Chlorination-improved adsorption capacity of microplastics for antibiotics: A combined experimental and molecular mechanism investigation.

Microplastics and antibiotics not only pollute aquatic environments and threaten human health, but are also tricky to remove. Microplastics adsorb antibiotics, and, before being released into the natural environment, most microplastics pass through some wastewater treatment and/or disinfection (such as chlorination) facilities. It is therefore necessary to understand how these treatment processes may affect or alter microplastics' properties, particularly their ability to adsorb antibiotics, and whether or not the two, when bound together, may present exacerbated harm to the environment. This study used both laboratory tests and molecular dynamics simulation to investigate the mechanism through which chlorinated microplastics (specifically polystyrene) adsorb the antibiotic tetracycline, and showed that chlorination gave the polystyrene a larger interaction area (> 21%) and more free energy (> 14%) to adsorb tetracycline. Van der Waals (vdW) forces played a more dominant role than electrostatics in facilitating tetracycline's adsorption. Moreover, a density functional theory analysis demonstrated that the vdW potentials of the microplastics decreased as more and more hydrogen atoms became replaced by chlorine, suggesting a facilitation of the adsorption of polycyclic antibiotic molecules. The experimental results confirmed the simulation's prediction that a higher degree of chlorination significantly increases the polystyrene's adsorption capacity, whereas pH and salinity had almost no effect on the adsorption. This study demonstrates that disinfection elevates the risk of antibiotics adhering to and accumulating on the surface of microplastics.

Farnesoid X receptor represses human sulfotransferase 1A3 expression through direct binding to the promoter.

Human sulfotransferases 1A3 (SULT1A3) has received particular interest, due to their functions of catalyzing the sulfonation of numerous phenolic substrates, including bioactive endogenous molecules and therapeutic agents. However, the regulation of SULT1A3 expression and the underlying mechanism remain unclear. Here, we aimed to investigate the regulation effects of bile acid-activated farnesoid X receptor (FXR) on SULT1A3 expression, and to shed light on the mechanism thereof. Our results demonstrated that FXR agonists (CDCA and GW4064) significantly inhibit the expression of SULT1A3 at mRNA and protein levels. In addition, overexpression of FXR led to decrease in SULT1A3 expression and knockdown of FXR significantly induced the expression of SULT1A3 in protein and mRNA levels, confirming that FXR expression manifestly showed negative regulatory effect on basal SULT1A3 expression. Furthermore, a combination of luciferase reporter gene and CHIP assays showed that FXR repressed SULT1A3 transcription through direct binding to the region at base pair positions -664 to -654. In conclusion, this study for the first time confirmed FXR was a negative transcriptional regulator of human SULT1A3 enzyme.

Effects of chlorination on microplastics pollution: Physicochemical transformation and chromium adsorption.

The large number of microplastics (MPs) that appear in the environment has drawn much attention. Few studies, however, have examined the transformation of MPs in water treatment processes and their effects on environmental pollutants. In this study, the alteration of the physicochemical characteristics of polyethylene and thermoplastic polyurethane upon chlorination, as well as the influence of this alteration on contaminants, were investigated. The findings indicated that microplastics underwent significant morphology and O-functional groups changes during chlorination. It is noteworthy that the mechanisms controlling the chlorination treatment of the two MPs are clearly different. The results of aggregation and adsorption experiments showed that the chlorination treatment enhanced the aggregation ability of the MPs in brine and their interaction with Cr(VI). The present discoveries further suggested that water treatment could alter the migration capacity of microplastics and the distribution of contaminants in the aqueous environment by altering the adsorption of microplastics to the contaminants.

The influence of verapamil on the pharmacokinetics of the pan-HER tyrosine kinase inhibitor neratinib in rats: the role of P-glycoprotein-mediated efflux.

Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has been approved for the treatment of HER2-positive (HER2+) early-stage and brain metastatic breast cancer. Thus far, the pharmacology effects and pharmacodynamics of neratinib have been well studied. However, the disposition of neratinib and its influencing factors in vivo remain unclear. P-glycoprotein (P-gp), one of the most extensively studied transporters, substantially restricts penetration of drugs into the body or deeper compartments (i.e., blood-brain barrier, BBB), regarding drug resistance and drug-drug interactions. Thereby, the aim of this study was to investigate the influence of verapamil (a P-gp inhibitor) on the pharmacokinetics of neratinib in rats. Here, we have established a high specific, selective and sensitive ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify plasma concentrations of neratinib in rats. Pharmacokinetic results showed that verapamil significantly increased the system exposure of neratinib, as Cmax increased by 2.09-fold and AUC0-t increased by 1.64-fold, respectively. Additionally, the in vitro transport of neratinib was evaluated using Madin-Darby canine kidney II (MDCK II) and human MDR1 gene overexpressed MDCK (MDCK-MDR1) cell line models. As a result, the net flux ratio was over than 2 and decreased over 50% by verapamil, suggesting that neratinib was a substrate of P-gp. Hence, our findings have highlighted the important role of P-gp in the system exposure of neratinib in vivo, and drug-drug interaction should be considered when coadministration of P-gp inhibitors with neratinib. These findings may support the further clinical development and application of neratinib.

