Reverse charge transfer and decomposition in Ca-Te compounds under high pressure.

Pressure alters the nature of chemical bonds and triggers novel reactions. Here, we employed first-principles calculations combined with the CALYPSO structural search technique to reveal the charge transfer reversal between Ca and Te under high pressure in the calcium-tellurium compound (CaxTe1-x, x = 1/4, 1/3, 1/2, 2/3). We predict several new phases with conventional and unconventional compounds and found an unfamiliar phenomenon: the Ca-Te compounds will reverse charge transfer between Ca and Te atoms and decompose into elemental solids under pressure. The Bader charge analyses indicate that the Ca2+ ion gains electrons and becomes an anion under high pressure. This leads to a weakened electrostatic interaction between Ca and Te and ultimately results in decomposition. The calculated band occupation number suggests that the occupation of Ca 3d orbitals under high pressure corresponds to this atypical phenomenon. Our results demonstrated the reverse charge transfer between Ca and Te and, in addition, clarified the mechanism of CaxTe1-x decomposition into solid Ca and Te elements under high pressure, providing important insights into the evolution of the properties of alkaline-earth chalcogenide compounds under high pressure.

Reproductive Toxicity and Teratogenicity of Fluorene-9-bisphenol on Chinese Medaka (Oryzias sinensis): A Study from Laboratory to Field.

Fluorene-9-bisphenol (BHPF), a bisphenol A (BPA) substitute, has been increasingly used as a material in syntheses of polymers that are widely used in road markings, artificial tracks, coating floors, building paints, etc., increasing the likelihood of BHPF contamination in the aquatic environment due to its release from the products. However, to date, it is unknown whether it may have actual impacts on fish in real environments. In this study, a 105-day exposure experiment of BHPF at various concentrations (0.01, 0.1, 1, and 10 µg/L) on Chinese medaka (Oryzias sinensis) was performed under laboratory conditions and found decreased fecundity, such as lower egg qualities and quantities, retarded oogenesis, and atretic follicles in the fish and deformed eyes and bodies in its F1 generation. Toxico-transcriptome analyses showed that estrogen-responsive genes were significantly suppressed by BHPF, indicating that antagonist properties of BHPF on estrogen receptors might be causes for the decreased fecundity. Field investigations (Beijing) demonstrated that BHPF was detectable in 60% surface waters, with a mean concentration of 10.49 ± 6.33 ng/L, by gas chromatography-mass spectrometry, and similar effects in wild Chinese medaka were also observed, some of which the parameters were found to be obviously correlated with the BHPF levels in corresponding waters.

Pressure induced weakness of electrostatic interaction and solid decomposition in Cs-I compounds.

This work utilized first-principles calculations and the CALYPSO structure search technique to systematically investigate the crystal structure stability of CsxIy compounds under high pressures ranging from 0 to 500 GPa. Several new phases with both conventional and unconventional stoichiometries were predicted. Interestingly, we discovered a counter-intuitive phenomenon where Cs-I compounds decompose into Cs and I elemental solids under pressure. To understand the physical mechanism behind this pressure-induced decomposition, we examine the phenomenon from two distinct perspectives: enthalpy of formation and interatomic interactions. Our results suggest that the main cause is the weakening of electrostatic interactions leading to the decomposition, while the weak covalent interaction plays a minor role. From an energy perspective, the decrease in the formation of enthalpy (ΔH) is primarily due to a reduction in the difference of internal energy (ΔU). These findings provide valuable insights into the decomposition mechanism and high-pressure properties of alkali metal halides. The counterintuitive phenomenon of high-pressure charge transfer and decomposition may inspire new ideas and perspectives in the fields of geology and the study of alkali metal halides under extreme conditions.

Polycyclic aromatic hydrocarbons (PAHs) in a sediment core from Lake Taihu and their associations with sedimentary organic matter.

