Non-negligible Toxicity to Fish in the Early Life Stages Triggered by Aqueous Leachate of Takeaway Plastic Containers.

Ordering takeout is a growing social phenomenon and may raise public health concerns. However, the associated health risk of compounds leaching from plastic packaging is unknown due to the lack of chemical and toxicity data. In this study, 20 chemical candidates were tentatively identified in the environmentally relevant leachate from plastic containers through the nontargeted chemical analysis. Three main components with high responses and/or predicted toxicity were further verified and quantified, namely, 3,5-di-tert-butyl-4-hydroxycinnamic acid (BHC), 2,4-di-tert-butylphenol (2,4-DTBP), and 9-octadecenamide (oleamide). The toxicity to zebrafish larvae of BHC, a degradation product of a widely used antioxidant Irganox 1010, was quite similar to that of the whole plastic leachate. In the same manner, RNA-seq-based ingenuity analysis showed that the affected canonical pathways of zebrafish larvae were quite comparable between BHC and the whole plastic leachate, i.e., highly relevant to neurological disease, metabolic disease, and even behavioral disorder. Longer-term exposure (35 days) did not cause any effect on adult zebrafish but led to decreased hatching rate and obvious neurotoxicity in zebrafish offspring. Collectively, this study strongly suggests that plastic containers can leach out a suite of compounds causing non-negligible impacts on the early stages of fish via direct or parental exposure.

The association between missing teeth and non-alcoholic fatty liver disease in adults.

AIMS: Long-term oral chronic inflammatory process is closely related to systemic inflammation, which is a main mechanism involved in non-alcoholic fatty liver disease (NAFLD). Tooth loss could reflect the accumulation of oral local inflammation, implying that number of missing teeth may associate with NAFLD. This study evaluated the association between missing teeth and presence of NAFLD in a general population. MATERIALS AND METHODS: A cross-sectional study of 24,470 adults was carried out from the Tianjin Chronic Low-grade Systemic Inflammation and Health Cohort Study. The self-reported number of missing teeth (excluding third molars) was recorded and classified into four categories: 0, 1-2, 3-5, and ≥6. The NAFLD was diagnosed by the liver ultrasonography. Associations were analysed by adjusted multivariable logistic regression. RESULTS: The multivariable-adjusted odds ratios (95% confidence interval) of NAFLD across the categories of missing teeth were as follows: in males, 1.00 (reference), 1.04 (0.93-1.16), 1.06 (0.90-1.24), and 1.40 (1.09-1.81) (p for trend = 0.04); in females, 1.00 (reference), 0.98 (0.83-1.15), 1.11 (0.90-1.37), and 1.07 (0.77-1.48) (p for trend = 0.45). CONCLUSIONS: The number of missing teeth was associated with a higher presence of NAFLD in males but not females.

Association Between Number of Missing Teeth and Hyperlipidemia: The TCLSIH Cohort Study.

Background: To explore the association between the number of missing teeth and the prevalence of hyperlipidemia in a Chinese adult population. Methods: 13,932 adults were investigated in the TCLSIH cohort study. The number of missing teeth was determined at baseline through a self-reported questionnaire, and then classified into three categories: 0, 1-2, and ≥3. We defined hyperlipidemia as total cholesterol (TC) ≥ 5.17 mmol/L or triglycerides (TG) ≥ 1.7 mmol/L or low-density lipoprotein (LDL) cholesterol ≥ 3.37 mmol/L or a self-report of physician-diagnosed hyperlipidemia during follow-up visits. Cox proportional-hazards regression models were employed to assess the relationship between the number of missing teeth and incident hyperlipidemia. Results: A total of 6756 first-incident cases of hyperlipidemia occurred during 42,048 person-years of follow-up (median follow-up, 4.2 years). After adjusted confounders, multivariable HRs and 95% CI for incident of hyperlipidemia across the categories of missing teeth were as follows: in male participants, 1.00 (reference), 1.10 (0.98, 1.22), and 1.03 (0.91, 1.16) (P for trend = 0.30); in female participants, 1.00 (reference), 1.09 (0.99, 1.19), and 1.18 (1.04, 1.33) (P for trend < 0.01). Conclusion: The number of missing teeth is associated with an increased risk of hyperlipidemia in female participants but not in male participants. Systemic chronic inflammation may potentially mediate this association.