O-Sulfation disposition of curcumin and quercetin in SULT1A3 overexpressing HEK293 cells: the role of arylsulfatase B in cellular O-sulfation regulated by transporters.

Extensive phase II metabolic reactions (i.e., glucuronidation and sulfation) have resulted in low bioavailability and decreased biological effects of curcumin and quercetin. Compared to glucuronidation, information on the sulfation disposition of curcumin and quercetin is limited. In this study, we identified that BCRP and MRP4 played a critical role in the cellular excretion of curcumin-O-sulfate (C-O-S) and quercetin-O-sulfate (Q-O-S) by integrating chemical inhibition with transporter knock-down experiments. Inhibited excretion of sulfate (C-O-S and Q-O-S) caused significant reductions in cellular O-sulfation of curcumin (a maximal 74.4% reduction) and quercetin (a maximal 76.9% reduction), revealing a strong interplay of sulfation with efflux transport. It was further identified that arylsulfatase B (ARSB) played a crucial role in the regulation of cellular O-sulfation by transporters. ARSB overexpression significantly enhanced the reduction effect of MK-571 on the cellular O-sulfation (fmet) of the model compound (38.8% reduction for curcumin and 44.2% reduction for quercetin). On the contrary, ARSB knockdown could reverse the effect of MK-571 on the O-sulfation disposition of the model compound (29.7% increase for curcumin and 47.3% increase for quercetin). Taken together, ARSB has been proven to be involved in cellular O-sulfation, accounting for transporter-dependent O-sulfation of curcumin and quercetin. A better understanding of the interplay beneath metabolism and transport will contribute to the exact prediction of in vivo drug disposition and drug-drug interactions.

The impact of chlorination on the tetracycline sorption behavior of microplastics in aqueous solution.

Considering the large volumes of treated water and incomplete elimination of pollutants, wastewater treatment plants (WWTPs) remain a considerable source of microplastics (MPs). Chlorine, the most frequently used disinfectant in WWTPs, has a strong oxidizing impact on MPs. However, little is documented, to date, about the impact of chlorination on the transformation of MPs and the subsequent environmental behaviors of the chlorinated MPs when released into the aquatic environment. This study explored the response of the physicochemical properties of specific thermoplastics, namely polyurethane (TPU) MPs and polystyrene (PS) MPs, to chlorination and their emerging pollutant [tetracycline (TC)] adsorption behavior in aqueous solution. The results indicated that the O/C ratio of the MP surface did not significantly change, and that there were increases in the O-containing functional groups of the TPU and PS MPs, after chlorination. The surface area of the chlorinated TPU MPs increased by 45 %, and that of the chlorinated PS increased by 21 %, compared with the pristine ones, which contributed to the TC adsorption. The adsorption isotherm fitting parameters suggested that the chlorinated TPU fitted the multilayer adsorption, and the chlorinated PS was inclined to the monolayer adsorption. The relative abundance of the O-containing functional groups, on the TPU surface, led to the release of CHCl3 molecules, and the clear surface irregularities and fissures occurred after chlorine treatment. No fissures were found on the surface of the chlorinated PS MPs. The hydrophobicity and electrostatic adsorption were proved to be the major impacts on the TC adsorption of the chlorinated MPs, and the subsequently formed hydrogen bonds led to the stronger adsorption capacity of the chlorinated TPU than the chlorinated PS MPs.

The effects of polypropylene microplastics on the DBP formation under the chlorination and chloramination processes.

