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The nutritional selenium (Se) has been demonstrated to have health-boosting effects on fish. However, its effect on fish energy metabolism remains unclear. This study explores the effect and underlying mechanism of the action of nutritional Se on energy metabolism in fish. Rainbow trout (Oncorhynchus mykiss) were fed a basal diet (0 mg Se/kg diet) and a diet containing an already established nutritional Se level (2 mg Se/kg diet, based on Se-yeast) for 30 days. After the feeding experiment, the plasma and liver biochemical profiles and liver transcriptome were analyzed. The results showed that the present nutritional level of Se significantly increased liver triglyceride, total cholesterol, and plasma total cholesterol contents (P < 0.05) compared with the control. Transcriptome analysis showed that 336 and 219 genes were significantly upregulated and downregulated, respectively. Gene enrichment analysis showed that many differentially expressed genes (DEGs) were associated with lipid metabolism pathways (fatty acid biosynthesis, fatty acid elongation, and unsaturated fatty acid biosynthesis), carbohydrate metabolism pathways (glycolysis, the pentose phosphate pathway, and the citrate cycle), and the oxidative phosphorylation pathway. Real-time quantitative PCR (Q-PCR) validation results showed that the expression profiles of 15 genes exhibited similar trends both in RNA sequencing (RNA-seq) and Q-PCR analysis. These results reveal that optimum dietary Se activates glucose catabolic processes, fatty acid biosynthetic processes, and energy production and hence produces higher liver lipid content. This study concludes that the previously established level of nutritional Se (Se-yeast) (2 mg/kg diet, fed basis) for rainbow trout promotes energy storage in the liver, which may benefit fish growth to some extent.

Macrocyclic peptides have the potential to address intracellular protein–protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons for applying this modality to intracellular targets and specifically for advancing chemical matter to address KRAS, a protein that represents the most common oncogene in human lung, colorectal and pancreatic cancers yet is one of the most challenging targets in human disease. Specifically, we focused on KRpep-2d, an arginine-rich KRAS-binding peptide with a disulfide-mediated macrocyclic linkage and a protease-sensitive backbone. These latter redox and proteolytic labilities obviated cellular activity. Extensive structure–activity relationship studies involving macrocyclic linker replacement, stereochemical inversion, and backbone α-methylation, gave a peptide with on-target cellular activity. However, we uncovered an important generic insight – the arginine-dependent cell entry mechanism limited its therapeutic potential. In particular, we observed a strong correlation between net positive charge and histamine release in an ex vivo assay, thus making this series unsuitable for advancement due to the potentially fatal consequences of mast cell degranulation. This observation should signal to researchers that cationic-mediated cell entry – an approach that has yet to succeed in the clinic despite a long history of attempts – carries significant therapy-limiting safety liabilities. Nonetheless, the cell-active molecules identified here validate a unique inhibitory epitope on KRAS and thus provide valuable molecular templates for the development of therapeutics that are desperately needed to address KRAS-driven cancers – some of the most treatment-resistant human malignancies., Targeting undruggable intracellular proteins with peptides: novel on-target macrocyclic peptide inhibitors of KRAS with broad inhibition of proliferation of multiple KRAS-dependent cancer cell lines.

Sarecycline is a narrow-spectrum antibiotic for the treatment of acne, which is a chronic inflammatory disease of the hair follicle sebaceous glands. In the study, UPLC-MS/MS was used to establish a rapid and accurate analytical method. The sarecycline was determined with poziotinib as internal standard (IS) in rat plasma. An ACQUITY UPLC HSS T3 column (2.1 × 100 mm, 1.8 μm) could performe chromatographic separation with the mobile phase (methanol: water of 0.1% formic acid) with gradient elution. The ions of target fragment were m/z 488.19→410.14 for sarecycline and m/z 492.06→354.55 for poziotinib, which could quantify the electrospray ionization of positive multiple reaction monitoring (MRM) mode. The linear calibration curve of the concentration range was 1–1,000 ng/mL for sarecycline with a lower limit of quantification (LLOQ) of 1 ng/mL. The mean recovery was between 82.46 and 95.85% for sarecycline and poziotinib in rat plasma. RSD for precision of inter-day and intra-day were between 3.24 and 13.36%, and the accuracy ranged from 105.26 to 109.75%. The developed and validated method was perfectly used in the pharmacokinetic study and bioavailability of sarecycline after intravenous and oral administration in rats.

The glass-forming ability, crystallization behavior and physical properties of GeS2-Sb2S3-CsX (X = Cl, Br, I) glasses and glass-ceramics (GCs) are systematically studied by various characterization techniques. With the introduction of cesium halides, transparent chalcogenide GCs containing the single nanocrystals of CsX can be obtained in a controlled fashion. The crystallization behavior was investigated in the line of (100-x) (0.5GeS2-0.5Sb2S3)-xCsX glasses. IR-transmitting chalcogenide GCs embedded with CsCl and CsBr nanocrystals of a large crystallinity have been fabricated successfully after thermal treatments, whereas surface crystallization of CsI is dominated in GeS2-Sb2S3–CsI glassy samples. Such distinct crystallization behaviors of CsX crystal phases are compared and discussed with microstructural results. We propose that the ionic diffusion ability of halogen in the GeS2-Sb2S3-CsX glassy network determines the nucleation and crystal growth of CsX. This finding is of guidance meaning for future design of chalcogenide GCs with novel optical functions and microstructures.