Sediment core is the recorder of polycyclic aromatic hydrocarbon (PAH) pollutions and the associated sedimentary organic matter (SOM), acting as crucial supports for pollution control and environmental management. Here, the sedimentary records of PAHs and SOM in the past century in Lake Taihu, China, were reconstructed from a 50-cm sediment core. On the one hand, the presence of PAHs ranged from 8.99 to 199.2 ng/g. Vertically, PAHs declined with the depth increased, and the sedimentation history of PAHs was divided into two stages with a discontinuity at 20 cm depth. In composition, PAHs in the sediment core were dominated by three-ring PAHs (44.6% ± 9.1%, mean ± standard deviation), and were followed by four-ring (27.0% ± 3.3%), and five-ring (12.1% ± 4.0%) PAHs. In toxicity assessment, the sedimentary records of benzo[a]pyrene-based toxic equivalency were well described by an exponential model with R-square of 0.95, and the environmental background toxic value was identified as 1.62 ng/g. On the other hand, different components of SOM were successfully identified by n-alkane markers (p < 0.01) and the variations of SOM were well explained (84.6%). A discontinuity of SOM was recognized at 22 cm depth. Association study showed that the sedimentary PAHs were associated with both anthropogenic and biogenic SOM (p < 0.05) with explained variances for most individual PAHs of 60%. It indicated the vertical distributions of PAHs were driven by sedimentary SOM. Therefore, environmental processes such as biogenic factors should attract more attentions as well as PAH emissions to reduce the impacts of PAHs.

The impact of China's high-speed rail investment on regional economy and air pollution emissions.

The high-speed rail (HSR) network in China has experienced rapid development since the 2000s. In 2016, the State Council of the People's Republic of China issued a revised version of the "Mid- and Long-term Railway Network Plan", detailing the expansion of the railway network and construction of an HSR system. In the future, the HSR construction efforts in China will further increase, which is considered to impact regional development and air pollutant emissions. Therefore, in this paper, we apply a transportation network-multiregional computable general equilibrium (CGE) model to estimate the dynamic effects of HSR projects on economic growth, regional disparities, and air pollutant emissions in China. The results indicate that HSR system improvement could generate a positive economic impact but could also increase emissions. The gross domestic product (GDP) growth per unit investment cost stimulated by HSR investment is found to be the largest in eastern China but the smallest in the northwest regions. Conversely, HSR investment in Northwest China contributes to a substantial reduction in regional disparities in terms of the GDP per capita. In regard to air pollution emissions, HSR construction in South-Central China results in the largest increase in CO2 and NOX emissions, while for CO, SO2, and fine particulate matter (PM2.5) emissions, the largest increase occurs due to HSR construction in Northwest China. At the regional level, the provinces with large changes in accessibility also experience large changes in their air pollutant emissions.

4,4'-(9-Fluorenylidene)dianiline (BAFL) is antiestrogenic and has adverse effects on female development in CD-1 mice.

Many phenolic compounds have been found to have endocrine disrupting activities, but their arylamine analogs, the phenolic hydroxyl groups substituted by aniline amino groups, have rarely been reported. 4,4'-(9-Fluorenylidene)dianiline (BAFL) is an arylamine analog of fluorene-9-bisphenol (BHPF) and BHPF has been reported to be a strong antiestrogen which could cause endometrial atrophy, ovarian damage and adverse pregnancy outcomes in animals. BAFL has been widely used as material to synthetize polymers, such as polyimides, polyamide, and polyamine, for various uses since the 1970s. Here, we assessed the antiestrogenicity of BAFL using a variety of methods and looked into its impacts on the development of females in CD-1 mice. With the aid of a yeast estrogen screen assay, we found BAFL possessed obviously antiestrogenic activity (IC50 = 8.15 × 10-6 M), which close to that of tamoxifen and BHPF. Using a 10-d mouse uterotrophic assay, we found that BAFL obviously decreased uterine weight in a dose-dependent way. Histological analyses of mouse uteri revealed that BAFL induced marked endometrial atrophy and inhibited the uterine development. Immunohistochemical analyses showed that Sprr2d, an estrogen-responsive gene encoding protein, was mainly expressed in endometrial epithelial cells and BAFL decreased the areas and levels of Sprr2d staining in mouse uteri. It was clear from uterine transcriptome investigations that BAFL significantly downregulated the expressions of multiple genes responding to estrogen. Molecular docking showed that BAFL could effectively occupy the antagonist-binding pocket of hERα, and one of the amino groups of BAFL formed hydrogen bonds with the side chains of Arg394 and Glu353 in the receptor. These results indicated that BAFL exhibited clearly antiestrogenic characteristics and could interfere with normal female development in mice, which should be avoided using in commodities that come into direct contact with humans. Moreover, this study indicated that the arylamine analogs of phenolic endocrine disrupting chemicals might also have endocrine disrupting activities.

