Design and structure-activity relationships of ether-linked alkylides: Hybrids of 3-O-descladinosyl macrolides and quinolone motifs.

Ketolides (3-keto) such as TE-802 and acylides (3-O-acyl) like TEA0929 are ineffective against constitutively resistant pathogens harboring erythromycin ribosomal methylation (erm) genes. Following our previous work on alkylides (3-O-alkyl), we explored the structure-activity relationships of hybrids combining (R/S) 3-descladinosyl erythromycin with 6/7-quinolone motifs, featuring extended ether-linked spacers, with a focus on their efficacy against pathogens bearing constitutive erm gene resistance. Optimized compounds 17a and 31f not only reinstated efficacy against inducibly resistant pathogens but also demonstrated significantly augmented activities against constitutively resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes, which are typically refractory to existing C-3 modified macrolides. Notably, hybrid 31f (coded ZN-51) represented a pioneering class of agents distinguished by its dual modes of action, with ribosomes as the primary target and topoisomerases as the secondary target. As a novel chemotype of macrolide-quinolone hybrids, alkylide 31f is a valuable addition to our armamentarium against macrolide-resistant bacteria.

The design and straightforward synthesis of multifunctional DNA microgels for the improved targeted delivery of antitumor drugs.

Multifunctional drug delivery platforms represent ideal approaches to reliably targeting pharmacological agents of interest to the complex tumor microenvironment (TME), yet the complicated synthesis processes, high costs, and toxicities associated with these agents have hindered their clinical application to date. In this study, the properties of the TME are leveraged to develop a multifunctional pNAB/AS DNA microgel that is able to actively target tumors. This microgel is generated by a straightforward one-step free radical precipitation polymerization procedure, exhibiting extremely high drug encapsulation efficiency (∼90%), and is responsive to three environmental stimuli including temperature, reduction, and an acidic pH while showing minimal drug leakage under physiological conditions. Through a synergistic combination of appropriate size and aptamer recognition, this microgel is able to reliably facilitate intratumoral drug accumulation and nuclear drug delivery. Critically, pNAB/AS-Dox treatment is associated with specific antitumor activity in vitro and in vivo while retaining a good biosafety profile and causing lower levels of off-target toxicity as compared to free drug treatment. Together, these findings emphasize the potential value of this multifunctional pNAB/AS DNA microgel as a platform amenable to targeted drug delivery to the TME, providing a foundation for further efforts to readily develop multifunctional drug delivery systems.

Influence of dietary bioactive compounds on the bioavailability and excretion of PFOA and its alternative HFPO-TA: Mechanism exploration.

Oral ingestion is considered an important route of human exposure to perfluorooctanoic acid (PFOA) and its alternative hexafluoropropylene oxide trimer acid (HFPO-TA). Bioactive compounds are widely used as dietary supplements and food additives. However, little is known about the influence of dietary bioactive compounds on the bioavailability of PFOA and HFPO-TA. Here, three dietary bioactive compounds, ß-carotene, quercetin and curcumin, were selected to study their influence on the relative bioavailability (RBA) of PFOA and HFPO-TA in soil using a mouse model. Compared to the control group (68.7 ± 6.27 %), quercetin and curcumin at medium and high doses (20 and 100 mg/kg/d) significantly (p < 0.05) decreased PFOA RBA to 55.2 ± 4.85-56.4 ± 4.57 % and 48.3 ± 5.49-48.6 ± 5.44 %, respectively. Mechanism study showed that medium- and high-dose quercetin as well as high-dose curcumin increased urinary excretion of PFOA by 33.6-35.6 % and 32.2 % through upregulating renal expression of multidrug resistance protein 2 (Mrp2) (1.52-1.63 folds) and Mrp4 (1.26-1.53 folds), thereby reducing PFOA accumulation. In PFOA-treated groups, quercetin at medium and high doses dramatically downregulated the hepatic expression of organic anion transport polypeptides (Oatp1a6, Oatp1b2), organic anion transport proteins (Oat1, Oat2), and fatty acid binding proteins (FABP4, FABP12), while curcumin at medium and high doses inhibited the hepatic expression of Oatp1a6, Oat1 and Oat2. These downregulated genes may reduce the transport of PFOA from blood to liver, and in turn decrease the PFOA RBA. However, ß-carotene, quercetin and curcumin exhibited no significant effect on RBA and excretion of HFPO-TA (p > 0.05). This indicated the different absorption mechanisms between PFOA and HFPO-TA, and further research is warranted. This study provided a novel perspective for establishing environmentally friendly ways to reduce health hazards from per- and polyfluoroalkyl substances (PFASs).