Context Dacomitinib and poziotinib, irreversible ErbB family blockers, are often used for treatment of non-small cell lung cancer (NSCLC) in the clinic. Objective This study investigates the effect of dacomitinib on the pharmacokinetics of poziotinib in rats. Materials and methods Twelve Sprague–Dawley rats were randomly divided into two groups: the test group (20 mg/kg dacomitinib for 14 consecutive days) and the control group (equal amounts of vehicle). Each group was given an oral dose of 10 mg/kg poziotinib 30 min after administration of dacomitinib or vehicle at the end of the 14 day administration. The concentration of poziotinib in plasma was quantified by UPLC-MS/MS. Both in vitro effects of dacomitinib on poziotinib and the mechanism of the observed inhibition were studied in rat liver microsomes and human liver microsomes. Results When orally administered, dacomitinib increased the AUC, Tmax and decreased CL of poziotinib (p

The bismuth-based borate Bi2ZnB2O7 (BZBO) crystal is a multi-functional material with potential non-linear optical and piezoelectric properties. In this study, the temperature-dependent behaviours of the dielectric permittivities, resonant frequencies, elastic compliances and piezoelectric coefficients for Bi2ZnB2O7 crystals were studied over the temperature range of −150–150 °C. The Bi2ZnB2O7 crystals were found to present minimal dielectric permittivity variations (

We studied the third-order nonlinear (TONL at 0.8 μm) properties of the chalcogenide glass-ceramic within the GeS2-Sb2S3–CsCl system, and found that the nano-crystallization of CsCl phase in the glass matrix could enhance the TONL properties significantly. As compared to the parent glass without crystallization, the maximum nonlinear refractive index (n2) of the GeS2-Sb2S3–CsCl chalcogenide glass ceramics is nearly tripled, while the maximum nonlinear absorption coefficient (β) is also increased by 62%. The calculation of figure of merits (FOMs) ascertained that glass ceramics embedded with smaller CsCl crystallites tend to have better TONL performance.

Purpose The purpose of the present study was to investigate the effects of vonoprazan on the pharmacokinetics of venlafaxine in vitro and in vivo. Methods The mechanism underlying the inhibitory effect of vonoprazan on venlafaxine was investigated using rat liver microsomes. In vitro, the inhibition was evaluated by determining the production of O-desmethylvenlafaxine. Eighteen male Sprague–Dawley rats were randomly divided into three groups: control group, vonoprazan (5 mg/kg) group, and vonoprazan (20 mg/kg) group. A single dose of 20 mg/kg venlafaxine was administrated to rats orally without or with vonoprazan. Plasma was prepared from blood samples collected via the tail vein at different time points and concentrations of venlafaxine and its metabolite, O-desmethylvenlafaxine, were determined by ultra-performance liquid chromatography-tandem mass spectrometry. Results We observed that vonoprazan could significantly decrease the amount of O-desmethylvenlafaxine (IC50 = 5.544 μM). Vonoprazan inhibited the metabolism of venlafaxine by a mixed inhibition, combining competitive and non-competitive inhibitory mechanisms. Compared with that in the control group (without vonoprazan), the pharmacokinetic parameters of venlafaxine and its metabolite, O-desmethylvenlafaxine, were significantly increased in both 5 and 20 mg/kg vonoprazan groups, with an increase in MRO-desmethylvenlafaxine. Conclusion Vonoprazan significantly alters the pharmacokinetics of venlafaxine in vitro and in vivo. Further investigations should be conducted to check these effects in humans. Therapeutic drug monitoring of venlafaxine in individuals undergoing venlafaxine maintenance therapy is recommended when vonoprazan is used concomitantly.

Metal oxide nanoparticles and carbon nanoparticles, as common nanoparticles (NPs), can cause autophagy in certain cells, which will lead to biohealth risk issues. This study determined the difference in autophagy induced by zinc oxide nanoparticles (ZnO NPs) and single-walled carbon nanotubes (SWCNTs) in respiratory epithelial cells. ICP-OES results showed that NPs uptake as well as the intercellular contents of particles affected cytotoxicity in a dose-dependent manner. ZnO NPs-30 nm had a distinct green dot structure representing autophagy, the SWCNTs exposure group had a few green light spots at a concentration of 10 μg/L. The ROS content of the ZnO NP-30 nm exposure group had the greatest increase at a concentration of 1000 μg/L, which was 2.5 times higher than that of the control, the SWCNTs exposure group showed a 2.2-fold increase. A slight downregulation of p-mTOR was detected, and the ZnO NPs-30 nm treatment group had the significant downregulation rate. The gene and protein expression levels of Beclin-1 and LC3B were upregulated as the exposure concentration increased. The protein expression of Beclin-1 and LC3B in the 1000 μg/L ZnO NPs-30 nm exposure group were 5.21 times and 4.12 times that of the control, respectively. The mRNA expression of Beclin-1 and LC3B in the 1000 μg/L ZnO NPs-30 nm exposure group were 5.04 times and 3.61 times that of the control, respectively. At any concentration, the effect of ZnO NPs-30 nm was greater than that of the SWCNTs. Interaction and crosstalk analysis showed that exposure to ZnO NPs-30 nm caused autophagy through the aggregation of undegraded autophagosomes, whereas SWCNTs exposure induced diminished intercellular oxidative stress to inhibit autophagy. Therefore, this study demonstrated that the effects of autophagy induced by ZnO NPs-30 nm and SWCNTs were different. The health risks of ZnO-30 nm NPs are higher than those of SWCNTs.