Antiestrogenic property of 9,9-bis[4-(2-hydroxyethoxy)phenyl]fluorene (BPEF) and its effects on female development in CD-1 mice.

Identifying chemicals with endocrine disrupting properties linked to disease outcomes is a key concern, as stated in the WHO-UNEP 2012 report on endocrine-disrupting chemicals. The chemical 9,9-bis[4-(2-hydroxyethoxy)phenyl]fluorene (BPEF) is widely and increasingly applied in synthesizing fluorene-based cardo polymers with superior optical, thermal and mechanical properties for various uses. However, little toxicological information is available regarding its safety. Here, we studied the endocrine disrupting property of BPEF by multiple toxicological tools and investigated its effects on female development in adolescent mice. Using the yeast two-hybrid bioassay, BPEF showed strong antiestrogenicity which was similar to that of tamoxifen, an effective antiestrogenic drug. In adolescent CD-1 mice, BPEF significantly decreased the uterine weight at relatively low doses and induced marked endometrial atrophy. Immunohistochemical staining and transcriptome analyses of the mice uteri revealed that BPEF could repressed the expressions of estrogen-responsive genes. Molecular simulation indicated that BPEF could be docked into the antagonist pocket of human estrogen receptor α, and the formation of hydrogen bonds and hydrophobic interactions between BPEF and the active site of receptor maintained their strong binding. All of the data demonstrated that BPEF possessed strong antiestrogenic property and might disrupt female development, suggesting it should be avoided in making products that might directly expose to people, particularly immature women.

Hepatic toxicity of fluorene-9-bisphenol (BHPF) on CD-1 mice.

Fluorene-9-bisphenol (BHPF), a substitute for bisphenol A (BPA), has been widely used in the synthesis of polyester polymers. Studies have reported multiple BHPF toxicities but its effect on the liver remains unknown. In this study, we performed short-term and subchronic toxicity tests, as well as primary hepatocyte experiments, to investigate the hepatic toxicity of BHPF using CD-1 mice. And microarray was used to analyze the changes of global gene expression in the liver of mice treated with BHPF. The results showed that the liver coefficient and the activities of serum aminotransferases were obviously elevated by BHPF at doses of 27.8 mg/kg body weight (bw)/day or higher in mice treated for 10 days. Histological analysis showed obvious changes, including narrowed hepatic sinuses, dilated central vein, leucocyte infiltration, and cytoplasmic vacuolation, in the livers of mice treated with BHPF at dosages of 2 mg/kg bw/3-day and higher for 36 days. Microarray analyses revealed 2623 differentially expressed genes (DEGs) in the livers of mice treated with 50 mg/kg bw/day of BHPF for 3 days, which could be enriched in GO terms of T cell activation, leukocyte migration, and leukocyte chemotaxis and KEGG pathways of natural killer cell-mediated cytotoxicity and autoimmune thyroid disease. The top 10 hub DEGs, including LTF and MMP8, were observed in the protein-protein interaction network obtained via STRING database analysis, and are proposed as potential biomarkers for liver injury studies. Primary hepatocyte experiments demonstrated the hepatotoxicity of BHPF at concentrations of 10-6 M and higher. This study indicates that BHPF could cause liver injury at relatively low levels, suggesting that the risk of human BHPF exposure should be of concern.

Visualized Metabolic Disorder and Its Chemical Inducer in Wild Crucian Carp from Taihu Lake, China.

