrogen receptor α that was involved in this migration promotion. In addition, cellular exposure of BPA stimulated the expression and activity of MMP‐9, a well‐known factor of cell migration. Taken together, these results indicate that environmental concentration of BPA exposure promotes cell migration through activating ERβ‐mediated integrin β1/MMP‐9 pathway, suggesting exposure to BPA in the colon may present a potential cancer risk.

Dichlorodiphenyldichloroethylene exposure reduces r‐GCS via suppressed Nrf2 in HepG2 cells

p,p′‐dichlorodiphenyldichloroethylene (p,p′‐DDE), the major isomer of persistent 1,1‐Bis(4‐chlorophenyl)−2,2,2‐trichloroethane metabolite, is highly associated with the risk of liver cancer. γ‐glutamyl‐cysteine synthetase (γ‐GCS), which is the rate‐limiting enzyme of glutathione (GSH) biosynthesis and an important scavenger of reactive oxygen species (ROS), is considered as a potential therapeutic target for many cancers. However, the association between the body burden of p,p′‐DDE and γ‐GCS has not been fully established. Here, we indicated that low doses of p,p′‐DDE exposure promoted the proliferation and decreased γ‐GCS activity of HepG2 cells in a dose‐ and time‐dependent manner. In addition, p,p′‐DDE elevated ROS content and attenuated glutathione peroxidase activity. This was accompanied with inhibitions of NF‐E2‐related factor 2 (Nrf2) at the mRNA and protein levels. ROS inhibitor supplement could significantly reverse these effects. Moreover, the addition of the proteasome inhibitor, MG132, strongly reversed the p,p′‐DDE‐reduced Nrf2 expression and γ‐GCS activity. Consistently, GSH content was in line with the alteration of γ‐GCS. Collectively, the results indicate that p,p′‐DDE treatment downregulates γ‐GCS activity in HepG2 cells by inducing ROS‐mediated Nrf2 loss.

Crucial role of pro-inflammatory cytokines from respiratory tract upon PM 2.5 exposure in causing the BMSCs differentiation in cells and animals

Fine particulate matter exposure may cause health risk, including cardiovascular diseases and cancer. Bone marrow mesenchymal stem cell (BMSC), a typical model for evaluating pollutant toxicity, has been closely linked to these diseases, due to its characteristics of differentiation. We therefore studied the BMSCs differentiation and its roles in inflammatory activation in the respiratory tract upon PM2.5 exposure using both in vitro and in vivo models. BMSCs differentiation into endothelial-like cells (ELCs) and cancer-associated fibroblasts cells (CAFs) was enhanced in response to conditioned medium from PM2.5–treated 16HBE cells. PM2.5 elevated inflammatory cytokines’ expression and secretion in 16HBE cells. However, induction of differentiation markers was reduced when IL-1β, IL-6 and COX-2 neutralizing antibodies were added to the conditioned medium. Furthermore, PM2.5 induced ROS formation and NADPH oxidase (NOX) expression in 16HBE cells. DPI (inhibitor of ROS from NOX) or NAC (inhibitor of ROS) supplement reduced PM2.5-induced inflammatory activation and BMSCs differentiation. Likewise, a concomitant disorder of mitochondrial morphology and respiratory chain was observed. In addition, Rot or AA (inhibitor of mitochondrial complex I or III) supplement restored PM2.5-induced toxic effects. Moreover, the results coincided with the in vitro data obtained from SD rats post-exposed to different doses of PM2.5 for 30 days. PM2.5 enhanced the BMSCs differentiation and inflammatory cytokines’ expression in respiratory organs of SD rats, including lung and trachea tissue. This study uncovers that PM2.5 promotes the BMSCs differentiation via inflammatory activation mediated by ROS induction from NOX and mitochondria in the respiratory tract.