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Purpose The aim of the present study was to investigate the interactions of the main components of Lygodium root (ie, p-coumaric acid, acacetin, apigenin, buddleoside and Diosmetin-7-O-β-D-glucopyranoside) with cytochrome P450 3A enzyme activity both in vitro and in vivo. Methods In vitro inhibition of drugs was assessed by incubating rat liver microsomes (RLMs) with a typical P450 3A enzyme substrate, midazolam, to determine their 50% inhibitory concentration (IC50) values. For the in vivo study, healthy male Sprague Dawley rats were consecutively administered acacetin or apigenin for 7 days at the dosage of 5 mg/kg after being randomly divided into 3 groups: Group A (control group), Group B (acacetin group) and Group C (apigenin group). Results Among the five main components of Lygodium root, only acacetin and apigenin showed inhibitory effects on the cytochrome P450 3A enzyme in vitro. The IC50 values of acacetin and apigenin were 58.46 μM and 8.20 μM, respectively. Additionally, the in vivo analysis results revealed that acacetin and apigenin could systemically inhibit midazolam metabolism in rats. The Tmax, AUC(0-t) and Cmax of midazolam in group B and group C were significantly increased (P

The Z-scheme overall solar water splitting is a mimic of natural photosynthesis to convert solar energy into chemical energy. Since the energy levels of most organic semiconductors match well with the hydrogen evolution potential, they have great application prospects as photocathodes in Z-scheme photoelectrochemical systems. However, due to the weak light absorption and difficult carriers separation, the photocurrent density and onset potential of organic photocathodes are still low. To solve these problems, we introduced copper nanosheets array (Cu NSA) framework under the organic layers to increase the surface reaction sites, improve the light absorption and enhance the distribution range of built-in electric field simultaneously. As a result, the photocurrent density and onset potential of poly(3-hexylthiophene):[6,6]-phenyl-C61-butyric acid (P3HT:PCBM) photocathode were enhanced significantly. The onset potential increased by 50 mV to 0.65 V vs. RHE, and the photocurrent density reached -1 mA cm-2 at 0 V vs. RHE, which was 18 times that of the sample without Cu NSA. The optimized photocathode was connected with titanium dioxide nanorods array photoanode in a tandem manner to realize the spontaneous overall water splitting. Without bias and cocatalyst, the photocurrent density was maintained at 110 μA cm-2 and the solar-to-fuel conversion efficiency was 0.14% in neutral solution. These results provide a feasible method for optimizing the performance of organic photocathode.

Zinc oxide nanoparticles (ZnO-NPs) can affect human health primarily via inhalation. This study evaluated the protective effects of theaflavins (TFs) and epigallocatechin gallate (EGCG) against ZnO-NP-induced cytotoxicity in rat tracheal epithelial (RTE) cells. After exposure to ZnO-NPs (100 µg/L), treatment with TFs and EGCG (10, 100 and 1000 µg/L) significantly inhibited the levels of reactive oxygen species (ROS), and the content of malondialdehyde (MDA). Treatment also alleviated apoptosis induced by oxidative stress, which was achieved by inhibiting cytochrome C (CytoC) and Caspase 3/8/9 mRNA expression. Upon treatment with the highest concentrations of TFs and EGCG (1000 µg/L), CytoC gene expression was downregulated by 59.10% and 77.27%, Caspase 3 gene expression by 50.03% and 60.01%, Caspase 8 gene expression by 45.11% and 55.57%, and Caspase 9 gene expression by 51.33% and 66.67%. In addition, about the interleukin family as interleukin 1β (IL-1β) and interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and the other inflammatory chemokines like C-C motif chemokine 2 (CCL2), C-X-C motif chemokine 8 (CXCL8) were upregulated in RTE cells in the presence of ZnO-NPs. All factors were gradually rescued after the addition of TFs and EGCG. These results showed that TFs and EGCG could effectively protect RTE cells from oxidative damage induced by ZnO-NPs through antiapoptotic and antioxidant effects.

Lithium niobate crystals (LiNbO3, LN) are multifunctional crystal materials with many outstanding properties. In this work, the electro-elastic properties of LN single crystals were explored at temperatures from −150 °C to 150 °C. The temperature dependences of dielectric permittivities, elastic compliances, electromechanical coupling factors and piezoelectric coefficients were determined using the impedance method. The LN crystals possessed large dielectric permittivities, the ε11T/ε0 and ε33T/ε0 were 83.2 and 29.4 at room temperature, respectively. The elastic compliances s11, s13, s33 and s44 presented a positive increase as the temperature increased, and the variations were 5.0%, 8.2%, 4.6% and 5.4%, respectively, showing a good temperature stability. Moreover, the temperature dependence of the electromechanical coupling factors and piezoelectric coefficients for different vibration modes were studied with a temperature range from −150 °C to 150 °C, where the thickness shear vibration mode d15 presented a large piezoelectric response and minimal temperature variation.

Similar to that of other enteroviruses, the replication of enterovirus 71 (EV71) occurs on rearranged membranous structures called replication organelles (ROs). Phosphatidylinositol 4-kinase III (PI4KB), which is required by enteroviruses for RO formation, yields phosphatidylinositol-4-phosphate (PI4P) on ROs. PI4P then binds and induces conformational changes in the RNA-dependent RNA polymerase (RdRp) to modulate RdRp activity. Here, we targeted 3D polymerase, the core enzyme of EV71 ROs, and found that the host factor Annexin A2 (ANXA2) can interact with 3D polymerase and promote the replication of EV71. Then, an experiment showed that the annexin domain of ANXA2, which possesses membrane-binding capacity, mediates the interaction of ANXA2 with EV71 3D polymerase. Further research showed that ANXA2 is localized on ROs and interacts with PI4KB. Overexpression of ANXA2 stimulated the formation of PI4P, and the level of PI4P was decreased in ANXA2-knockout cells. Furthermore, ANXA2, PI4KB, and 3D were shown to be localized to the viral RNA replication site, where they form a higher-order protein complex, and the presence of ANXA2 promoted the PI4KB-3D interaction. Altogether, our data provide new insight into the role of ANXA2 in facilitating formation of the EV71 RNA replication complex. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12250-021-00417-4.

