| In recent years, nanotechnology is becoming one of the main driving forces of promoting the economic development in the world. It has already significantly affected modern society in many areas, such as bio-medicine, energy, electronics, transportation, architecture and the environment. Therefore, the importance of nanotechnology has been acquired increasing attention. Countries around the world have developed their nanotechnology development plan in line with national interests. Acompanying a number of nano-products have already on the market, nanotechnology is being shifted from basic research to applied research and to industrial transformation. Since2006, there have been1317kinds of nano products appeared in worldwide consumer market.Nanotechnology have increasingly wide application prospects which is health-related fields with people, such as environmental and biomedical field. For example, nanotechnology is used to clear the toxic and organic contaminants in water, control air pollution and achieve remedy of diseases which combines low toxicity and efficient targeted therapy. Therefore, there has been increased possibility that human exposed to different types of nanomaterials. However, the negative effects of nanomaterials on environment or human body is unknown. Materials, at nanoscale, show quantum size effect, small bulk effect, surface effect and macroscopic quantum tunneling effect. So nanomaterials may present unique effects after their expsoure to human body due to their unique physical/chemical properties. In this context, nanotoxicology was proposed as a new branch of toxicology to address the adverse health effects caused by nanomaterials and development of nanotechnology.Titanium oxide nanoparticels (TNPs) have attracted widespread attention due to its broad application prospect, such as environment, cosmetics and food adititive. However, it has been reported that TNPs can cause injury to brain, lungs, liver and even cancer. TNPs may be taken up directly to the brain from olfactory epithelium to the various parts of brain via the olfactory nerves. It produced the sustained accumulation in the brain tissues which induces brain pathological changes and oxidative stress-mediated responses. TNPs could induce some neurons to turn into filamentous shapes and others into inflammatory cells. It also induces hepatocytes necrosis, apoptosis and fibrosis.Breastfeeding is a continuation of the reproductive process. The lactation period of human lasts long. Milk provides babies the nutrients they need which is beneficial to their health and development. It also contains a number of antibodies that can protect infants from common childhood diseases attacks. Medication of women during lactation period may have negative impact on the parent and the offspring or both. The medication may transfer to pups through milk. Milk producing and the transferred medication may have a negative impact on women and newborns. Recently, people have increased contact opportunity to nano-products. So the safety of nanomaterials to lactating women and infants is worthy of concern and attention. It has been reported that C60and TNPs transfer to pups through milk, while it can also be absorbed by pups. However, the two studies did not systematically expounded whether the nanomaterials have negative impact on lactating dams or the transfer mechanism of nanomaterials.Due to the large-scale application of TNPs as well as the unknown potential negative effects on lactating dams, we select two sizes of TNPs in order to study the toxicological effects on lactating dams and their pups. And we conducted research around the lactating mammary glands (MGs) to elaborate the mechanism of nanomaterials transfer to milk. This mechanism has guiding significance to safety of nanomaterials and medication applicaion during lactation period.The biodistribution of two sizes of TNPs after i.v. exposure to lactating dams shows that TNPs accumulate in lactating MGs. However, the TNPs didn’t cause systemic toxicity to dams during exposure period and postexposure period. The dams’ organ index didn’t show significant difference between the dams exposed to TNPs and the PBS control group. The accumulation of TNPs in MGs cause oxidative stress and mammary epithelium cell shedding. Hyperplasia and adipocytes was found both in TNP1and TNP2exposure group at dose of6and8mg/kg BW. What noteworthy is that quantification of numbers of shedding epithelial cells showed that8mg/kg BW dose exposure of TNP1induces more shedding epithelial cells than its larger-sized counterpart. It also demostrates that TNP induced milk blood barrier disruption manifested by both cell shedding and loss of tight junctions. Theredore, the accumulation of TNPs in lactating MG disturbs the oxidant/antioxidant equilibrium and subsequent epithelial cells shed with tight junction loss. These results indicate that there is correlation between epithelial cells shedding and tight junction loss of mammary gland and TNP transfer to milk. MG epithelial cell shedding has another consequence that whether nutrient quality of milk will be deteriorated. The four proteins, including β-casein, a-lactalbumin, lactoferrin and epidermal growth factor, were chosen in the reason of their important function in the three aspects. The levels of four proteins, both mRNA and protein, were not meaningfully decreased after exposure to TNPs at8mg/kg BW. These data also suggest that exposure of TNPs does not impair milk secretion of dam, or deteriorate the nutrient quality of milk. Our data also showed that there was no significant difference in the pups that displayed hair growth and eye opening between the TNPs treated group at dose of8mg/kg BW and PBS control group.Part IILung cancer is one of the main causes of death among all diseases. The five-year survival rate of lung cancer is merely16.3%. Cancer treatments include surgery, radiotherapy and chemotherapy. However, drug resistance and the dose-limiting toxicity are key reasons to account for unsuccessful cancer chemotherapy. Discovery of single target-specific drugs has been the focus of cancer drug development. Research in this area has led to the successful drugs such as Gleevec, Tarceva and Iressa. Single-target drugs have gradually showed some disadvantages, such as lack of efficacy, serious side effects, and development of drug resistance. Recently, multi-level and multi-targeting therapies have shown potential applications in cancer treatment. Such therapies, including multi-component drugs or multi-targeting drugs, may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive the growth of tumors. Synergistic action of such drugs may overcome side effects that resulted from high doses of single-target drugs, increase drug selectivity, and offer an opportunity for more precise control of biological systems. Drug combinations that simultaneously impact multiple targets are more effective to overcome MDR and lower side-effects in cancer cell inhibition and tumor shrinkage.The thiazolidinone derivatives are useful anticancer agents with P-gp-evading property and minimal side effects. By screening compound combinations prepared from a thiazolidinone compound library in a drug-resistant variant H460/TaxR NSCLC cell line, a four-compound combination was identified that synergistically inhibit the growth of cancer cells from both lines. We found that (1) thiazolidinone compound combinations that have synergistic inhibitory effects on P-gp overexpressing NSCLC;(2) individual compound in this combination act as either tubulin polymerizationinhibitors or histone deacetylase (HDAC) inhibitors. |
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