A variety of anthropogenic chemicals can disrupt the equilibrium of intrinsic biological metabolites in organisms, leading to metabolic disorders and an increased risk of metabolic syndromes. However, exposure to pollutants that induce metabolic disorders in wildlife as a cause of adverse effects is unknown. In this study, approximately 3108 compounds, including 11 groups of metabolites and 388 pollutants, were simultaneously identified in the blood of wild crucian carp (Carassius auratus) captured in three bays of Taihu Lake, China. A visualized network linking thousands of co-regulated metabolites was automatically produced for the screened signals. This comprehensive view of the differences in blood metabolite profiles in carp from the north and south bays showed that triglycerides (TGs) were the intrinsic molecules most affected by differing environmental pollution in each bay. The regional differences in metabolite profiles were linked to exposure to screened perfluorinated compounds that displayed corresponding regional differences in concentrations and effects on TGs in in vivo exposure tests. Perfluoroundecanoic acid (PFUnDA) was the key pollutant responsible for the variation in blood TGs in wild crucian carp, and exposure to PFUnDA resulted in extremely high biological activity on lipid deposition in the liver tissues of crucian carp at environmental levels.

Discovery of a widespread metabolic pathway within and among phenolic xenobiotics.

Metabolism is an organism's primary defense against xenobiotics, yet it also increases the production of toxic metabolites. It is generally recognized that phenolic xenobiotics, a group of ubiquitous endocrine disruptors, undergo rapid phase II metabolism to generate more water-soluble glucuronide and sulfate conjugates as a detoxification pathway. However, the toxicological effects of the compounds invariably point to the phase I metabolic cytochrome P450 enzymes. Here we show that phenolic xenobiotics undergo an unknown metabolic pathway to form more lipophilic and bioactive products. In a nontargeted screening of the metabolites of a widely used antibacterial ingredient: triclosan (TCS), we identified a metabolic pathway via in vitro incubation with weever, quail, and human microsomes and in vivo exposure in mice, which generated a group of products: TCS-O-TCS. The lipophilic metabolite of TCS was frequently detected in urine samples from the general population, and TCS-O-TCS activated the constitutive androstane receptor with the binding activity about 7.2 times higher than that of the parent compound. The metabolic pathway was mediated mainly by phase I enzymes localized on the microsomes and widely observed in chlorinated phenols, phenols, and hydroxylated aromatics. The pathway was also present in different phenolic xenobiotics and formed groups of unknown pollutants in organisms (e.g., TCS-O-bisphenol A and TCS-O-benzo(a)pyrene), thus providing a cross-talk reaction between different phenolic pollutants during metabolic processes in organisms.

Trophodynamics of Emerging Brominated Flame Retardants in the Aquatic Food Web of Lake Taihu: Relationship with Organism Metabolism across Trophic Levels.

Despite the increasing use and discharge of novel brominated flame retardants, little information is available about their trophodynamics in the aquatic food web, and their subsequent relationships to compound metabolism. In this study, concentrations of 2,4,6-tribromophenyl allyl ether (ATE), 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH), tetrabromo- o-chlorotoluene (TBCT), pentabromobenzyl acrylate (PBBA), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), bis(2-ethylhexyl)-3,4,5,6-tetrabromo-phthalate (TBPH), and decabromodiphenyl ethane (DBDPE) were measured in 17 species, including plankton, invertebrates, and fish from Lake Taihu, South China. Trophodynamics of the compounds were assessed, and metabolic rates were measured in the liver microsomes of crucian (trophic level [TL]: 2.93), catfish (TL: 3.86), and yellow-head catfish (TL: 4.3). Significantly positive relationships were found between trophic levels and lipid-normalized concentrations of ATE, BTBPE, and TBPH; their trophic magnification factors (TMFs) were 2.85, 2.83, and 2.42, respectively. Consistently, the three chemicals were resistant to metabolism in all fish microsomes. No significant relationship was observed for ßTBECH ( p = 0.116), and DBDPE underwent trophic dilution in the food web (TMFs = 0.37, p = 0.021). Moreover, these two chemicals showed steady metabolism with incubation time in all fish microsomes. TBCT and PBBA exhibited significant trophic magnifications in the food web (TMF = 4.56, 2.01). Though different metabolic rates were observed for the two compounds among the tested fish species, TBCT and PBBA both showed metabolic resistance in high-trophic-level fish. These results indicated that metabolism of organisms at high trophic levels plays an important role in the assessment of trophic magnification potentials of these flame retardant chemicals.

Structure-dependent activity of phthalate esters and phthalate monoesters binding to human constitutive androstane receptor.