The yttrium calcium oxyborate crystal (YCa4O(BO3)3, YCOB) has been actively studied for high-temperature piezoelectric sensing applications. In this work, the stability of electric properties of YCOB crystal annealed in critical conditions (high-temperatures of 900–1100 °C with a low oxygen partial pressure of 4 × 10−6 atm for 24 h) was investigated and the recovery mechanism for the electrical resisitivity, dielectric permittivity and dielectric loss were studied, taking advantage of the X-ray photoelectron spectra and the first principle calculations. The electrical resistivity of the annealed YCOB crystal was slightly decreased when compared to the pristine counterpart, being (2–5) × 107 Ω·cm at 850 °C. The dielectric permittivity and dielectric loss were found to increase after annealing, showing recoverable behaviours after thermal treatment above 650 °C in air. The calculated vacancy formation energy indicates that the oxygen vacancy is the dominant defects in YCOB. The formation of oxygen vacancy weakens the chemical bonding strength between B (Ca or Y) and O atoms, introduces extra donor levels in the band gap, which excites the electrons to conduction band more easily thus enhances the electrical conductivity and dielectric loss. The recovered electrical properties are believed to be associated with the reduced vacancy defects at elevated temperatures in air. Keywords: YCOB crystal, Recoverable dielectric properties, First principle calculations

MK-7680, a cyclic nucleotide prodrug, caused significant kidney tubule injury in female rats when administered orally at 1000 mg/kg/day for 2 weeks using 10% Polysorbate 80 as vehicle. However, kidney injury was absent when MK-7680 was administered at the same dose regimen using 100% Polyethylene Glycol 200 (PEG 200) as the vehicle. Subsequent investigations revealed that MK-7680 triphosphate concentrations in kidney were much lower in rats treated with MK-7680 using PEG 200 compared with 10% Polysorbate 80 vehicle, whereas plasma exposures of MK-7680 prodrug were similar. In vitro studies demonstrated that PEG 200 is an inhibitor of human renal uptake transporter organic anion transporter 3 (OAT3), of which MK-7680 is a substrate. Furthermore, PEG 200 and PEG 400 were found to interfere in vitro with human renal transporters OAT3, organic cation transporter (OCT) 2, multidrug resistance-associated protein (MRP) 2 and 4, and multidrug and toxin extrusion protein (MATE) 1 and 2K, but not OAT1. These results support a conclusion that PEG 200 may prevent MK-7680-induced kidney injury by inhibiting its active uptake into proximal tubular cells by OAT3. Caution should be exercised therefore when using PEGs as vehicles for toxicity assessment for compounds that are substrates of renal transporters.

The design and preparation of new membrane material are of great importance. In this work, a hydrophilic ionic liquid (IL) grafted polyamide 6 (PA6) (IL-g-PA6) porous membrane materials were designed and prepared via radiation induced grafting method. The improved hydrophilicity, solubility and the unique ion structure of IL-g-PA6 made it suitable to prepare porous membrane using simple immersion precipitation phase inversion method. SEM images showed opened sponge-like pores for both PA6 and IL-g-PA6 porous membranes, while the pore size decreased and porosity increased as ionic liquid was grafted on PA6. It is believed that the mass transfer process was slowed down by enhanced hydrophilicity and solubility of IL-g-PA6, which lead to a different porous structure from that of PA6. Besides, even though the pore size of 2%-50 K membrane was much smaller, the water flux of which was 2.6 times higher than that of PA6 membrane. Moreover, the chromate sorption on 8%-50 K membrane was 2.7 times higher than that of PA6 membrane, which implies that the IL-g-PA6 porous membranes are good sorbent for heavy metal ions. The special interaction between grafted ionic liquid and heavy metal ions would account for the excellent adsorption property.

Sewage sludge, the major by-product during the primary treatment and subsequent biotreatment of wastewater, is increasingly generated around the world. KMnO4Fe(II) consists both oxidation properties of KMnO4 and flocculation ability by in-situ formed Fe(III) and is widely used in water treatment. In this study, KMnO4Fe(II) was used as chemical conditioners to synchronously improve sludge dewatering performance and catalyze the biomass pyrolysis of waste activated sludge for preparing multi-functional material to remedy arsenic containing groundwater. The results showed that the sludge dewaterability was significantly improved due to the moderate pre-oxidation of extracellular polymeric substances by KMnO4, and then the sludge particles were re-flocculated by Fe(III) generated from KMnO4Fe(II). The conditioned sludge cake was then utilized for preparing sludge-based carbon (Fe-Mn-SBC) which was systematically characterized. The surface area of Fe-Mn-SBC was characteristic of high surface area (100.08 m2/g) which had a great adsorption capacity on arsenic. Besides, Fe-Mn-SBC could effectively oxidize As(III) to As(V), and addition of low dose of H2O2 can further improve total arsenic removal due to catalytic peroxidation of Fe-Mn-SBC. Besides, it was found that the presence of humic acid could inhibit the hydroxy iron formation and compete for the active adsorption sites and then resulted in the decrease in arsenic removal, and the co-existing humic acid could also be removed by adsorption of Fe-Mn-SBC. This work proposed a novel sludge treatment process by combining enhanced sludge dewatering with catalytic pyrolysis for preparing multi-functional materials, and they are promising in treatment of water containing combined pollutants.

In this study, a series of Eu-implanted AlN films with different Eu ions dose and different annealing temperature were prepared. The crystalline quality of Eu implanted AlN has been explored by X-ray diffraction and Raman scattering. The optical properties has been investigated by cathodoluminescence. The X-ray diffraction patterns show Eu-implanted AlN thin films annealed at 1040 °C have high crystalline quality and the strain induced by less dose Eu can be released in some extent after more dose Eu was implanted, which is consistent with the Raman spectra. According to cathodoluminescence spectra, Eu emission intensity was increased and then decreased with the increase of annealing temperature, and was increased with the increase of Eu doses. Finally, the schematic diagram of abundant emission lines and corresponding mid-gap states in the AlN was constructed.