With the increased use of microplastics in modern society, tonnes of various microplastics (MPs) end up in natural and engineered water systems if not properly handled. Being a class of organics, the role of MPs during the disinfection of water treatment systems is still unclear at this stage. In the current experimental study, the formation of 6 typical disinfection by-products (DBPs) was investigated using varying concentrations of polypropylene (PP) MPs under various aquatic chemistry conditions and disinfectants. All investigated DBPs were detected, during the chlorination of PP, with an average CHCl3 concentration of 378 µg/g, and other DBPs, including CHCl2Br, TCA, DCAN, 1,1-DCP, and TCNM, were present in less than 60 µg/g, on average. When PP coexisted with Suwannee River Fulvic acid (SRFA), a suppression of DBP formation was observed with a 56% net reduction compared with a condition of PP alone. The dynamic balance of being a DBP precursor, or a scavenger, by absorbing the organics of PP is subjected to aquatic chemistry. Increasing the pH decreases the HOCl concentrations, reducing the PP oxidation capacity and DBP formation. As salinity increases, the aggregation of PP can reduce the reaction sites on the surface of PP and enhance the adsorption of SRFA, hence lowering the formation of DBPs.

Cinobufotalin inhibits the epithelial-mesenchymal transition of hepatocellular carcinoma cells through down-regulate ß-catenin in vitro and in vivo.

Hepatocellular carcinoma (HCC) is one of the malignant tumors with high incidence and mortality. The prognosis of HCC is poor due to the high postoperative recurrence rate and metastasis rate. Epithelial-mesenchymal transition (EMT) plays a key role in the metastasis of HCC, which is closely related to the invasion, intrahepatic metastasis and low survival rate. Here we demonstrated that cinobufotalin can upregulate epithelial markers (E-cadherin) and downregulate mesenchymal markers (N-cadherin, snail, slug and ZEB1) in HepG2, SMMC-7721 and SNU-368 cells. We further found that the mRNA and protein expression of ß-catenin and its target genes (i.e. MMP7 and DKK1), which are related to tumor invasion and metastasis, were decreased after cinobufotalin treatment. Overexpression of ß-catenin promoted EMT of HepG2 and SMMC-7721 cells, and cinobufotalin could antagonize this induction. While Knockdown of ß-catenin could inhibit EMT and cinobufotalin enhanced this inhibition. In addition, cinobufotalin significantly suppressed the tumor EMT, as demonstrated by increased E-cadherin expression and decreased N-cadherin and vimentin expression, and inhibited formation and metastasis of lung metastases in vivo. In conclusion, our study has revealed a novel anticancer mechanism of cinobufotalin, which inhibits EMT progress by downregulating ß-catenin, and then prevents the migration and invasion of HCC. These results provide convincing evidence for the development of cinobufotalin as a potential HCC metastasis inhibitor.

Effects of microplastics on DBPs formation under the chlorination of natural organic matters.

Microplastics have attracted extensive attention and concern because they inflict damage on human beings and the environment. When the microplastics enter the water system, they inevitably flow into the water treatment system and encounter disinfectants during the disinfection procedure. Chlorine can react with microplastics to form different kinds of disinfection byproducts (DBPs). O-containing functional groups on the surface of microplastics may play a major role in DBP formation. Without O-containing functional groups, microplastics can also form DBPs but with totally different mechanisms. Reactive oxygen species (ROS, i.e., •OH) and reactive chlorine substances (RCS, i.e., Cl• and ClO•) may attack the microplastics and form DBP precursors. With relatively low surface area and very little pore volume, microplastics cannot affect the DBP formation between Suwannee River fulvic acid (SRFA) and chlorine. When SRFA exists, microplastics with few O-containing functional groups can hardly form DBPs because of the inhibition of ROS and RCS.

HGF/c-MET pathway contributes to cisplatin-mediated PD-L1 expression in hepatocellular carcinoma.

Cisplatin has been reported to promote the expression of programmed cell death ligand-1 (PD-L1) in some cancer cells. However, the underlying mechanism through which PD-L1 is transcriptionally regulated by cisplatin in hepatocellular carcinoma (HCC) cells remains largely unknown. In the present study, we found that the expression of hepatocyte growth factor (HGF), p-Akt, p-ERK, and PD-L1 was increased in cisplatin-treated SNU-368 and SNU-739 cells. HGF stimulation also increased PD-L1 expression in these cells. Moreover, Inhibition of HGF/c-MET, PI3K/Akt, and MEK/ERK signaling pathways can dramatically block cisplatin or HGF-induced PD-L1 expression in SNU-368 and SNU-739 cells. In vivo, combination PHA665752 with cisplatin significantly reduced tumor weight with increased infiltration of CD8+ T cells in the tumor. Taken together, our study suggested that HGF/c-Met axis-induced the activation of PI3K/Akt and MEK/ERK pathways contributes to cisplatin-mediated PD-L1 expression. These findings may provide an alternative avenue for the treatment of HCC.

The CAG promoter maintains high-level transgene expression in HEK293 cells.