Association between tooth loss and handgrip strength in a general adult population.

Tooth loss is a prevailing condition in China due to the high prevalence of oral diseases. Since previous studies explored the association between tooth loss and handgrip strength showed incongruous results, the aim of this study was to investigate the association between tooth loss and handgrip strength in Tianjin, China. Cross-sectional data in the present study used baseline data of Tianjin Chronic Low-grade Systemic Inflammation and Health (TCLSIH) Cohort Study during 2013-2016. Eligible adults (n = 26275) were classified into four groups depending on the number of missing teeth (excluding third molars): 0, 1-2, 3-5 and ≥6. Handgrip strength was measured using a handheld type dynamometer. Analysis of covariance was used to examine the relationships between tooth loss and handgrip strength and handgrip strength per body weight according to gender. After adjustment for potential confounders, the relationships existed between increasing categories of tooth loss and handgrip strength, as well as handgrip strength per weight. The data of stratified analysis showed that there was a trending association between decreased handgrip strength and fewer retained teeth both in males and females less than 60 years of age (P for trend <0.01); whereas no significant association 60 years of age or older. Moreover, loss of more than 3 teeth was significantly associated with reduced muscle strength (P <0.01). Tooth loss is independently associated with handgrip strength in Chinese adults less than 60 years of age.

Medium composition optimization, structural characterization, and antioxidant activity of exopolysaccharides from the medicinal mushroom Ganoderma lingzhi.

To contribute towards effective exploitation and utilization of natural antioxidants, response surface methodology (RSM) was employed to optimize the medium composition for the production of exopolysaccharides from the medicinal mushroom Ganoderma lingzhi (GLEPS). An optimal medium for GLEPS production was gave through Plackett-Burman design, path of steepest ascent, and Box-Behnken design as follows: glucose (59.62 g/L), yeast extract (10.03 g/L), CaCO3 (0.2 g/L), thiamine (45.13 mg/L), KH2PO4 (1.0 g/L), peptone (1.5 g/L), Tween 80 (10.26 mL/L), ZnSO4 (0.3 g/L), mannitol (1.5 g/L), MgSO4 (0.5 g/L), and aspartate (8.86 g/L). The GLEPS yield obtained was 3.57 ±â€¯0.21 g/L-3.16-fold higher than that produced in basal medium alone. The resulting GLEPS rich in uronic acid, d-mannose, l-rhamnose, and d-glucose, was a heteropolysaccharide with high-molecular weights (475,000 kDa and 21.6 kDa, 87.97%). It was demonstrated that the GLEPS with higher carbohydrate and uronic acid contents exhibited strong in vitro antioxidant activities via radical scavenging, reductive capacity, and chelation of transition metal catalysis. These findings indicated that RSM is an efficient tool to predict the composition of culture medium required for maximizing GLEPS yield, and GLEPS had potent antioxidant activities and could be explored as a novel natural antioxidant in functional food or medicine.

A Combination of Targeted Sunitinib Liposomes and Targeted Vinorelbine Liposomes for Treating Invasive Breast Cancer.