Lithium niobate (LiNbO3, LN) crystal is a multi-functional material with favorable piezoelectric, nonlinear optical and electro-optic properties. In this study, the electromechanical properties of the radial extensional (RE) and the thickness extensional (TE) modes of the congruent LN are studied and the temperature dependent behaviors are revealed. The RE mode electromechanical coupling factors (kp) for the Y- and Z-oriented discs are calculated and found to be 3.8% and 24.7%, respectively, which are nearly the same as the experimental results of 3.8% and 25.2%, respectively. The maximum RE and thickness shear (TS) modes electromechanical coupling factors are obtained to be 47.6% and 68.5% for the Yx/25° and Yx/167° crystal cuts, respectively. The LN crystal possesses good temperature stability of the electromechanical coupling factors (RE and TE modes) from 20 °C to 500 °C, where the variations of kp and kt for the Y-oriented discs are

γ-Al2O3 was incorporated with SiO2 and used as carrier to support Ni and Cu oxides for catalytic ozonation of heavy oil produced water. The change of catalytic activity was in accordance wi...

Three transition metal sulfides with different electrochemical potentials were studied as additives to investigate their effect on the electrochemical performance of Li–S batteries. The study showed that all these transition metal sulfides improved the cycling stability of Li–S batteries due to their high conductivity and strong chemical adsorption with polysulfides. Among these three transition metal sulfide additives, NbS2 obtained the best electrochemical performance in Li–S batteries (0.2C and multirate). Possible reasons were analyzed by related experiments and characterizations.

Long noncoding RNA (lncRNA) small nucleolar RNA host gene 7 (SNHG7) has been widely reported in various cancers, including lung adenocarcinoma (LUAD). However, it is largely unknown whether SNHG7 is involved in docetaxel resistance of LUAD. In the current study, we identified the high expression of SNHG7 in docetaxel-resistant cells. Through functional assays, we determined that silencing of SNHG7 decreased IC50 value of LUAD cells to docetaxel and suppressed proliferation and autophagy in LUAD cells, and reversed M2 polarization in macrophages. Mechanistically, we uncovered that SNHG7 promoted autophagy via recruiting human antigen R (HuR) to stabilize autophagy-related genes autophagy related 5 (ATG5) and autophagy related 12 (ATG12). Moreover, exosomal SNHG7 was transmitted from docetaxel-resistant LUAD cells to parental LUAD cells and thus facilitated docetaxel resistance. Additionally, exosomal SNHG7 activated the phosphatidylinositol 3-kinase (PI3K)/AKT pathway to promote M2 polarization in macrophages via recruiting cullin 4A (CUL4A) to induce ubiquitination and degradation of phosphatase and tensin homolog (PTEN). Taken together, we concluded that exosomal SNHG7 enhances docetaxel resistance of LUAD cells through inducing autophagy and macrophage M2 polarization. All findings in the study suggested that SNHG7 may be a promising target for relieving docetaxel resistance in LUAD.

BackgroundGraphene oxide (GO) has been proven in many studies to promote the proliferation and differentiation of a variety of stem cells, but its effect on the apoptosis of adipose-derived mesenchymal stem cells (Ad-MSCs) is still unclear. Apoptosis is one of the most important factors in the treatment of diabetic wounds by stem cells. Therefore, we explored its therapeutic effect on diabetic wounds by studying the effect of GO on the apoptosis of Ad-MSCs.MethodsqRT-PCR was used to detect the expression of lncRNAs, miRNAs and mRNAs in Ad-MSCs. RNA immunoprecipitation (RIP), RNA pull-down and luciferase assays were used to detect the interaction of the specific lncRNA, miRNA and mRNA. The effects of Linc00324 on Ad-MSCs cells apoptosis were explored by flow cytometer, TUNEL assay and Western blot. Diabetic wound was established to explore the function of Linc00324 on Ad-MSCs repairing ability in vivo.ResultsGO inhibited the apoptosis of Ad-MSCs caused by high glucose, and Linc00324 was one of the factors contributing to its effect. In terms of mechanism, RIP and RNA-Pull-down confirmed Linc00324 could directly interact with miR-7977, and then acted as a miRNA sponge to regulate the expression of miR-7977 target gene STK4 (MST1) and downstream signaling pathways. In addition, GO reduced the apoptosis of Ad-MSCs in wounds and promoted wound healing. Conclusions Overall, this study highlights that GO maybe a superior auxiliary material for Ad-MSCs to repair diabetic wounds via Linc00324/miR-7977/STK4 pathway.

Pectinases are a group of enzymes with broad application, including in plant fiber processing, pectic wastewater treatment, paper pulping, fruit juice extraction, and clarification. With an increasing industrial demand for these enzymes, it is useful to isolate organisms that produce large amounts of pectinase and possess wide ranges of stability factors like temperature and pH. In this study, 17 out of 29 bacteria (58.62%) from forest soil samples were pectinolytic. However, only four bacteria (S-5, S-10, S-14, and S-17) showed high pectin hydrolysis zones (ranging from 0.2 cm to 1.7 cm). These four bacteria were identified based on colony morphology, microscopic characterization, biochemical characteristics, and 16S rDNA sequencing. They were designated as Streptomyces sp. (S-5, S-14), Cellulomonas sp. (S-10), and Bacillus sp. (S-17). Interestingly, bacteria showed cellulase and xylanase activity in addition to pectinase. The quantitative assay for pectinase activity of the four isolates provided proof that they are pectinase producers and can be considered potential candidates for industrial uses. The crude enzyme extracts of these bacteria are applicable in oil and juice extraction from sesame seeds and apples, respectively.

Third-order optical nonlinearity (TONL) of chalcogenide glasses (ChGs) in Ge-In-S (GIS) ternary system is characterized at two near-infrared wavelengths of 0.8 μm and 1.064 μm. It is found that the GIS ChGs with non-stoichiometric compositions exhibit extremely large TONL properties, and its origin has been explained from both aspects of glass structure and wavelength-dispersion dependence of the TONL properties. Nevertheless, calculation of figure of merits indicates that the GIS ChGs are suitable for n2-based TONL optical devices at long wavelength, while suitable for β-based devices at short wavelength.