The present study investigated the human constitutive androstane receptor (CAR) binding activities of 23 phthalate esters and 10 phthalate monoesters using a fast and sensitive human CAR yeast two-hybrid assay. Of 23 phthalate esters, 16 were evaluated as positive, and the 10% relative effective concentrations (REC10) ranged from 0.28 (BBP) to 29.51 µM (DEHP), whereas no obvious binding activities were found for the phthalate esters having alkyl chains more than six carbons in length. Of 10 phthalate monoesters, only monoethyl phthalate (MEP), monoisobutyl phthalate (MIBP), and mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) elicited human CAR binding activities. The REC10 values of MEP and MIBP were 4.27 and 14.13 µM, respectively, higher than those of their corresponding phthalate esters (1.45 µM for DEP and 0.83 µM for DIBP), whereas TBMEHP (0.66 µM) was much lower than TBHP (>10(2) µM). A molecular docking method was performed to simulate the interaction modes between phthalates and human CAR, and active phthalates were found to lie at almost the same site in the human CAR pocket. The docking results suggest that the strong binding of phthalates to human CAR arises primarily from hydrophobic interactions, π-π interactions, and steric effects and that weak hydrogen bonds and weak halogen bonds greatly contribute to the high binding activity of TBMEHP. In conclusion, the current study clarified that an extensive array of phthalates are activators of human CAR.

Ubiquitous occurrence of chlorinated byproducts of bisphenol A and nonylphenol in bleached food contacting papers and their implications for human exposure.

The occurrence of bisphenol A (BPA), nonylphenol (NP), and their six chlorinated byproducts were investigated in 74 food contacting papers (FCPs) from China, the U.S.A., Japan, and Europe using a sensitive dansylation LC-MS/MS method. BPA (

Acridine yellow G blocks glioblastoma growth via dual inhibition of epidermal growth factor receptor and protein kinase C kinases.

Amplification of the epidermal growth factor receptor (EGFR), frequently expressed as a constitutively active deletion mutant (EGFRvIII), occurs commonly in glioblastoma multiformes (GBM). However, blockade of EGFR is therapeutically disappointing for gliomas with PTEN deletion. To search for small molecules treating this aggressive cancer, we have established a cell-based screening and successfully identified acridine yellow G that preferentially blocks cell proliferation of the most malignant U87MG/EGFRvIII cells over the less malignant U87MG/PTEN cells. Oral administration of this compound markedly diminishes the brain tumor volumes in both subcutaneous and intracranial models. It directly inhibits EGFR and PKCs with IC(50) values of ~7.5 and 5 µM, respectively. It dually inhibits EGFR and PKCs, resulting in a blockade of mammalian target of rapamycin signaling and cell cycle arrest in the G(1) phase, which leads to activation of apoptosis in the tumors. Hence, combinatorial inhibition of EGFR and PKCs might provide proof of concept in developing therapeutic agents for treating malignant glioma and other human cancers.

Inverse antagonist activities of parabens on human oestrogen-related receptor γ (ERRγ): in vitro and in silico studies.

Parabens are p-hydroxybenzoic acid esters that have been used extensively as preservatives in foods, cosmetics, drugs and toiletries. These intact esters are commonly detected in human breast cancer tissues and other human samples, thus arousing concern about the involvement of parabens in human breast cancer. In this study, an in vitro nuclear receptor coactivator recruiting assay was developed and used to evaluate the binding activities of parabens, salicylates and benzoates via antagonist competitive binding on the human oestrogen-related receptor γ (ERRγ), which is known as both a diagnostic biomarker and a treatment target of breast cancer. The results showed that all of the test parabens (methyl-, ethyl-, propyl-, butyl- and benzylparaben) possessed clear inverse antagonist activities on ERRγ, with a lowest observed effect level (LOEL) of 10(-7)M and the 50% relative effective concentrations (REC50) varying from 3.09×10(-7) to 5.88×10(-7)M, whereas the salicylates possessed much lower activities and the benzoates showed no obvious activity. In silico molecular docking analyses showed that parabens fitted well into the active site of ERRγ, with hydrogen bonds forming between the p-hydroxyl group of parabens and the Glu275/Arg316 of ERRγ. As the paraben levels reported in breast cancer tissues are commonly higher than the LOELs observed in this study, parabens may play some role via ERRγ in the carcinogenesis of human breast cancer. In addition, parabens may have significant effects on breast cancer patients who are taking tamoxifen, as ERRγ is regarded as a treatment target for tamoxifen.