Current perspectives and trend of nanomedicine in cancer: A review and bibliometric analysis.

The limitations of traditional cancer treatments are driving the creation and development of new nanomedicines. At present, with the rapid increase of research on nanomedicine in the field of cancer, there is a lack of intuitive analysis of the development trend, main authors and research hotspots of nanomedicine in the field of cancer, as well as detailed elaboration of possible research hotspots. In this review, data collected from the Web of Science Core Collection database between January 1st, 2000, and December 31st, 2021, were subjected to a bibliometric analysis. The co-authorship, co-citation, and co-occurrence of countries, institutions, authors, literature, and keywords in this subject were examined using VOSviewer, Citespace, and a well-known online bibliometrics platform. We collected 19,654 published papers, China produced the most publications (36.654%, 7204), followed by the United States (29.594%, 5777), and India (7.780%, 1529). An interesting fact is that, despite China having more publications than the United States, the United States still dominates this field, having the highest H-index and the most citations. Acs Nano, Nano Letters, and Biomaterials are the top three academic publications that publish articles on nanomedicine for cancer out of a total of 7580 academic journals. The most significant increases were shown for the keywords "cancer nanomedicine", "tumor microenvironment", "nanoparticles", "prodrug", "targeted nanomedicine", "combination", and "cancer immunotherapy" indicating the promising area of research. Meanwhile, the development prospects and challenges of nanomedicine in cancer are also discussed and provided some solutions to the major obstacles.

Ferulic Acid Combined With Bone Marrow Mesenchymal Stem Cells Attenuates the Activation of Hepatic Stellate Cells and Alleviates Liver Fibrosis.

Bone marrow mesenchymal stem cells (BMSCs) can effectively alleviate liver fibrosis, but the efficacy of cell therapy alone is insufficient. In recent years, a combination of traditional Chinese medicine (TCM) and cell therapy has been increasingly used to treat diseases in clinical trials. Ferulic acid (FA) is highly effective in treating liver fibrosis, and a combination of cells and drugs is being tested in clinical trials. Therefore, we combined BMSCs and Ferulic acid to treat CCl4-induced fibrosis and determine whether this combination was more effective than single treatment. We used BMSCs and FA to treat CCl4-induced fibrosis in rat models, observed their therapeutic effects, and investigated the specific mechanism of this combination therapy in liver fibrosis. We created a BMSC/hepatic stellate cell (HSC) coculture system and used FA to treat activated HSCs to verify the specific mechanism. Then, we used cytochalasin D and angiotensin II to investigate whether BMSCs and FA inactivate HSCs through cytoskeletal rearrangement. MiR-19b-3p was enriched in BMSCs and targeted TGF-ß receptor II (TGF-ßR2). We separately transfected miR-19b-3p into HSCs and BMSCs and detected hepatic stellate cell activation. We found that the expression of the profibrotic markers α-SMA and COL1-A1 was significantly decreased in the combination group of rats. α-SMA and COL1-A1 levels were also significantly decreased in the HSCs with the combination treatment. Cytoskeletal rearrangement of HSCs was inhibited in the combination group, and RhoA/ROCK pathway gene expression was decreased. Following angiotensin II treatment, COL1-A1 and α-SMA expression increased, while with cytochalasin D treatment, profibrotic gene expression decreased in HSCs. The expression of COL1-A1, α-SMA and RhoA/ROCK pathway genes was decreased in the activated HSCs treated with a miR-19b-3p mimic, indicating that miR-19b-3p inactivated HSCs by suppressing RhoA/ROCK signalling. In contrast, profibrotic gene expression was significantly decreased in the BMSCs treated with the miR-19b-3p mimic and FA or a miR-19b-3p inhibitor and FA compared with the BMSCs treated with the miR-19b-3p mimic alone. In conclusion, the combination therapy had better effects than FA or BMSCs alone. BMSC and FA treatment attenuated HSC activation and liver fibrosis by inhibiting cytoskeletal rearrangement and delivering miR-19b-3p to activated HSCs, inactivating RhoA/ROCK signalling. FA-based combination therapy showed better inhibitory effects on HSC activation.

