Nanodiamond Coating in Energy and Engineering Fields: Synthesis Methods, Characteristics, and Applications.

Nanodiamonds are metastable allotropes of carbon. Based on their high hardness, chemical inertness, high thermal conductivity, and wide bandgap, nanodiamonds are widely used in energy and engineering applications in the form of coatings, such as mechanical processing, nuclear engineering, semiconductors, etc., particularly focusing on the reinforcement in mechanical performance, corrosion resistance, heat transfer, and electrical behavior. In mechanical performance, nanodiamond coatings can elevate hardness and wear resistance, improve the efficiency of mechanical components, and concomitantly reduce friction, diminish maintenance costs, particularly under high-load conditions. Concerning chemical inertness and corrosion resistance, nanodiamond coatings are gradually becoming the preferred manufacturing material or surface modification material for equipment in harsh environments. As for heat transfer, the extremely high coefficient of thermal conductivity of nanodiamond coatings makes them one of the main surface modification materials for heat exchange equipment. The increase of nucleation sites results in excellent performance of nanodiamond coatings during the boiling heat transfer stage. Additionally, concerning electrical properties, nanodiamond coatings elevate the efficiency of solar cells and fuel cells, and great performance in electrochemical and electrocatalytic is found. This article will briefly describe the application and mechanism analysis of nanodiamonds in the above-mentioned fields.

Molecular mechanisms of miR172a and its target gene LbrTOE3 regulating maturation in Lilium.

MAIN CONCLUSION: Lbr-miR172a could promote the growth phase transition and shorten maturation in Lilium, while LbrTOE3 inhibited this process and prolonged the growth period. Lilium is an ornamental flower with high economic value for both food and medicinal purposes. However, under natural conditions, Lilium bulbs take a long time and cost more to grow to commercial size. This research was conducted to shorten the maturation time by subjecting Lilium bulbs to alternating temperature treatment. To explore the molecular mechanism of the vegetative phase change (VPC) in Lilium after variable temperature treatment, the key module miR172a-TOE3 was selected based on a combined omics analysis. Gene cloning and transgene functional validation showed that overexpression of Lbr-mir172a promoted a phase change, while overexpression of LbrTOE3 inhibited this process. Subcellular localization and transcriptional activation assays indicated that LbrTOE3 was predominantly localized in the nucleus and showed transcriptional activity. In situ hybridization showed that LbrTOE3 expression was significantly downregulated after alternating temperature treatment. This study elucidates the molecular mechanisms of the phase transition of Lilium and provides a scientific basis for the phase transition in other plants.

Desert Abiotic Carbon Sequestration Weakening by Precipitation.

Desert carbon sequestration plays an active role in promoting carbon neutralization. However, the current understanding of the effect of hydrothermal interactions and soil properties on desert carbon sequestration after precipitation remains unclear. Based on the experiment in the hinterland of the Taklimakan Desert, we found that the heavy precipitation will accelerate the weakening of abiotic carbon sequestration in deserts under the background of global warming and intensified water cycle. The high soil moisture can significantly stimulate sand to release CO2 at an incredible speed by rapidly increasing microbial activity and organic matter diffusion. At this time, the CO2 flux in the shifting sand was synergistically affected by soil temperature and soil moisture. As far as soil properties are concerned, with less organic carbon substrate and stronger soil alkalinity, the carbon sequestration of shifting sand is gradually highlighted and strengthened at low temperature. On the contrary, the carbon sequestration of shifting sand is gradually weakened. Our study provides a new way to assess the contribution of desert to the global carbon cycle and improve the accuracy and scope of application.

Influence of Bisphenol Compounds at Nanomolar Concentrations on Chromosome Damage Induced by Metabolically Activated Carcinogens in HepG2 Cells.