Regular chemotherapy cannot eradicate invasive breast cancer cells and the residual cancer cells will form vasculogenic mimicry (VM) channels under hypoxic conditions to provide nutrients for cancer masses prior to angiogenesis. This phenomenon is a major reason for the recurrence of invasive breast cancer after treatment. In this study, a novel type of targeted liposomes was developed by modifying a mitochondria-tropic material, D-a-tocopheryl polyethylene glycol 1000 succinate- triphenylphosphine conjugate (TPGS1000-TPP), to encapsulate sunitinib and vinorelbine separately and a combination of the two targeted drug liposomes was used to treat invasive breast cancer as well as VM channels. Evaluations were performed in breast cancer MCF-7 cells and highly invasive breast cancer MDA-MB-435S cells in vitro and in mice. The results determined that the functional material (TPGS1000-TPP) and suitable size of the liposomes (90-100 nm) resulted in prolonged blood circulation, an enhanced permeability retention (EPR) effect in cancer tissue, and a mitochondrial targeting effect. Targeted drug liposomes were internalized via cellular uptake and accumulated in the mitochondria of invasive breast cancer cells or VM channel-forming cancer cells to induce acute cytotoxic injury and apoptosis. Activated apoptotic enzymes caspase 9 and caspase 3 as well as down-regulated VM channel-forming indicators (MMP-9, EphA2, VE-Cadherin, FAK and HIF-1α) contributed to significantly enhanced efficacy. Therefore, a combination of targeted sunitinib liposomes and targeted vinorelbine liposomes may provide an effective strategy for treating invasive breast cancer and prevent relapse arising from VM channels.

Targeting Epirubicin Plus Quinacrine Liposomes Modified with DSPE-PEG2000-C(RGDfK) Conjugate for Eliminating Invasive Breast Cancer.

Recurrence of invasive breast cancer could arise from the residual cancer cells after comprehensive treatment. It is possible that residual invasive cancer cells are capable of forming highly patterned vasculogenic mimicry (VM) channels, leading to relapse and metastasis. In the present study, a new type of targeting epirubicin plus quinacrine liposomes was developed by modifying functional DSPE-PEG2000 with C(RGDfK), a cyclic peptide containing Arg-Gly-Asp. These liposomes could potentially eliminate invasive breast cancer and destroy VM channels. Evaluations were made in human invasive breast cancer cells and their xenografts in nude mice. The results showed that the targeting epirubicin plus quinacrine liposomes could enhance the accumulation and uptake of the drugs in cancer tissues, kill cancer cells directly, activate apoptotic enzymes, destroy the VM channels and downregulate the VM channel-forming marker molecules (EphA2, FAK, PI3K, MMP 9, MMP 14, VE-Cad and HIF-α), thereby exhibiting a strong overall anticancer efficacy. The targeting epirubicin plus quinacrine liposomes provided a promising strategy to treat invasive breast cancer and to prevent the relapse arising from VM channels after chemotherapy.

Multifunctional targeting daunorubicin plus quinacrine liposomes, modified by wheat germ agglutinin and tamoxifen, for treating brain glioma and glioma stem cells.

Most anticancer drugs are not able to cross the blood-brain barrier (BBB) effectively while surgery and radiation therapy cannot eradicate brain glioma cells and glioma stem cells (GSCs), hence resulting in poor prognosis with high recurrence rates. In the present study, a kind of multifunctional targeting daunorubicin plus quinacrine liposomes was developed for treating brain glioma and GSCs. Evaluations were performed on in-vitro BBB model, murine glioma cells, GSCs, and GSCs bearing mice. Results showed that the multifunctional targeting daunorubicin plus quinacrine liposomes exhibited evident capabilities in crossing the BBB, in killing glioma cells and GSCs and in diminishing brain glioma in mice. Action mechanism studies indicated that the enhanced efficacy of the multifunctional targeting drugs-loaded liposomes could be due to the following aspects: evading the rapid elimination from blood circulation; crossing the BBB effectively; improving drug uptake by glioma cells and GSCs; down-regulating the overexpressed ABC transporters; inducing apoptosis of GSCs via up-regulating apoptotic receptor/ligand (Fas/Fasl), activating apoptotic enzymes (caspases 8, 9 and 3), activating pro-apoptotic proteins (Bax and Bok), activating tumor suppressor protein (P53) and suppressing anti-apoptotic proteins (Bcl-2 and Mcl-1). In conclusion, the multifunctional targeting daunorubicin plus quinacrine liposomes could be used as a potential therapy for treating brain glioma and GSCs.