Identification of DNA methylation-driven genes by integrative analysis of DNA methylation and transcriptome data in pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is a painful and fatal disease that undoubtedly remains a health care priority and offers significant therapeutic challenges. The significance of epigenetic modifications, including DNA methylation in tumor development, has gained the attention of researchers. Identifying DNA methylation-driven genes and investigating the mechanisms underlying the tumorigenesis of PAAD are of substantial importance for developing methods of physiological evaluation, treatment planning and prognostic prediction for PAAD. In the present study, a comprehensive analysis of DNA methylation and gene expression data from 188 clinical samples was performed to identify DNA methylation-driven genes in PAAD. In addition, the diagnostic and prognostic value of DNA methylation-driven genes was evaluated using receiver operating characteristic curve, survival and recurrence analyses. A total of 7 DNA methylation-driven genes, namely zinc finger protein 208 (ZNF208), eomesodermin (EOMES), prostaglandin D2 receptor (PTGDR), chromosome 12 open reading frame 42 (C12orf42), integrin subunit α 4 (ITGA4), dedicator of cytokinesis 8 and protein phosphatase 1 regulatory inhibitor subunit 14D (PPP1R14D), were identified. All of them may be used to diagnose PAAD with excellent specificity and sensitivity (area under curve, >0.8). Of the 7 DNA methylation-driven genes, 6 were significantly associated with overall survival (OS) and recurrence-free survival (RFS) P<0.05). Among them, ZNF208, EOMES, PTGDR, C12orf42 and ITGA4 were significantly negatively associated with the OS rate and positively associated with the recurrence rate, while PPP1R14D was significantly positively associated with the OS rate and negatively associated with the recurrence rate. The present study provides novel insight into the epigenetic alterations associated with the occurrence and progression of PAAD, thereby increasing the mechanistic understanding of this disease, offering potential novel molecular biomarkers and contributing to the development of therapeutic targets for PAAD.

Effects of Food Constituents on Absorption and Bioaccessibility of Dietary Synthetic Phenolic Antioxidant by Caco-2 Cells.

One typical synthetic phenolic antioxidant 2,6-di-tert-butyl-hydroxytoluene (BHT) is widely used in foodstuff. Concerns are rising on the toxicity of BHT and its metabolites through dietary exposure. In this study, the effects of food macronutrients (i.e., lipid, carbohydrate, fiber, protein, and fasted (as control)) on absorption and bioaccessibility of BHT by Caco-2 cells were investigated. Food components decreased the absorption and bioaccessibility by Caco-2 cells. The highest absorption rate by Caco-2 cells was fasted state (first-order rate constant = 4.26 h-1), followed by carbohydrate (2.36 h-1), fiber (1.39 h-1), lipid (1.34 h-1), and protein (1.15 h-1). The order of bioaccessibility of BHT and its metabolites was fasted (100 ± 11.5%) > protein (83.1 ± 2.69%) > fiber (65.8 ± 2.67%) > carbohydrate (56.8 ± 1.58%) ≈ lipid (56.7 ± 0.82%). A solid-phase microextraction test together with a computational in vitro kinetic model suggested that the macronutrients may bind to BHT to reduce its free concentration and decrease the bioaccessibility. To our knowledge, this is the first study to report food influence on the absorption and bioaccessibility of BHT by Caco-2 cells. Results here can provide important implications for the safety regulation for dietary synthetic phenolic antioxidants.