Bisphenol (BP) compounds are endocrine-disrupting organic pollutants. BPs may increase the messenger RNA (mRNA) transcripts of nuclear receptors (NRs) regulating the expression of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes. Their impact on the genotoxicity of metabolically activated carcinogens, however, remains unknown. In this study, effects of the bisphenols A, F, S, and AF on the expression of the aryl hydrocarbon receptor (AhR), the pregnane X receptor (PXR), the constitutive androstane receptor, and individual xenobiotic-metabolizing CYP enzymes in a human hepatoma (HepG2) cell line were investigated, along with in silico binding studies of BPs to each receptor. The results indicated that each BP at 1 to 100 nM concentrations increased the mRNA transcripts and protein levels of AhR, PXR, CYP1A1, 1A2, 1B1, 2E1, and 3A4. The predicted affinities of the BPs for binding AhR were comparable to those of potent agonists. Pretreatment of HepG2 cells with each BP potentiated the induction of micronuclei by benzo[a]pyrene, aflatoxin B1, benzene, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; this effect was abolished/reduced by inhibitors of NRs and/or CYPs. Our study suggests that BPs at human exposure levels may aggravate chromosome damage by several impactful carcinogens in human cells by inducing relevant CYP enzymes, mostly via NR modulation.

Potent aneugenicity of 1-methylpyrene in human cells dependent on metabolic activation by endogenous enzymes.

1-Methylpyrene (1-MP) is a common environmental pollutant and animal carcinogen. After sequential activation by cytochromes P450 and sulfotransferases, it induced gene mutations and micronuclei in mammalian cells. The type of micronuclei formed, entire chromosomes or fragments, was not analysed. In this study, 1-MP and its primary metabolite, 1-hydroxymethylpyrene (1-HMP), were investigated for the induction of centromere-positive and -negative micronuclei in the human hepatoma cell line HepG2 and its derivative C3A, expressing relevant enzymes at higher levels. Under a short-exposure (9 h)/long-recovery regime (2 cell cycles in total), 1-MP and 1-HMP provided negative test results in HepG2 cells. However, they induced micronuclei in C3A cells, the effect being blocked by 1-aminobenzotriazole (inhibitor of cytochromes P450s) and reduced by pentachlorophenol (inhibitor of sulfotransferases). Immunofluorescence staining of centromere protein B in the micronuclei revealed purely clastogenic effects under this regime. Unexpectedly, 1-MP and 1-HMP at concentrations 1/5-1/4 of that required for micronuclei formation led to mitotic arrest and spindle aberrations, as detected by immunofluorescence staining of ß- and γ-tubulin. Following extended exposure (72 h, 2 cell cycles, no recovery), damage to the spindle apparatus and centrosomes was detected at even lower concentrations, with concurrent formation of micronuclei. At low concentrations (1-8 µM 1-MP, 0.25-0.5 µM 1-HMP), the micronuclei induced were unexceptionally centromere-positive. Thus, the chromosome-damaging mechanism of 1-MP was regime and concentration dependent: potently aneugenic under persistent exposure, while clastogenic at higher concentrations following a short-exposure/long-recovery regime. This is a convincing evidence for the existence of metabolic activation-dependent aneugens.

Potent Clastogenicity of Bisphenol Compounds in Mammalian Cells-Human CYP1A1 Being a Major Activating Enzyme.

Bisphenols (BPs) are environmental pollutants with relevant DNA damage in human population; however, they are generally inactive in standard mutagenicity assays, possibly due to insufficient metabolic activation. In this study, induction of micronuclei and double-strand DNA breaks by BPA, BPF, and BPS in Chinese hamster V79-derived cell lines expressing various human CYP enzymes and a human hepatoma (C3A) (metabolism-proficient) cell line were investigated. Molecular docking of BPs to human CYPs indicated some substrate-enzyme potentials, including CYP1A1 for each compound, which did not induce micronuclei in V79-derived cell lines expressing human CYP1A2, 2E1, or 3A4 but became positive in human CYP1A1-expressing (V79-hCYP1A1) cells. In V79-hCYP1A1 and C3A cells, all compounds induced double-strand DNA breaks and micronuclei formation, which were blocked/significantly attenuated by 1-aminobenzotriazole (CYP inhibitor) or 7-hydroxyflavone (selective CYP1A1 inhibitor). Coexposure of C3A cells to pentachlorophenol (sulfotransferase 1 inhibitor) or ketoconazole (UDP-glucuronosyltransferase 1A inhibitor) potentiated micronuclei induction by each compound, with thresholds lowered from 2.5-5.0 to 0.6-1.2 µM. Immunofluorescence staining of centromere protein B with micronuclei formed in C3A cells by each compound indicated pure clastogenic effects. In conclusion, BPs are potently clastogenic in mammalian cells, which require activation primarily by human CYP1A1 and are negatively modulated by phase II metabolism.