Label- and slide-free tissue histology using 3D epi-mode quantitative phase imaging and virtual H&E staining.

Histological staining of tissue biopsies, especially hematoxylin and eosin (H&E) staining, serves as the benchmark for disease diagnosis and comprehensive clinical assessment of tissue. However, the process is laborious and time-consuming, often limiting its usage in crucial applications such as surgical margin assessment. To address these challenges, we combine an emerging 3D quantitative phase imaging technology, termed quantitative oblique back illumination microscopy (qOBM), with an unsupervised generative adversarial network pipeline to map qOBM phase images of unaltered thick tissues (i.e., label- and slide-free) to virtually stained H&E-like (vH&E) images. We demonstrate that the approach achieves high-fidelity conversions to H&E with subcellular detail using fresh tissue specimens from mouse liver, rat gliosarcoma, and human gliomas. We also show that the framework directly enables additional capabilities such as H&E-like contrast for volumetric imaging. The quality and fidelity of the vH&E images are validated using both a neural network classifier trained on real H&E images and tested on virtual H&E images, and a user study with neuropathologists. Given its simple and low-cost embodiment and ability to provide real-time feedback in vivo, this deep learning-enabled qOBM approach could enable new workflows for histopathology with the potential to significantly save time, labor, and costs in cancer screening, detection, treatment guidance, and more.

Genome and transcriptome of Chinese medaka (Oryzias sinensis) and its uses as a model fish for evaluating estrogenicity of surface water.

Ecological toxicity assessments of contaminants in aquatic environments are of great concern. However, a dilemma in ecological toxicity assessments often arises when linking the effects found in model animals in the laboratory and the phenomena observed in wild fishes in the field due to species differences. Chinese medaka (Oryzias sinensis), widely distributed in East Asia, is a satisfactory model animal to assess aquatic environment in China. Here, we domesticated this species and assembled its genome (814 Mb) using next-generation sequencing (NGS). A total of 21,922 high-confidence genes with 41,306 transcripts were obtained and annotated, and their expression patterns in tissues were determined by RNA-sequencing. Six mostly sensitive biomarker genes, including vtg1, vtg3, vtg6, zp3a.2, zp2l1, and zp2.3 to estrogen exposure were screened and validated in the fish exposed to concentrations of estrone (E1), 17ß-estradiol (E2), and estriol (E3) under laboratory condition. Field investigations were then performed to evaluating the gene expression of biomarkers in wild Chinese medaka and levels of E1, E2, and E3 in the fish habitats. It was found that in 40 sampling sites, the biomarker genes were obviously highly expressed in the wild fish from about half sites, and the detection frequencies of E1, E2, and E3, were 97.5%, 42.5%, and 45% with mean concentrations of 82.48, 43.17, 52.69 ng/L, respectively. Correlation analyses of the biomarker gene expressions in the fish with the estrogens levels which were converted to EEQs showed good correlation, indicating that the environmental estrogens and estrogenicity of the surface water might adversely affect wild fishes. Finally, histologic examination of gonads in male wild Chinese medaka was performed and found the presence of intersex in the fish. This study facilitated the uses of Chinese medaka as a model animal for ecotoxicological studies.

Early prediction of response to Vorinostat in an orthotopic rat glioma model.