Size-distribution-based assessment of human inhalation and dermal exposure to airborne parent, oxygenated and chlorinated PAHs during a regional heavy haze episode.

The adverse health effects of haze and particle-bound contaminants in China have recently caused increasing concern, and particle size plays a significant role in affecting human exposure to haze-correlated pollutants. To this background, size-segregated particulate samples (nine size fractions (<0.4, 0.4-0.7, 0.7-1.1, 1.1-2.1, 2.1-3.3, 3.3-4.7, 4.7-5.8, 5.8-9.0 and > 9.0 µm) were collected in three scale-gradient cities in northern China and analysed for a series of parent, oxygenated and chlorinated polycyclic aromatic hydrocarbons (PAHs, O-PAHs and Cl-PAHs). The total geometric mean concentrations of PAHs and O-PAHs for Beijing, Zhengzhou and Xinxiang were 98.1 and 27.2, 77.9 and 77.5, 41.0 and 30.7 ng m-3, respectively, which were 50-200 times higher than those for Cl-PAHs (0.5, 0.7 and 0.4 ng m-3). Though unimodal size-distribution patterns were found for all these contaminants for these three cities, PAHs represented distinctly higher concentration levels around the peak fraction (0.7-2.1 µm) than O-PAHs and Cl-PAHs. With 4-6 ring PAHs as dominant components in all samples, the percentage proportion of 2-3 ring PAHs (ranging from 1% to 26%) generally increased with particle size increasing, implying the sources of these compounds varied little among the 9 size fractions in all three cities. The International Commission on Radiological Protection (ICRP) model and permeability coefficient method were synchronously applied to the size-segregated data for inhalation and dermal exposure assessment to intensively estimate the human exposure doses to airborne PAHs. Further, the incremental lifetime cancer risk (ILCR) was calculated and it's found that ILCR from inhalation was higher than that from dermal uptake for children and adults in Beijing and Zhengzhou, while the ILCR for Xinxiang presented a contrary pattern, revealing dermal uptake to be an equally significant exposure pathway to airborne PAHs compared to inhalation.

BLT1 signaling in epithelial cells mediates allergic sensitization via promotion of IL-33 production.

BACKGROUND: Epithelial cells (ECs) play a crucial role in allergic sensitization to inhaled protease allergens by instructing type 2 innate lymphoid cells (ILC2) and dendritic cells (DCs) via release of pro-type 2 cytokines, particularly interleukin-33 (IL-33). Leukotriene B4 (LTB4) is a well-known leukocyte chemoattractant via engagement of its receptor 1 (BLT1). However, the role of LTB4-BLT1 axis in allergic sensitization via activation of ECs is still unknown. METHODS: We evaluated the effect of LTB4-BLT1 axis on IL-33 expression and ILC2 activation in vivo and in vitro. Chimeric mice were established to evaluate the contribution of BLT1 expression in nonimmune cell to allergic sensitization. RESULTS: Genetical or pharmacological interruption of LTB4-BLT1 axis during sensitization phase markedly reduced papain-induced IL-33 expression, decreased ILC2 activation and DC migration, thereby impairing the priming of allergic Th2 responses. Furthermore, papain inhalation induced a rapid release of LTB4 preceding IL-33, and intranasal administration of LTB4 to naïve WT mice significantly increased IL-33 expression and ILC2 activation in lung, which was absent in Il33-/- or Ltb4r1-/- mice. Furthermore, BLT1 was expressed in primary mouse ECs or normal human bronchial ECs (NHBE), and papain induced LTB4 release by NHBE, which in turn amplified IL-33 production dependent on Akt activation via BLT1. Consequently, bone marrow chimeric mice lacking BLT1 in radio-resistant structural cells failed to develop allergic lung inflammation to papain. CONCLUSION: Our study reveals a functional role of LTB4-BLT1 axis in nonimmune cells, most likely lung ECs, in controlling allergic sensitization as an upstream regulator of IL-33.