A pH-Responsive Polycaprolactone-Copper Peroxide Composite Coating Fabricated via Suspension Flame Spraying for Antimicrobial Applications.

In this study, a pH-responsive polycaprolactone (PCL)-copper peroxide (CuO2) composite antibacterial coating was developed by suspension flame spraying. The successful synthesis of CuO2 nanoparticles and fabrication of the PCL-CuO2 composite coatings were confirmed by microstructural and chemical analysis. The composite coatings were structurally homogeneous, with the chemical properties of PCL well maintained. The acidic environment was found to effectively accelerate the dissociation of CuO2, allowing the simultaneous release of Cu2+ and H2O2. Antimicrobial tests clearly revealed the enhanced antibacterial properties of the PCL-CuO2 composite coating against both Escherichia coli and Staphylococcus aureus under acidic conditions, with a bactericidal effect of over 99.99%. This study presents a promising approach for constructing pH-responsive antimicrobial coatings for biomedical applications.

Endogenous H2S-activated Ag nanoparticles embedded in programmed DNA-cubes for specific visualization of colorectal cancer cells.

To avoid the unexpected aggregation and reduce the cytotoxicity of nanomaterials as optical probes in cell imaging applications, we propose a programmed DNA-cube as a carrier for silver nanoparticles (Ag NPs) to construct a specific hydrogen sulfide (H2S) responsive platform (Ag NP@DNA-cube) for diagnosing colorectal cancer (CRC) in this study. The DNA-cube maintains good dispersion of Ag NPs while providing excellent biocompatibility. Based on the characteristic overexpression of endogenous H2S in CRC cells, the Ag NPs are etched by H2S within target cells into silver sulfide quantum dots, thereby selectively illuminating the target cells. The Ag NP@DNA-cube exhibits a specific fluorescence response to CRC cells and achieves satisfactory imaging.

Evolution law of atmospheric boundary layer in Gurbantünggüt Desert based on reanalysis dataset and in situ observation data.

As a special geographical unit on the earth, deserts have certain differences in planetary boundary layer (PBL) characteristics from other surface types. In order to find out the long-term evolution law of the Gurbantünggüt Desert, on the basis of evaluating the availability of reanalysis data, using the most effective reanalysis data and situ measured data in this area, the evolution law of the atmospheric boundary layer in the desert area was studied. The results show that among the ERA5, MERRA2, JRA-55 and NCEP-FNL reanalysis data, the ERA5 data has the smallest error with the measured data in the comparison of ground elements or high-altitude meteorology parameters, and can be used for the long-term evolution of the atmospheric boundary layer in desert areas. Based on the ERA5 dataset, the annual planetary boundary layer height (PBLH) of the desert fluctuated between 1979 and 1985, but showed a downward trend overall. From 1986 to 2019, the PBLH generally shows an upward trend, and by 2020, the PBLH decreases again. The PBLH in the summer of the desert was contrary to the inter-annual change trend of the PBLH throughout the year. The spatial distribution shows that the PBLH has the characteristics of north-south anisotropy. The characteristics of the ABL in the Gurbantünggüt Desert in different thermal states in summer vary greatly. Based on the sounding observational data, the average PBLH of the stable boundary layer in the Gurbantünggüt Desert in summer is 496 m, the average PBLH of the convective boundary layer is 1693 m, and the average PBLH of the neutral boundary layer is 1208 m. The ABL in desert areas from 02:00 to 08:00 and 23:00 is dominated by stable boundary layers, of which the proportion of stable boundary layers at 05:00 is as high as 67%. During the day, the boundary layer from 14:00 to 17:00 is mainly the convective boundary layer, accounting for more than 50%, and the boundary layer at 20:00 is mainly a neutral boundary layer, accounting for 55%.