Over 60-year clinical use of vancomycin led to the emergence of vancomycin-resistant bacteria and threatened our health. To combat vancomycin-resistant strains, numerous vancomycin analogues were developed, such as Telavancin, Oritavancin and Dalbavancin. Extra structures embedded on C-terminus has been proved to be an effective strategy to promote antibacterial activity of vancomycin against vancomycin-resistant strains. Here, we reported a facile strategy, inspired by native chemical ligation, for vancomycin C-terminus functionalization and derivatization. The introduction of C-terminal hydrazide on vancomycin not only provided us an accessible method for C-terminus functionalization through carbonyl azide and thioester, also acted as an efficient site for vancomycin structure modifications. Based on hydrazide-vancomycin, we effectively conjugated cysteine and cysteine containing peptides onto vancomycin C-terminus, and two fluorescent FITC-vancomycin were prepared through Cys-Maleimide conjugation. Meanwhile, we introduced lipophilic structures onto vancomycin C-terminus via the hydrazide moiety. The obtained vancomycin derivatives were evaluated against both Gram-positive and negative bacteria strains.

Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib is currently under clinical investigation, and understanding its drug-drug interactions is extremely important for its future development and clinical application. The cocktail method is most suitable for evaluating the activity of cytochrome P450 enzymes (CYPs). As poziotinib is partially metabolized by CYPs, cocktail probes are used to study the interaction between drugs metabolized by each CYP subtype. Midazolam, bupropion, dextromethorphan, tolbutamide, chlorzoxazone, phenacetin, and their metabolites were used to examine the effects of poziotinib on the activity of cyp1a2, 2b1, 2d1, 2c11, 2e1, and 3a1/2, respectively. The in vitro experiment was carried out by using rat liver microsomes (RLMs), whereas the in vivo experiment involved the comparison of the pharmacokinetic parameters of the probes after co-administration with poziotinib to rats to those of control rats treated with only probes. UPLC-MS/MS was used to detect the probes and their metabolites in rat plasma and rat liver microsomes. The in vitro results revealed that the half-maximal inhibitory concentration values of bupropion and tolbutamide in RLMs were 8.79 and 20.17 μM, respectively, indicating that poziotinib showed varying degrees of inhibition toward cyp2b1 and cyp2c11. Poziotinib was a competitive inhibitor of cyp2b1 and cyp2c11, with Ki values of 16.18 and 17.66 μM, respectively. No time- or concentration-dependence of inhibition by poziotinib was observed toward cyp2b1 and cyp2c11 in RLMs. Additionally, no obvious inhibitory effects were observed on the activity of cyp1a2, cyp2d1, cyp2e1, and cyp3a1/2. In vivo analysis revealed that bupropion, tolbutamide, phenacetin, and chlorzoxazone showed significantly different pharmacokinetic parameters after administration (p < 0.05); there was no significant difference in the pharmacokinetic parameters of dextromethorphan and midazolam. These results show that poziotinib inhibited cyp2b1 and cyp2c11, but induced cyp1a2 and cyp2e1 in rats. Thus, poziotinib inhibited cyp2b1 and cyp2c11 activity in rats, suggesting the possibility of interactions between poziotinib and these CYP substrates and the need for caution when combining them in clinical settings.

Background: Diazepam is a benzodiazepine drug used to treat anxiety, insomnia, and muscle spasms. Imperatorin is a phytochemical isolated from medicinal plants and is widely used in herbal medicine. The aim of this study was to investigate the interactions between imperatorin and diazepam in vitro and in vivo and to provide scientifically based guidance for the safe clinical use of the drug. Methods: In vitro inhibition of imperatorin was assessed by incubating rat liver microsomes with diazepam to determine IC50 values and the type of inhibition. For in vivo assessment, six rats were pretreated with 50 mg/kg imperatorin for two weeks, six were administered saline, and a single dose of 10 mg/kg diazepam was administered orally to both groups 30 min after administration of imperatorin. Results: Imperatorin inhibited the in vitro metabolism of diazepam via the competitive mechanism of CYP450. The IC50 values of imperatorin to nordazepam and temazepam were 1.54 μM and 1.80 μM, respectively. The inhibitory constant values for temazepam and nordazepam were 1.24 μM and 1.29 μM, respectively. Long-term administration of imperatorin significantly increased the AUC(0-12h), AUC(0-∞), and Cmax of diazepam, while Vz/F and CLz/F were decreased significantly (P < 0.05). In turn, the AUC(0-12h), AUC(0-∞), and Cmax of nordazepam and temazepam decreased significantly, and Vz/F and CLz/F increased significantly (P < 0.05). Conclusions: This study demonstrates that imperatorin inhibits the metabolism of diazepam both in vitro and in vivo. These data indicated that more attentions might be paid when taking diazepam together with food or herbs containing IMP, although it still need further investigation in the future.