Inhalation bioaccessibility of PAHs in PM2.5: Implications for risk assessment and toxicity prediction.

In this study, 46 PM2.5 samples collected from Nanjing, China were analyzed for total PAH concentration, with 14 samples assessed for PAH inhalation bioaccessibility and dioxin toxicity. The concentration of 19 PAH compounds in PM2.5 ranged from 4.03 to 102 ng m-3. When PAH inhalation bioaccessibility was assessed using simulated epithelial lung fluid, mean bioaccessibility values ranged from 3.21% (Benzo(c)fluorene) to 44.2% (Acenaphthylene). Benzo(a)pyrene concentration in 50% of the PM2.5 samples exceeded the Chinese air quality standard of 2.5 ng m-3, however, when bioaccessibility was considered, all samples were below the criterion. Similarly, the cancer risk probability for all PM2.5 samples was >10-4 incidences on the basis of total PAH concentration, while only 37% of samples posed a risk >10-4 after incorporation of bioaccessibility. Dioxin toxicity of PM2.5-bound PAHs was also investigated by characterizing mRNA expression of cytochrome P450 superfamily members in human lung cells (A549 cell). Compared to total PAH concentration, the use of bioaccessible concentration was better at predicting dioxin toxicity of PM2.5-associated PAHs (correlation coefficient R2 = 0.40-0.83 with p < 0.05). This study indicates that PAH inhalation bioaccessibility is an important consideration when assessing and predicting the risk posed by PM2.5 particles, which is particularly important for countries with deteriorating air quality.

Cellular responses of normal (HL-7702) and cancerous (HepG2) hepatic cells to dust extract exposure.

Cancerous human liver cell line has been used to test the hepatic toxicity of indoor dust, showing its organic extract decreases cell viability. However, little is known about its impact on normal human liver cell line. In the present study, we compared the cellular responses between carcinoma cell line (HepG2) and normal cell line (HL-7702) after exposing to 10-640 µg/100 µL organic dust extract for 24 h. The dust extract caused cytotoxicity, oxidative damage, inflammatory response and loss of mitochondrial transmembrane potential (MMP) in both cells. The inhibition of cell viability in HL-7702 cells was stronger than that in HepG2 cells, with HL-7702 cells having lower LC50. Higher production of oxidative stress, more loss of MMP and stronger suppression of antioxidant enzymes mRNA level occurred in HepG2 cells, while mRNA expression and hepcidin secretion were enhanced in HL-7702 cells at 40/100 µL, indicating the dust extract probably perturbed their liver Fe homeostasis. Our data showed considerable differences in cellular responses between normal and cancerous cell lines. To obtain accurate data, normal hepatocytes should be employed as they better match with the in vivo tissue than cancerous cell lines.

Diesel exhaust particle promotes tumor lung metastasis via the induction of BLT1-mediated neutrophilic lung inflammation.

BLT1, the primary functional receptor of Leukotriene B4 (LTB4), is involved in tissue inflammation by mediating leukocyte recruitment, and recently LTB4-dependent inflammation was reported to promote lung tumor growth. Exposure to diesel exhaust particle (DEP), the major component of particulate matter 2.5 (PM2.5), can elicit lung inflammation, which may increase the risk of lung cancer. However, it remains unknown about the critical factors mediating DEP-induced lung inflammation and the subsequent effect on tumor metastasis. In this study, we found that DEP exposure led to acute lung inflammation, characterized by abundant infiltration of neutrophils and elevated lung levels in LTB4, as well as several pro-inflammatory cytokines and chemokines, including IL-1ß, IL-6, TNF-α, CXCL1/2. Furthermore, DEP exposure promoted lung metastasis of 3LL and 4T1 cells. BLT1 blockade by its specific antagonist U75302 significantly inhibited neutrophilic lung inflammation following DEP exposure. Importantly, BLT1 blockade before the onset of inflammation significantly reduced DEP-enhanced lung metastasis, which was associated with greatly decreased infiltrating neutrophils in lungs. Interestingly, BLT1 blockade after the occurrence of lung metastases had no effect on the magnitude of lung metastasis, suggesting that inhibition of BLT1-mediated lung inflammation was insufficient to suppress established metastatic tumor. Administration of BLT2 inhibitor LY255283 fails to inhibit DEP-induced lung inflammation and tumor metastasis. Collectively, our results demonstrate that DEP exposure causes BLT1-mediated lung neutrophilic inflammation, which is critical for tumor lung metastasis, and suggest that interruption of the LTB4-BLT1 axis could be useful for preventing PM2.5-induced inflammation and subsequent susceptible to lung metastasis.