The vast majority of therapeutic recombinant proteins are produced in mammalian cell lines. However, proteins generated in nonhuman cell lines, such as Chinese hamster ovary (CHO) cells, are decorated with human-like glycan structures that differ from those of human cells, and these may induce immunogenic responses in human cells. Human embryonic kidney cells (HEK293F) are also extensively used as hosts for the expression of recombinant therapeutic proteins, but their utility is limited by the low expression of transgenes in these cells. Here, we investigated recombinant protein expression from eight frequently used promoters in transfected HEK293F cells. The expression levels and stability of the transgenes were evaluated by flow cytometry and qRT-PCR. The most efficient expression (in terms of both mRNA and protein yields) was achieved using a cytomegalovirus (CMV) major immediate-early enhancer combined with the chicken beta-actin promoter (CAG) promoter, as compared to all other tested promoters under both transient and stable transfection conditions. In addition, application of mild hypothermia (i.e., 33 °C) after transfection improved the positive effect of the CMV enhancer fused to the chicken beta-actin promoter (CAG promoter) on enhanced green fluorescent protein (eGFP) expression. Although the temperature sensitivity of the CMV promoter is greater than that of CAG promoter, recombinant protein levels were still highest when expression was driven by the CAG promoter. When eGFP was replaced with hepatitis B surface antigen, the CAG promoter still showed the highest transgene expression. In conclusion, our data show that the CAG promoter is a strong promoter for recombinant protein expression in HEK293F cells.

Effect of Composition on the Crystallization, Water Absorption, and Biodegradation of Poly(ε-caprolactam-co-ε-caprolactone) Copolymers.

Poly(ester amide)s have aroused extensive research interest due to the combination of the degradability of polyester and the higher mechanical properties of polyamide. In this work, a series of poly(ε-caprolactam-co-ε-caprolactone) (P(CLA-co-CLO)) copolymers with different compositions were synthesized by anionic copolymerization. The structure, crystallization behavior, water absorption, and biodegradation behavior of these copolymers were investigated by means of nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), wide-angle X-ray diffraction (WAXD), and polarized optical micrographs (POM). The results indicated that the composition of P(CLA-co-CLO) copolymers can be adjusted by the molar feed ratio. The PCL blocks decreased the crystallization rate of PA6 blocks but had little effect on the melting behavior of PA6, while the crystallized PA6 acted as a heterogeneous nucleating agent and greatly improved the crystallization rate of PCL. Moreover, the introduction of PCL blocks greatly reduced the water absorption of P(CLA-co-CLO) copolymers and endow them a certain degree of degradability.

Sorption Behavior and Mechanisms of Organic Contaminants to Nano and Microplastics.

Nano and microplastics (NPs/MPs) have received widespread attention in recent years. Because of their large specific surface area and hydrophobicity, NPs/MPs can adsorb various organic contaminants. This article gives a brief review of the sorption behavior of organic contaminants to NPs/MPs, summarizes the possible sorption mechanisms, and analyzes the influencing factors in the environment on the sorption behavior and mechanisms of NPs/MPs. The main mechanisms of sorption of organic contaminants to NPs/MPs are partitioning, surface sorption (hydrogen bonding, π-π interaction, electrostatic interaction, and van der Waals force), and pore filling. The sorption behavior of organic contaminants to NPs/MPs is not only affected by the properties of the NPs/MPs and the organic contaminants, but also by the solution chemistry, such as the pH, ionic strength, and dissolved organic matter.

Effects of different 2A peptides on transgene expression mediated by tricistronic vectors in transfected CHO cells.

Multicistronic vectors can increase transgene expression and decrease the imbalance of gene expression in the Chinese hamster ovary (CHO) cell expression system. Small, self-cleaving 2A peptides have a high cleavage efficiency and are essential for constructing high-expression multicistronic vectors. In this study, we investigated the effects of two different 2A peptides on transgene expression in CHO cells via their mediating action on tricistronic vectors. The enhanced green fluorescent protein (eGFP) and red fluorescent protein (RFP) genes were linked by the porcine teschovirus-1 (P2A) and Thosea asigna virus (T2A) peptides in a multicistronic vector. We transfected CHO cells with these vectors and screened for the presence of blasticidin-resistant colonies. Flow cytometry and real-time quantitative PCR (qPCR) were used to detect the expression levels of eGFP and RFP and the copy numbers of stably transfected cells. The results showed that P2A could enhance eGFP and RFP expression by 1.48- and 1.47-fold, respectively, compared to T2A. The expression levels of the genes were not proportional to their copy numbers. In conclusion, we found that P2A can effectively drive transgene expression in CHO cells and a potent 2A peptide can be used for recombinant protein production in the CHO cell system.