Alcoholic Setdb1 suppression promotes hepatosteatosis in mice by strengthening Plin2.

BACKGROUND AND AIMS: Hepatosteatosis is one of the early features of alcoholic liver disease (ALD) and pharmaceutical or genetic interfering of the development of hepatosteatosis will efficiently alleviate the progression of ALD. Currently, the role of histone methyltransferase Setdb1 in ALD is not yet well understood. METHOD: Lieber-De Carli diet mice model and NIAAA mice model were constructed to confirm the expression of Setdb1. The hepatocyte-specific Setdb1-knockout (Setdb1-HKO) mice was established to determine the effects of Setdb1 in vivo. Adenovirus-Setdb1 were produced to rescue the hepatic steatosis in both Setdb1-HKO and Lieber-De Carli mice. The enrichment of H3k9me3 in the upstream sequence of Plin2 and the chaperone-mediated autophagy (CMA) of Plin2 were identified by ChIP and co-IP. Dual-luciferase reporter assay was used to detect the interaction of Setdb1 3'UTR and miR216b-5p in AML12 or HEK 293 T cells. RESULTS: We found that Setdb1 was downregulated in the liver of alcohol-fed mice. Setdb1 knockdown promoted lipid accumulation in AML12 hepatocytes. Meanwhile, hepatocyte-specific Setdb1-knockout (Setdb1-HKO) mice exhibited significant lipid accumulation in the liver. Overexpression of Setdb1 was performed with an adenoviral vector through tail vein injection, which ameliorated hepatosteatosis in both Setdb1-HKO and alcoholic diet-fed mice. Mechanistically, downregulated Setdb1 promoted the mRNA expression of Plin2 by desuppressing H3K9me3-mediated chromatin silencing in its upstream sequence. Pin2 acts as a critical membrane surface-associated protein to maintain lipid droplet stability and inhibit lipase degradation. The downregulation of Setdb1 also maintained the stability of Plin2 protein through inhibiting Plin2-recruited chaperone-mediated autophagy (CMA). To explore the reasons for Setdb1 suppression in ALD, we found that upregulated miR-216b-5p bound to the 3'UTR of Setdb1 mRNA, disturbed its mRNA stability, and eventually aggravated hepatic steatosis. CONCLUSIONS: Setdb1 suppression plays an important role in the progression of alcoholic hepatosteatosis via elevating the expression of Plin2 mRNA and maintaining the stability of Plin2 protein. Targeting hepatic Setdb1 might be a promising diagnostic or therapeutic strategy for ALD.

Discovery of Biaryl Amide Derivatives as Potent, Selective, and Orally Bioavailable RORγt Agonists for Cancer Immunotherapy.

The master transcription factor receptor retinoic acid receptor-related orphan receptor γt (RORγt) regulates the differentiation of T-helper 17 (Th17) cells and the production of interleukin-17 (IL-17). Activation of RORγt+ T cells in the tumor microenvironment promotes immune infiltration to more effectively inhibit tumor growth. Therefore, RORγt agonists provide a reachable approach to cancer immunotherapy. Herein, a series of biaryl amide derivatives as novel RORγt agonists were designed, synthesized, and evaluated. Starting from the reported RORγt inverse agonist GSK805 (1), "functionality switching" and structure-based drug optimization led to the discovery of a promising RORγt agonist lead compound 14, which displayed potent and selective RORγt agonist activity and significantly improved metabolic stability. With excellent in vivo pharmacokinetic profiles, compound 14 demonstrated robust efficacy in preclinical tumor models of mouse B16F10 melanoma and LLC lung adenocarcinoma. Taken together, current studies indicate that 14 deserves further investigation as a potential lead RORγt agonist for cancer immunotherapy.

EF-Hand Domain-Containing Protein D2 (EFHD2) Correlates with Immune Infiltration and Predicts the Prognosis of Patients: A Pan-Cancer Analysis.