Determination of 2,6-di-tert-butyl-hydroxytoluene and its transformation products in indoor dust and sediment by gas chromatography-mass spectrometry coupled with precolumn derivatization.

We developed an analytical method to simultaneously determine 2,6-di-tert-butyl-hydroxytoluene (BHT) and its four transformation products in indoor dust and sediment samples. BHT, 2,6-di-tert-butylcyclohexa-2,5-diene-1,4-dione (BHT-Q), and 3,5-di-tert-butyl-4-hydroxybenzaldehyde (BHT-CHO) were measured by gas chromatography-mass spectrometry (GC-MS) after ultrasonic extraction with hexane/dichloromethane (1:3), while 2,6-di-tert-butyl-4-(hydroxymethyl) phenol (BHT-OH) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH) were derivatized using N, O-bis (trimethylsilyl) trifluoroacetamide before GC-MS analysis. The limits of detection (LODs) and quantification (LOQs) of the developed method were 0.02-0.34 and 0.08-1.14ngg-1. The recoveries for BHT and its transformation products were 71.1-118% with relative standard deviations <10.6% at different spiking levels. The method was applied to indoor dust and sediment samples, showing that BHT was found in all samples with concentrations being 0.22-47.37µgg-1 in dust and 0.09-6.93µgg-1 in sediment. BHT-Q was the dominant transformation product, followed by BHT-CHO, BHT-OH, and BHT-COOH. Different metabolite profiles for BHT indicated various transformation pathways, making it necessary to study their transformation mechanism and environmental behaviors in the future studies.

Molecular Mechanisms of Perfluorooctanoate-Induced Hepatocyte Apoptosis in Mice Using Proteomic Techniques.

The stability of perfluorooctanoate (PFOA) coupled with its wide use cause serious concerns regarding its potential risk to human health. The molecular mechanisms of PFOA-induced hepatotoxicity relevant to human health was investigated using both in vivo (mouse model) and in vitro (human hepatocyte cells, HL-7702) techniques. Both male and female Balb/c mice were administered PFOA at 0.05, 0.5, or 2.5 mg/kg-d for 28-d, with serum PFOA concentrations after exposure being found at environmentally relevant levels. Liver samples were examined for histology and proteomic change using iTRAQ and Western Blotting, showing dose-dependent hepatocyte apoptosis and peroxisome proliferation. At high doses, genotoxicity resulting from ROS hypergeneration was due to suppression of Complex I subunits in the electron transport chain and activation of PPARα in both genders. However, at 0.05 mg/kg-d, Complex I suppression occurred only in females, making them more sensitive to PFOA-induced apoptosis. In vitro assays using HL-7702 cells confirmed that apoptosis was also induced through a similar mechanism. The dose/gender-dependent toxicity mechanisms help to explain some epidemiological phenomena, i.e., liver cancer is not often associated with PFOA exposure in professional workers. Our results demonstrated that a proteomic approach is a robust tool to explore molecular mechanisms of toxic chemicals at environmentally relevant levels.