Liposomes, modified with PTD(HIV-1) peptide, containing epirubicin and celecoxib, to target vasculogenic mimicry channels in invasive breast cancer.

Refractoriness of invasive breast cancer is closely related with the vasculogenic mimicry (VM) channels, which exhibit highly drug resistance to conventional chemotherapies. In the present study, the nanostructured targeting epirubicin plus celecoxib liposomes were developed by modifying a human immunodeficiency virus peptide lipid-derivative conjugate (DSPE-PEG2000-PTDHIV-1) for elimination of invasive breast cancer cells along with their VM channels. The studies were undertaken on invasive human breast cancer MDA-MB-435S cells and MDA-MB-435S xenografts in nude mice. The constructed targeting epirubicin plus celecoxib liposomes were approximately 100 nm in size. In vitro results showed that the targeting liposomes exhibited strong transport ability across cell and nuclei membranes of invasive breast cancer, were able to penetrate and destruct the invasive breast cancer spheroids, initiated apoptosis via activating apoptotic enzymes (caspase 8, 3), and destroyed the VM channels via down-regulating the protein indicators (MMP-9, VE-Cad, FAK, EphA2 and HIF-1α) in invasive breast cancer cells. In vivo results demonstrated that the targeting liposomes displayed a prolonged circulation time in blood system, accumulated more in tumor location, were able to eliminate the VM channels and angiogenesis in tumor tissues, and resulted in a robust overall anticancer efficacy in invasive breast cancer MDA-MB-435S xenografts in nude mice. In conclusion, the nanostructured targeting epirubicin plus celecoxib liposomes could eliminate invasive breast cancer along with the VM channels, hence providing a promising strategy for treatment of invasive breast cancer.

Multifunctional liposomes loaded with paclitaxel and artemether for treatment of invasive brain glioma.

Invasive brain glioma is the most lethal type of cancer and is highly infiltrating. This leads to an extremely poor prognosis and makes complete surgical removal of the tumor virtually impossible. Non-penetration of therapeutic drugs across the blood-brain barrier (BBB), brain cancer stem cells (CSCs), and brain cancer vasculogenic mimicry (VM) results in relapse after surgical and radio therapy. We developed a functional targeting chemotherapy for transporting drugs across the BBB, destroying VM channels, and eliminating CSCs and cancer cells in the brain. The studies were undertaken on brain glioma cells in vitro and in brain glioma-bearing rats. Using paclitaxel as the anticancer drug and artemether as the regulator of apoptosis and inhibitor of VM channels, a kind of functional targeting paclitaxel plus artemether liposomes was developed by modifying two new functional materials: a mannose-vitamin E derivative conjugate (MAN-TPGS1000) and a dequalinium-lipid derivative conjugate (DQA-PEG2000-DSPE). The transport mechanism across the BBB was associated with receptor-mediated endocytosis by MAN-TPGS1000 conjugate via glucose transporters and adsorptive-mediated endocytosis by DQA-PEG2000-DSPE conjugate via electric charge-based interactions. The efficacy was related to the destruction of VM channels by regulating VM indicators, as well as the induction of apoptosis in brain cancer cells and CSCs by activating apoptotic enzymes and pro-apoptotic proteins and inhibiting anti-apoptotic proteins. These data suggest that the chemotherapy using functional targeting paclitaxel plus artemether liposomes could provide a new strategy for treating invasive brain glioma.

The anticancer efficacy of paclitaxel liposomes modified with mitochondrial targeting conjugate in resistant lung cancer.