Artificial spider silk from ion-doped and twisted core-sheath hydrogel fibres.

Spider silks show unique combinations of strength, toughness, extensibility, and energy absorption. To date, it has been difficult to obtain spider silk-like mechanical properties using non-protein approaches. Here, we report on an artificial spider silk produced by the water-evaporation-induced self-assembly of hydrogel fibre made from polyacrylic acid and silica nanoparticles. The artificial spider silk consists of hierarchical core-sheath structured hydrogel fibres, which are reinforced by ion doping and twist insertion. The fibre exhibits a tensile strength of 895 MPa and a stretchability of 44.3%, achieving mechanical properties comparable to spider silk. The material also presents a high toughness of 370 MJ m-3 and a damping capacity of 95%. The hydrogel fibre shows only ~1/9 of the impact force of cotton yarn with negligible rebound when used for impact reduction applications. This work opens an avenue towards the fabrication of artificial spider silk with applications in kinetic energy buffering and shock-absorbing.

Buckled Structures: Fabrication and Applications in Wearable Electronics.

Wearable electronics have attracted a tremendous amount of attention due to their many potential applications, such as personalized health monitoring, motion detection, and smart clothing, where electronic devices must conformably form contacts with curvilinear surfaces and undergo large deformations. Structural design and material selection have been the key factors for the development of wearable electronics in the recent decades. As one of the most widely used geometries, buckling structures endow high stretchability, high mechanical durability, and comfortable contact for human-machine interaction via wearable devices. In addition, buckling structures that are derived from natural biosurfaces have high potential for use in cost-effective and high-grade wearable electronics. This review provides fundamental insights into buckling fabrication and discusses recent advancements for practical applications of buckled electronics, such as interconnects, sensors, transistors, energy storage, and conversion devices. In addition to the incorporation of desired functions, the simple and consecutive manipulation and advanced structural design of the buckled structures are discussed, which are important for advancing the field of wearable electronics. The remaining challenges and future perspectives for buckled electronics are briefly discussed in the final section.

Viral polymerase inhibitors T-705 and T-1105 are potential inhibitors of Zika virus replication.

Since 2015, 69 countries and territories have reported evidence of vector-borne Zika virus (ZIKV) transmission. Currently, there are no effective licensed vaccines or drugs available for the treatment or prevention of ZIKV infection. We tested a series of compounds for their ability to inhibit ZIKV replication in cell culture. The compounds in T-705 (favipiravir) and T-1105 were found to have antiviral activity, suggesting that these compounds are promising candidates for further development as specific antiviral drugs against ZIKV.

Synthesis and in vivo antimalarial activity of novel naphthoquine derivatives with linear/cyclic structured pendants.

AIM: Naphthoquine (NQ) was discovered by our institute as an antimalarial candidate in 1980s, and currently employed as an artemisinin-based combination therapy partner drug. Resistance to NQ was found in mouse model in laboratory, and might emerge in future as widely used. METHODOLOGY: We herein report the design and synthesis of NQ derivatives by replacing t-butyl moiety with linear/cyclic structured pendants. All the target compounds 6a-l and intermediates 5a-h were tested for their in vivo antimalarial activity against Plasmodium berghei K173 strain in mice. RESULTS: Compounds 6a and 6j were found to have a comparable or slightly more potent activity (the 50% effective dose [ED50], which is required to decrease parasitemia by 50%: 0.38-0.43 mg/kg) than NQ (ED50: 0.48 mg/kg). CONCLUSION: The newly designed compounds 6a and 6j might be promising antimalarial candidates for further research.

Effects of cidofovir on human papillomavirus-positive cervical cancer cells xenografts in nude mice.

Cidofovir (CDV) is an acyclic nucleoside phosphonate analog that shows broad spectrum anti-DNA virus activity. In this study, we have investigated the influence of cidofovir on the tumor xenografts derived from HeLa and SiHa cells on nude mice. The HeLa/SiHa xenografts in nude mice were established by inoculating cells subcutaneously. Administration of cidofovir by intratumoral injection led to significant tumor reduction. Enhanced protein levels of p53 and p-pRb within the tumor samples were observed. Immunohistology analysis of the tumor sections indicated decreased PCNA index and increased apoptosis index. Our study gives more evidence and explanation on in vivo inhibition effect of cidofovir on HPV genome-positive cervical carcinoma cell line xenografts.