Effects of organophosphorus flame retardant TDCPP on normal human corneal epithelial cells: Implications for human health.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is one of the most detected organophosphorus flame retardants (OPFRs) in the environment, especially in indoor dust. Continuous daily exposure to TDCPP-containing dust may adversely impact human cornea. However, its detrimental effects on human corneal epithelium are largely unknown. In this study, we investigated the cell apoptosis in normal human corneal epithelial cells (HCECs) after TDCPP exposure and elucidated the underlying molecular mechanisms. Our data indicated a dose-dependent decrease of cell viability after TDCPP exposure with LC50 at 202 µg/mL. A concentration-dependent apoptotic sign was observed in HCECs after exposing to ≥2 µg/mL TDCPP. Endoplasmic reticulum stress induction was evidenced by up-regulation of its biomarker genes (ATF-4, CHOP, BiP, and XBP1). Furthermore, alternation of Bcl-2/Bax expression, mitochondrial membrane potential loss, cellular ATP content decrease, and caspase-3 and -9 activity increase were observed after exposing to 2 or 20 µg/mL TDCPP. Taken together, the data implicated the involvement of endoplasmic reticulum stress in TDCPP-induced HCEC apoptosis, probably mediated by mitochondrial apoptotic pathway. Our findings showed TDCPP exposure induced toxicity to human cornea. Due to TDCPP's presence at high levels in indoor dust, further study is warranted to evaluate its health risk on human corneas.

Effects of novel brominated flame retardant TBPH and its metabolite TBMEHP on human vascular endothelial cells: Implication for human health risks.

As a replacement for polybrominated diphenyl ethers, bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a novel flame retardant and has been detected in many environmental matrix including human blood. TBPH can be metabolized into mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) by carboxylesterase. However, their adverse effects on human vascular endothelium and their potential impacts on human cardiovascular disease are unknown. In this study, their adverse effects and associated molecular mechanisms on human vascular endothelial cells (HUVECs) were investigated. A concentration-dependent inhibition on HUVECs' viability and growth was observed for TBMEHP but not for TBPH. TBMEHP induced a marked G0/G1 cell cycle arrest and robust cell apoptosis at 1µg/mL by inducing expression of p53, GADD45α and cyclin dependent kinase (CDK) inhibitors (p21and p27) while suppressing the expression of cyclin D1, CDK2, CDK6, and Bcl-2. Unlike TBMEHP, TBPH caused early apoptosis after G2/M phase arrest only at 10µg/mL via up-regulation of p21 and down-regulation of CDK2 and CDK4. TBMEHP decreased mitochondrial membrane potential and increased caspase-3 activity at 1µg/mL, suggesting that activation of p53 and mitochondrial pathway were involved in the cell apoptosis. The data showed that TBPH and TBMEHP induced different cell cycle arrest and apoptosis through different molecular mechanisms with much higher toxicity for TBMEHP. Our study implies that the metabolites of TBPH, possibly other novel brominated flame retardants, may be of potential concern for human cardiovascular disease.

Molecular mechanisms of PFOA-induced toxicity in animals and humans: Implications for health risks.

As an emerging persistent organic pollutant (POP), perfluorooctanoate (PFOA) is one of the most abundant perfluorinated compounds (PFCs) in the environment. This review summarized the molecular mechanisms and signaling pathways of PFOA-induced toxicity in animals and humans as well as their implications for health risks in humans. Traditional PFOA-induced signal pathways such as peroxisome proliferating receptor alpha (PPARα), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), and pregnane-X receptor (PXR) may not be important for PFOA-induced health effects on humans. Instead, pathways including p53/mitochondrial pathway, nuclear lipid hyperaccumulation, phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT), and tumor necrosis factor-α/nuclear factor κB (TNF-α/NF-κB) may play an important role for PFOA-induced health risks in humans. Both in vivo and in vitro studies are needed to better understand the PFOA-induced toxicity mechanisms as well as the associated health risk in humans.

Molecular mechanisms of dust-induced toxicity in human corneal epithelial cells: Water and organic extract of office and house dust.