Background: EF-hand domain-containing protein D2 (EFHD2) has recently been reported to participate in initiation of cancer. More evidence indicates that EFHD2 plays an important role in tumors, but the pan-cancer analysis of EFHD2 is still very limited. Methods: In this study, we downloaded the original mRNA expression data and SNP data of 33 kinds of tumor data. The gene expression data of different tissues were downloaded from the GTEX database, combined with TCGA data and corrected to calculate the difference of gene expression. The data of total survival time (OS) and progression-free survival (PFS) of TCGA patients were downloaded from the Xena database to further survey the relationship between the EFHD2 expression and prognosis. The CIBERSORT algorithm was used to analyze the RNA-seq data of 33 kinds of cancer patients in different subgroups. In this study, NCI-60 drug sensitivity data and RNA-seq data were downloaded to explore the relationship between genes and common antineoplastic drug sensitivity through correlation analysis. In this study, GSEA analysis was carried out from the Molecular Signature database through the packages of "clusterprofiler" and "enrichplot." By comparing the differences of signal pathways between high and low gene expression groups, the possible molecular mechanism of prognostic differences among 33 kinds of tumors was determined. Results: Our results indicated that EFHD2 was highly expressed in 23 kinds of tumors. In addition, EFHD2 was associated with stage in many kinds of tumors. The expression of EFHD2 was closely related to the OS of 12 kinds of cancer patients. In addition, Kaplan-Meier- (KM-) plot survival analysis indicated that the high expression of EFHD2 was related to the poor OS of 5 kinds of cancer, and the expression of EFHD2 was closely related to the PFI of 5 kinds of cancer patients. The expression of EFHD2 was closely related to immune infiltration, among which 18 cancers were significantly correlated with CD8T cells, 14 cancers were significantly correlated with T regulatory (Tregs) cells, 15 cancers were significantly correlated with CD4 memory activated Tcells, and EFHD2 was significantly correlated with common tumor-related regulatory genes such as TGF beta signaling, TNFA signaling, hypoxia, scorch death, DNA repair, autophagy, and iron death-related genes. The expression level of EFHD2 was significantly correlated with each tumor of TMB, including STAD, SARC, ACC, THYM, KICH, THCA, and TGCT. In MSI, there were significant differences in THYM, STAD, THCA, and TGCT. We used the CellMiner database to explore the sensitivity between EFHD2 gene and common antineoplastic drugs and found that the prediction of high expression of EFHD2 was related to the resistance of many antineoplastic drugs. In renal cell carcinoma, the high expression of EFHD2 is mainly concentrated in ALLOGRAFT_REJECTION, REACTIVE_OXYGEN_SPECIES_PATHWAY, INTERFERON_GAMMA_RESPONSE, IL6_JAK_STAT3_SIGNALING, INTERFERON_ALPHA_RESPONSE, and other signal pathways. GO results showed that the genes were mainly enriched in response to interferon-gamma, antigen processing and presentation, cellular response to interferon-gamma, and other pathways. KEGG results demonstrated that EFHD2 was mainly rich in phagosome, Epstein-Barr virus infection, Staphylococcus aureus infection, and other pathways. The results of Kaplan-Meier survival analysis demonstrated that the high expression of EFHD2 was significantly related to the poor prognosis. Conclusion: Our findings highlight the predictive value of EFHD2 in cancer and provide a potential research direction for elucidating the role of EFHD2 in tumorigenesis and drug resistance.

Predicting Organization Performance Changes: A Sequential Data-Based Framework.

The business environment is increasingly uncertain due to the rapid development of disruptive information technologies, the changing global economy, and the COVID-19 pandemic. This brings great uncertainties to investors to predict the performance changes and risks of companies. This research proposes a sequential data-based framework that aggregates data from multiple sources including both structured and unstructured data to predict the performance changes. It leverages data generated from the early risk warning system in China stock market to measure and predict organization performance changes based on the risk warning status changes of public companies. Different from the models in existing literature that focus on the prediction of risk warning of companies, our framework predicts a portfolio of organization performance changes, including business decline and recovery, thus helping investors to not only predict public company risks, but also discover investment opportunities. By incorporating sequential data, our framework achieves 92.3% macro-F1 value on real-world data from listed companies in China, outperforming other static models.