The massive use of silver nanoparticles (AgNPs) is potentially harmful to exposed humans. Although previous studies have found that AgNPs can induce cell autophagy, few studies have focused on the toxic pathways and mechanisms of autophagy induced by AgNPs in rat respiratory epithelial (RTE) cells. In this study, RTE cells were exposed to two kinds of AgNPs in vitro to ascertain the influence of mTOR-autophagy pathway-associated protein expression, including Beclin1, LC3B, Atg5, and Atg7. After exposure to different sizes and concentrations of AgNPs for 12 h, the uptake of silver in RTE cells reached 0.45 μg/L to 1.11 μg/L, indicating that AgNPs can enter RTE cells, leading to toxic effects. Our study found that this toxic effect was related to autophagy caused by ROS accumulation that was mediated by the mTOR pathway. With increasing AgNP exposure concentrations, the expression of p-mTOR was significantly downregulated, and expression of the autophagy-related proteins Beclin1, LC3B, Atg5, and Atg7 was significantly increased in RTE cells in all exposed groups. At a concentration of 1000 μg/L, the expression of LC3BII/LC3BI in all exposed groups was 24.49 times and 12.71 times that of the control, and the expression of Atg7 in all exposed groups was 23.21 times and 13.21 times that of the control. The upregulation of autophagy-related proteins in the AgNP-10 nm exposure groups was greater than that of the AgNP-100 nm exposure group. In summary, the mTOR pathway mediates AgNP-induced autophagy in RTE cells, which leads to damage to the respiratory system barrier and human health risks. This study can facilitate the development of prevention and intervention policies against adverse consequences induced by AgNPs.

The efficient industrial conversion of plant-derived cellulose to simple sugars and other value-added chemicals requires various highly stable and reactive enzymes. Industrial processes especially synchronous saccharification and fermentation (SSF)-based production of cellulosic bio-ethanol require enzymes that are active at lower temperatures. In this study, we have identified, characterized, and expressed the cold-adaptive endo-1,4-β-glucanase (BpEG) isolated from the Burkholderia pyrrocinia JK-SH007. The analysis of the predicted amino acid sequence indicated that BpEG belongs to GH family 8. The BpEG without the signal peptide was cloned into the expression vector pET32a and significantly expressed in Escherichia coli BL21 (DE3) competent cells. The SDS-PAGE and Western blot analysis of BpEG revealed that the recombinant BpEG was approximately 60 kDa. Purified recombinant BpEG exhibited hydrolytic activity against carboxymethyl cellulose (CMC) and phosphoric acid swollen cellulose (PASC), but not crystalline cellulose and xylan substrates. High performance, anion exchange, chromatography-pulsed amperometric detector (HPAEC-PAD) analysis of the enzymatic products obtained from depolymerization of 1,4-β-linked biopolymers of different lengths revealed an interesting cutting mechanism employed by endoglucanases. The recombinant BpEG exhibited 6.0 of optimum pH and 35°C of optimum temperature, when cultured with CMC substrate. The BpEG enzyme exhibited stable activity between pH 5.0 and 9.0 at 35°C. Interestingly, BpEG retained about 42% of its enzymatic activity at 10°C compared to its optimal temperature. This new cold-adaptive cellulase could potentially achieve synchronous saccharification and fermentation (SSF) making BpEG a promising candidate in the fields of biofuel, biorefining, food and pharmaceutical industries., Graphical Abstract BpEG randomly cleaves cellulose polymers in low temperature.

International audience; In this work, we successfully prepared gold nanoparticles (AuNPs) within a germanium-tin-sulfur (Ge-Sn-S, GSS) chalcogenide glass (ChG). The formation of AuNPs in the GSS ChG relies on the reduction capacity of Sn(2+)ions, which we found their existence in the glass matrix by the characteristic emissions at nearly 450 nm. The AuNPs exhibit strong optical activity which caused a significant enhancement of third-order optical nonlinearity of the GSS ChG as well as photon luminescence of the Sn(2+)ions. In addition, optical properties the AuNPs-embedded GSS ChGs can be modified by further gold doping and one-step heat-treatment process.

Lusutrombopag is a second oral thrombopoietin (TPO) receptor agonist that selectively acts on human TPO receptors. In the study, UPLC-MS/MS was used to establish a selective and sensitive method to determine lusutrombopag with poziotinib as IS (internal standard) in rat plasma. Samples were prepared by precipitating protein with acetonitrile as a precipitant. Separation of lusutrombopag and poziotinib was performed on a CORTECS UPLC C18 column (2.1 ∗ 50 mm, 1.6 μm). The mobile phase (acetonitrile and water containing 0.1% formic acid) with gradient elution was set at a flow rate of 0.4 ml/min. The mass spectrometric measurement was conducted under positive ion mode using multiple reaction monitoring (MRM) of m/z 592.97 ⟶ 491.02 for lusutrombopag and m/z for poziotinib (IS) 492.06 ⟶ 354.55. The linear calibration curve of the concentration range was 2–2000 ng/ml for lusutrombopag, with a lower limit of quantification (LLOQ) of 2 ng/ml. RSD of interday and intraday precision were both no more than 9.66% with the accuracy ranging from 105.82% to 108.27%. The extraction recovery of lusutrombopag was between 82.15% and 90.34%. The developed and validated method was perfectly used in the pharmacokinetic study of lusutrombopag after oral administration in rats.

Germanium (Ge)-sulfur (S) (GeS) binary system is a simple and green chalcogenide glass system. In this work, we prepared a Ge-rich non-stoichiometric GeS film and investigated its optical property and network structure. Findings show that improving or modifying the optical properties (optical transmittance, refractive index, etc.) of the GeS film with a one-step annealing process, and the structural evolution of GeS film network that is attribute to the annealing-induced property changing is identified.

As the last resort for intractable Gram-positive bacterial infections, vancomycin is losing efficacy with the emergence of vancomycin-resistant bacteria, especially vancomycin-resistant Enterococci (VRE). To combat this threat, we rationally designed and synthesized 39 novel vancomycin derivatives by respective or combined modifications using metal-chelating, lipophilic, and galactose-attachment strategies for extensive structure-activity relationship (SAR) analysis. In a proposed mechanism, the conjugation of dipicolylamine on the seventh amino acid resorcinol position or C-terminus endowed the vancomycin backbone with binding capacity for the pyrophosphate moiety in lipid II while maintaining the intrinsic binding affinity for the dipeptide terminus of the bacterial cell wall peptidoglycan precursor. The in vitro antibacterial activities were evaluated, and the optimal compounds indicated 16- to 1024-fold higher activity against VRE than that of vancomycin. Compound 11 b (3',5'-bis(dipicolylaminomethyl)tyrosine [1,2,3]triazolylmethoxylethyoxyl ethylaminomethyl-N-decylvancomycin) was found to have particularly potent activity against VRE through synergistic effects brought about by combining two peripheral modifications.