Lung cancer is the leading cause of cancer-related death in humans and the multidrug resistance (MDR) is the major obstacle to successful chemotherapy of lung cancer. In this study, a d-α-tocopheryl polyethylene glycol 1000 succinate-triphenylphosphine conjugate (TPGS1000-TPP) was synthesized as the mitochondrial targeting molecule, and was incorporated onto the surface of paclitaxel liposomes to treat the drug-resistant lung cancer. Evaluations were performed on the human lung cancer A549 cells, the drug-resistant lung cancer A549/cDDP cells, and the drug-resistant lung cancer A549/cDDP cells xenografted nude mice. The yield of TPGS1000-TPP conjugate synthesized was about 50% and the particle size of targeting paclitaxel liposomes developed was approximately 80 nm. In comparison with taxol and regular paclitaxel liposomes, the targeting paclitaxel liposomes exhibited the strongest anticancer efficacy in vitro and in the drug-resistant A549/cDDP xenografted tumor model. The targeting paclitaxel liposomes could significantly enhance the cellular uptake, be selectively accumulated into the mitochondria, and cause the release of cytochrome C. This targeting delivery of drug initiated a cascade of caspase 9 and 3 reactions, activated the pro-apoptotic Bax and Bid proteins and suppressed the anti-apoptotic Bcl-2 protein, thereby enhancing the apoptosis by acting on the mitochondrial signaling pathways. In conclusion, the targeting paclitaxel liposomes have the potential to treat drug-resistant lung cancer.

Modulation of drug-resistant membrane and apoptosis proteins of breast cancer stem cells by targeting berberine liposomes.

The recurrence of breast cancer is associated with drug-resistance of cancer stem cells (CSCs), while overexpression of cell membrane ATP-binding cassette (ABC) transporters and resistance of mitochondrial apoptosis-related proteins are responsible for the drug-resistance of CSCs. The targeting berberine liposomes were developed to modulate the resistant membrane and mitochondrial proteins of breast CSCs for the treatment and prevention of breast cancer relapse. Evaluations were performed on human breast CSCs and CSC xenografts in nude mice. The targeting berberine liposomes were shown to cross the CSC membrane, inhibit ABC transporters (ABCC1, ABCC2, ABCC3, ABCG2) and selectively accumulate in the mitochondria. Furthermore, the pro-apoptotic protein Bax was activated while the anti-apoptotic protein Bcl-2 was inhibited resulting in opening of the mitochondrial permeability transition pores, release of cytochrome c, and activation of caspase-9/caspase-3 enzymes. Significant efficacy of the administrations in mice was observed, indicating that the targeting berberine liposomes are a potential therapy for the treatment and prevention of breast cancer relapse arising from CSCs.

Mitochondrial targeting liposomes incorporating daunorubicin and quinacrine for treatment of relapsed breast cancer arising from cancer stem cells.

Breast cancer stem cells play a crucial role in the relapse of breast cancers because they are resistant to a standard chemotherapy and the residual cancer stem cells are able to proliferate indefinitely. The objectives of present study were to construct a kind of mitochondrial targeting daunorubicin plus quinacrine liposomes for treating and for preventing the recurrence of breast cancer arising from the cancer stem cells. MCF-7 cancer stem cells were identified as CD44(+)/CD24(-) cells and cultured in free-serum medium. Evaluations were performed on MCF-7 cancer stem cells, MCF-7 cancer stem cell mammospheres, and the relapsed tumor by xenografting MCF-7 cancer stem cells into female NOD/SCID mice. The particle size of mitochondrial targeting daunorubicin plus quinacrine liposomes was approximately 98 nm. The mitochondrial targeting liposomes evidently increased the mitochondrial uptake of drugs, were selectively accumulated into mitochondria, activated the pro-apoptotic Bax protein, dissipated the mitochondrial membrane potential, opened the mitochondrial permeability transition pores, released cytochrome C by translocation, and initiated a cascade of caspase 9 and 3 reactions, thereby inducing apoptosis of MCF-7 cancer stem cells. The mitochondrial targeting liposomes showed the strongest efficacy in treating MCF-7 cancer cells in vitro, in treating MCF-7 cancer stem cells in vitro, and in treating the relapsed tumor in mice. Mitochondrial targeting daunorubicin plus quinacrine liposomes would provide a new strategy for treating and preventing the relapse of breast cancers arising from cancer stem cells.