Human CYP enzyme-activated genotoxicity of 2,2',4,4'-tetrabromobiphenyl ether in mammalian cells.

Polybrominated biphenyl ethers (PBDEs) are a group of persistent organic pollutants with endocrine-disrupting, neurotoxic, tumorigenic and DNA-damaging activities. They are hydroxylated by human liver microsomal CYP enzymes, however, their mutagenicity remains unknown. In this study, 2,2',4,4'-tetrabromobiphenyl ether (BDE-47, relatively abundant in human tissues) was investigated for micronuclei induction and DNA damage in mammalian cells. The results indicated that BDE-47 up to 80 µM under a 6 h/18 h (exposure/recovery, covering 2 cell cycles) regime did not induce micronuclei in V79-Mz and V79-derived cell lines expressing human CYP1A1 or 1A2, while it was moderately positive in human CYP2B6-, 2E1-and 3A4-expressing cell lines (V79-hCYP2B6, V79-hCYP2E1-hSULT1A1 and V79-hCYP3A4-hOR, respectively). Following 24 h exposure, BDE-47 induced micronuclei in V79-hCYP2E1-hSULT1A1 and V79-hCYP3A4 cells at increased potencies. In the human hepatoma (HepG2) cells BDE-47 (48 h exposure) was inactive up to 40 µM, however, pretreatment of the cells with ethanol (0.2%, v:v, inducer of CYP2E1) or rifampicin (10 µM, inducer of CYP3A4) led to significant micronuclei formation by BDE-47; pretreatment with bisphenol AF (100 nM) also potentiated BDE-47-induced micronuclei formation (which was blocked by a CYP2E1 inhibitor trans-1,2-dichloroethylene or a CYP3A inhibitor (ketoconazole). Immunofluorescent staining of centromere protein B with the micronuclei formed by BDE-47 in HepG2 cells pretreated with ethanol or rifampicin demonstrated selective formation of centromere-containing micronuclei. The increased phosphorylation of both histones H2AX and H3 in HepG2 by BDE-47 also indicated an aneugenic potential. Therefore, this study suggests that BDE-47 is an aneugen activated by several human CYP enzymes.

Discovery of tetrahydroquinolines and benzomorpholines as novel potent RORγt agonists.

The retinoic acid receptor-related orphan receptor γt (RORγt) is an important nuclear receptor that regulates the differentiation of Th17 cells and production of interleukin 17(IL-17). RORγt agonists increase basal activity of RORγt and could provide a potential approach to cancer immunotherapy. Herein, hit compound 1 was identified as a weak RORγt agonist during in-house library screening. Changes in LHS core of 1 led to the identification of tetrahydroquinoline compound 6 as a partial RORγt agonist (max. act. = 39.3%). Detailed structure-activity relationship on substituent of the LHS core, amide linker and RHS arylsulfonyl moiety was explored and a novel series of tetrahydroquinolines and benzomorpholines was discovered as potent RORγt agonists. Tetrahydroquinoline compound 8g (EC50 = 8.9 ± 0.4 nM, max. act. = 104.5%) and benzomorpholine compound 9g (EC50 = 7.5 ± 0.6 nM, max. act. = 105.8%) were representative compounds with high RORγt agonistic activity in dual FRET assay, and they showed good activity in cell-based Gal4 reporter gene assay and Th17 cell differentiation assay (104.5% activation at 300 nM of 8g; 59.4% activation at 300 nM of 9g). The binding modes of 8g and 9g as well as the two RORγt inverse agonists accidentally discovered were also discussed.

1-Methylpyrene induces chromosome loss and mitotic apparatus damage in a Chinese hamster V79-derived cell line expressing both human CYP1A2 and sulfotransferase 1A1.