Glioblastoma is the most common primary brain tumor and is uniformly fatal despite aggressive surgical and adjuvant therapy. As survival is short, it is critical to determine the value of therapy early on in treatment. Improved early predictive assessment would allow neuro-oncologists to personalize and adjust or change treatment sooner to maximize the use of efficacious therapy. During carcinogenesis, tumor suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. Suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza) is an orally active, potent inhibitor of histone deacetylase (HDAC) activity. A major shortcoming of the use of HDAC inhibitors in the treatment of patients with brain tumors is the lack of reliable biomarkers to predict and determine response. Histological evaluation may reflect tumor viability following treatment, but is an invasive procedure and impractical for glioblastoma. Another problem is that response to SAHA therapy is associated with tumor redifferentiation and cytostasis rather than tumor size reduction, thus limiting the use of traditional imaging methods. A noninvasive method to assess drug delivery and efficacy is needed. Here, we investigated whether changes in (1)H MRS metabolites could render reliable biomarkers for an early response to SAHA treatment in an orthotopic animal model for glioma. Untreated tumors exhibited significantly elevated alanine and lactate levels and reduced inositol, N-acetylaspartate and creatine levels, typical changes reported in glioblastoma relative to normal brain tissues. The (1)H MRS-detectable metabolites of SAHA-treated tumors were restored to those of normal-like brain tissues. In addition, reduced inositol and N-acetylaspartate were found to be potential biomarkers for mood alteration and depression, which may also be alleviated with SAHA treatment. Our study suggests that (1)H MRS can provide reliable metabolic biomarkers at the earliest stage of SAHA treatment to predict the therapeutic response.

Malformations of the endangered Chinese sturgeon, Acipenser sinensis, and its causal agent.

The anadromous Chinese sturgeon (Acipenser sinensis) is endangered and listed among the first class of protected animals in China. The possible causes for the decline of this species are the effects of synthetic chemicals, and loss of critical habitat. Chinese sturgeon in the Yangtze River have accumulated triphenyltin (TPT) to 31-128 ng/g wet weigh (ww) in liver, which is greater than the concentrations of tributyltin (<1.0 ng/g ww). Maternal transfer of TPT has resulted in concentrations of 25.5 +/- 13.0 ng/g ww in eggs of wild Chinese sturgeon, which poses a significant risk to the larvae naturally fertilized or hatched in the Yangtze River. The incidence of deformities in fry was 7.5%, with 1.2% of individuals exhibiting ocular abnormal development, and 6.3% exhibited skeletal/morphological deformations. The incidences of both ocular and skeletal/morphological deformations were directly proportional to the TPT concentration in the eggs of both the Chinese sturgeon and the Siberian sturgeon (Acipenser baerii) in controlled laboratory studies. The rates of deformities in the controlled studies were consistent with the rates caused at the similar concentrations in eggs collected from the field. Thus, TPT is the causal agent to induce the malformation of larvae of Chinese sturgeon. The incidence of deformed larvae of Chinese sturgeon is an indicator of overall population-level effects of TPT on Chinese sturgeon, because TPT at environmentally relevant concentrations can result in significantly decrease both quality and quantity of eggs and spawning frequency of fish.

Targeted Delivery of DNA Topoisomerase Inhibitor SN38 to Intracranial Tumors of Glioblastoma Using Sub-5 Ultrafine Iron Oxide Nanoparticles.

Effectively delivering therapeutics for treating brain tumors is hindered by the physical and biological barriers in the brain. Even with the compromised blood-brain barrier and highly angiogenic blood-tumor barrier seen in glioblastoma (GBM), most drugs, including nanomaterial-based formulations, hardly reach intracranial tumors. This work investigates sub-5 nm ultrafine iron oxide nanoparticles (uIONP) with 3.5 nm core diameter as a carrier for delivering DNA topoisomerase inhibitor 7-ethyl-10-hydroxyl camptothecin (SN38) to treat GBM. Given a higher surface-to-volume ratio, uIONP shows one- or three-folds higher SN38 loading efficiency (48.3 ± 6.1%, mg/mg Fe) than those with core sizes of 10 or 20 nm. SN38 encapsulated in the coating polymer exhibits pH sensitive release with <10% over 48 h at pH 7.4, but 86% at pH 5, thus being protected from converting to inactive glucuronide by UDP-glucuronosyltransferase 1A1. Conjugating αv ß3 -integrin-targeted cyclo(Arg-Gly-Asp-D-Phe-Cys) (RGD) as ligands, RGD-uIONP/SN38 demonstrates targeted cytotoxicity to αv ß3 -integrin-overexpressed U87MG GBM cells with a half-maximal inhibitory concentration (IC50 ) of 30.9 ± 2.2 nm. The efficacy study using an orthotopic mouse model of GBM reveals tumor-specific delivery of 11.5% injected RGD-uIONP/SN38 (10 mg Fe kg-1 ), significantly prolonging the survival in mice by 41%, comparing to those treated with SN38 alone (p < 0.001).