Human corneal epithelial (HCE) cells are continually exposed to dust in the air, which may cause corneal epithelium damage. Both water and organic soluble contaminants in dust may contribute to cytotoxicity in HCE cells, however, the associated toxicity mechanisms are not fully elucidated. In this study, indoor dust from residential houses and commercial offices in Nanjing, China was collected and the effects of organic and water soluble fraction of dust on primary HCE cells were examined. The concentrations of heavy metals in the dust and dust extracts were determined by ICP-MS and PAHs by GC-MS, with office dust having greater concentrations of heavy metals and PAHs than house dust. Based on LC50, organic extract was more toxic than water extract, and office dust was more toxic than house dust. Accordingly, the organic extracts induced more ROS, malondialdehyde, and 8-Hydroxydeoxyguanosine and higher expression of inflammatory mediators (IL-1ß, IL-6, and IL-8), and AhR inducible genes (CYP1A1, and CYP1B1) than water extracts (p<0.05). Extracts of office dust presented greater suppression of superoxide dismutase and catalase activity than those of house dust. In addition, exposure to dust extracts activated NF-κB signal pathway except water extract of house dust. The results suggested that both water and organic soluble fractions of dust caused cytotoxicity, oxidative damage, inflammatory response, and activation of AhR inducible genes, with organic extracts having higher potential to induce adverse effects on primary HCE cells. The results based on primary HCE cells demonstrated the importance of reducing contaminants in indoor dust to reduce their adverse impacts on human eyes.

Bioaccessibility, sources and health risk assessment of trace metals in urban park dust in Nanjing, Southeast China.

Arsenic, Cd, Co, Cr, Cu, Mn, Ni, Pb, V, and Zn total concentrations and bioaccessibilities in 15 urban park dust samples were determined. The oral bioaccessibility measured by the Simple Bioaccessibility Extraction Test (SBET) decreased in the order of Pb>Cd>Zn>Mn>Cu>Co>V>Ni>As>Cr. The Tomlinson pollution load index (PLI) and geoaccumulation index (I(geo)) were calculated to evaluate the pollution extent to which the samples were contaminated. Sources were identified using principal component analysis and Pb isotope compositions. Most elements except Co and V were considered to mainly originate from anthropogenic sources. Non-carcinogenic and carcinogenic risks to humans through urban park dust exposure were assessed using the oral bioaccessibilities of the elements. Ingestion was the main pathway for non-carcinogenic risk. The hazard quotients were below the safe level (=1) for all elements, however, Pb (0.154) and As (0.184) posed potential higher risks to children than adults. The carcinogenic effects occurring were below the acceptable level (10(-4)) for As and <10(-6) for Cd, Co, Cr, and Ni.

Mechanisms of housedust-induced toxicity in primary human corneal epithelial cells: Oxidative stress, proinflammatory response and mitochondrial dysfunction.

Human cornea is highly susceptible to damage by dust. Continued daily exposure to housedust has been associated with increasing risks of corneal injury, however, the underlying mechanism has not been elucidated. In this study, a composite housedust sample was tested for its cytotoxicity on primary human corneal epithelial (PHCE) cells, which were exposed to dust at 5-320µg/100µL for 24h. PHCE cell viability showed a concentration-dependent toxic effect, attributing to elevated intracellular ROS. Moreover, when exposed at >20-80µg/100µL, dust-induced oxidative damage was evidenced by increased malondialdehyde and 8-hydroxy-2-deoxyguanosine (1.3-2.3-fold) and decreased antioxidative capacity (1.6-3.5-fold). Alteration of mRNA expression of antioxidant enzymes (SOD1, CAT, HO-1, TRXR1, GSTM1, GSTP1, and GPX1) and pro-inflammatory mediators (IL-1ß, IL-6, IL-8, TNF-α, and MCP-1) were also observed. Furthermore, the mitochondrial transmembrane potential was dissipated from 9.2 to 82%. Our results suggested that dust-induced oxidative stress probably played a vital role in the cytotoxicity in PHCE cells, which may have contributed to dust-induced impairment of human cornea.