1-Methylpyrene (1-MP) is a ubiquitous environmental pollutant and rodent carcinogen. Its mutagenic activity depends on sequential activation by various CYP and sulfotransferase (SULT) enzymes. Previously we have observed induction of micronuclei and mitotic arrest by 1-MP in a Chinese hamster (V79)-derived cell line expressing both human CYP1A2 and SULT1A1 (V79-hCYP1A2-hSULT1A1), however, the mode of chromosome damage and the involvement of mitotic tubulin structures have not been clarified. In this study, we used immunofluorescent staining of centromere protein B (CENP-B) with the formed micronuclei, and that of ß- and γ-tubulin reflecting the structures of mitotic spindle and centrioles, respectively, in V79-hCYP1A2-hSULT1A1 cells. The results indicated that 1-MP induced micronuclei in V79-hCYP1A2-hSULT1A1 cells from 0.125 to 2 µM under a 24 h/0 h (exposure/recovery) regime, while in the parental V79-Mz cells micronuclei were induced by 1-MP only at concentrations ≥ 8 µM; in both cases, the micronuclei induced by 1-MP were predominantly CENP-B positive. Following 54 h of exposure, 1-MP induced mitotic spindle non-congression and centrosome amplification (multipolar mitosis) in V79-hCYP1A2-hSULT1A1 cells, and anaphase/telophase retardation, at concentrations ≥ 0.125 µM with concentration-dependence; while in V79-Mz cells it was inactive up to 8 µM. This study suggests that in mammalian cells proficient in activating enzymes 1-MP may induce chromosome loss and mitotic disturbance, probably by interfering with the mitotic spindle and centrioles.

Human CYP2E1-activated mutagenicity of dioxin-like PCBs 105 and 118-Experimental data consistent with molecular docking results.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants with human carcinogenicity. Many lower chlorinated and non-dioxin-like PCBs have been observed to be mutagenic following activation by human CYP2E1, while activation of dioxin-like (DL-) PCBs by this enzyme has never been evidenced. In this study, each DL-PCB was analyzed by molecular docking to human CYP2E1 protein for predicting a substrate interaction. All compounds demonstrated high affinities with the active site of human CYP2E1, binding energy being -8.7 ∼ -9.7 kcal/mol. However, most compounds demonstrated ligand-heme distances as ≥ 6.8 Å, while the values for 2,3,3',4,4'- (PCB 105) and 2,3',4,4',5-pentachlorobiphenyl (PCB 118) were 5.3 and 5.4 Å, respectively (valid for electron transfer). Experimentally, both PCB 105 and 118 induced micronuclei in a V79-derived cell line engineered for expression of human CYP2E1 at low micromolar concentrations, while inactive or weakly positive in V79-Mz control cells; these effects were blocked or reduced by 1-aminobenzotriazole, a suicide CYP inhibitor. However, DL-PCBs 77, 81 and 126 were all negative in both cell lines. In a human hepatoma (C3A) cell line, PCB 105 and 118 induced micronuclei marginally, while with ethanol pretreatment (to stabilize CYP2E1) both compounds induced micronuclei efficiently, and co-exposure to trans-1,2-dichloroethylene (a selective CYP2E1 inhibitor) led to clearly negative results with both compounds. Finally, both PCB 105 and 118 induced PIG-A gene mutations in C3A cells, which was blocked by trans-1,2-dichloroethylene. In summary, in silico and experimental results consistently suggest that DL- PCBs 105 and 118 may be activated by human CYP2E1 for mutagenic activities.

Discovery of carboxyl-containing biaryl ureas as potent RORγt inverse agonists.

GSK805 (1) is a potent RORγt inverse agonist, but a drawback of 1 is its low solubility, leading to a limited absorption in high doses. We have explored detailed structure-activity relationship on the amide linker, biaryl and arylsulfonyl moieties of 1 trying to improve solubility while maintaining RORγt activity. As a result, a novel series of carboxyl-containing biaryl urea derivatives was discovered as potent RORγt inverse agonists with improved drug-like properties. Compound 3i showed potent RORγt inhibitory activity and subtype selectivity with an IC50 of 63.8 nM in RORγ FRET assay and 85 nM in cell-based RORγ-GAL4 promotor reporter assay. Reasonable inhibitory activity of 3i was also achieved in mouse Th17 cell differentiation assay (76% inhibition at 0.3 µM). Moreover, 3i had greatly improved aqueous solubility at pH 7.4 compared to 1, exhibited decent mouse PK profile and demonstrated some in vivo efficacy in an imiquimod-induced psoriasis mice model.