Adsorption behaviors of metal porphyrins on graphene were studied by investigating adsorption kinetics, thermodynamics and density functional theoretical calculation. The interactions between poly aromatic nuclei structure of graphene and metal porphyrins were confirmed by XPS, TEM analysis and adsorption results, which account for adsorption of metal porphyrins. As the poly aromatic nuclei structure is the main structure of asphaltene, it also acted as active sites for adsorption of metal porphyrins. The differences of adsorption results between graphene and asphaltene indicated that the aliphatic side chains and other structures of asphaltene also have influence on adsorption process. Furthermore, chemical and physical adsorptions were also confirmed during the adsorption process of porphyrins on graphene.

This work described the application of Co–Mn–Fe hydrotalcites (Co–Mn–Fe LDHs) as heterogeneous catalysts for Fenton reaction process. The Co–Mn–Fe LDHs were synthesized by the co-precipitation method and were characterized by X-ray diffractometry (XRD), infrared spectroscopy (IR), zeta potential, and BET surface area measurement. The catalytic activity of different kinds of hydrotalcites was evaluated by the degradation of Direct Scarlet 4BS (4BS). The Co–Mn–Fe LDHs showed the best catalytic performance among four catalysts. The presence of the Mn2+/Mn3+ at surface of catalyst could accelerate the reduction of Co3+–Co2+, and then increased in the catalytic activity of the Co–Mn–Fe LDHs. The effect of initial pH, catalyst dosage, dye concentration, and reaction temperature on the degradation of 4BS had been investigated. Radical reaction mechanism was proposed by the addition of radical scavenger. The degradation kinetic followed pseudo-first-order model. The activation energy of Co–Mn–Fe LDHs was determined to be 37.3 kJ/mol. The catalytic activity of Co–Mn–Fe LDHs was maintained after four cycles of reaction, which proved the reusability of catalyst. Finally, the possible reaction mechanisms involved in the heterogeneous Fenton system were proposed.

Diapophytoene desaturase (CrtN) is a potential novel target for intervening in the biosynthesis of the virulence factor staphyloxanthin. In this study, 38 1,4-benzodioxan-derived CrtN inhibitors were designed and synthesized to overwhelm the defects of leading compound 4a. Derivative 47 displayed superior pigment inhibitory activity, better hERG inhibitory properties and water solubility, and significantly sensitized MRSA strains to immune clearance in vitro. Notably, 47 displayed excellent efficacy against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate MRSA, VISA), and NRS271 (linezolid-resistant MRSA, LRSA) comparable to that of linezolid and vancomycin in vivo.

Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H2O2 killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271.

Silver-ion-sconducting solid electrolytes with low activation energy are important because of their distinctive application potential in solid-state batteries operated within a broad temperature range, especially below room temperature. Achieving glassy solid electrolytes with high ionic conductivity, low activation energy, and good thermal stability is a continuous challenge for the design and synthesis of novel fast ion-conducting glasses. Here, we report markedly low activation energy and high room-temperature ionic conductivity in melt-quenched GeS2–Sb2S3–AgI chalcogenide glasses. Homogeneous 2.5GeS2–27.5Sb2S3–70AgI glass presenting high glass transition temperature of 135 °C shows high ionic conductivity of 9.18 × 10–3 S/cm at 25 °C and low activation energy of 0.07 eV, which is the lowest among those of Ag-ion glassy electrolytes. Structural characterization by using Raman spectra suggests that, in the disordered network structure of GeS2–Sb2S3–AgI glasses, the formation of chain fragments composed ...

Bismuth layered Aurivillius oxides have attracted longstanding research interest due to their unique structural characteristics and outstanding performance in ferroelectric dielectrics. The complex phase evolution process as a function of temperature and pressure in this family also provides fascinating platforms for understanding the chemical origin of their versatility. Herein, high-quality single crystals of a bismuth layered Aurivillius oxide, Bi2W2O9, with dimensions up to 29 × 23 × 11 mm3 were successfully grown via the top-seeded solution growth (TSSG) method using a mixture of WO3 and Li2B4O7 as a flux. The material crystallizes in an unexpected centrosymmetric orthorhombic Pbcn (no. 60) space group with unit cell parameters a = 23.705(2), b = 5.4148(6), and c = 5.4345(6) A. A complete survey of the anisotropic and variable-temperature thermal and dielectric properties was carried out with the aim of gaining detailed insights into their polymorphism evolution process. The results demonstrate that, with increasing temperature, the compound undergoes complicated phase transitions and, by analogy, signatures of the transitions are summarized and compared with those in Bi2WO6 and Bi2MoO6. The phase sequences and transition mechanisms of Bi2W2O9 are proposed by careful inspection and estimation.

Developing novel antibiotics is urgently needed with emergency of drug resistance. Vancomycin, the last resort for intractable Gram-positive bacterial infections, is ineffective against Gram-negative bacteria and vancomycin resistant bacteria. Herein, we report a series of novel vancomycin derivatives carrying LPS binding peptides, vancomycin-LPS binding peptide conjugates (VPCs). The LPS binding peptides were conjugated onto 4 sites of vancomycin via CuAAC or maleimide- sulfydryl addition, and the formed VPCs were screened against VISA/VRE and Gram-negative strains. VPCs exhibited enhanced activity against vancomycin resistant bacteria and obtained the activity against Gram-negative bacteria in vitro, providing a novel strategy for vancomycin modification and glycopeptide antibiotics synthesis.