QSAR-QSIIR-based prediction of bioconcentration factor using machine learning and preliminary application.

Bioconcentration factor (BCF) is one of the important parameters for developing human health ambient water quality criteria (HHAWQC) for chemical pollutants. Traditional experimental method to obtain BCF is time-consuming and costly. Therefore, prediction of BCF by modeling has attracted much attention. QSAR (Quantitative Structure-Activity Relationship) model based on molecular descriptor is often used to predict BCF, however, in order to improve the accuracy of prediction, previous models are only applicable for prediction for a single category of substance and a single species, and cannot meet the needs of BCF prediction of pollutants lacing toxicity data. In this study, optimized 17 traditional molecular descriptor and five kinds of bioactivity descriptor were selected from more than 200 molecular descriptor and 25 kinds of biological activity descriptors. A QSAR-QSIIR (Quantitative Structure In vitro-In vivo Relationship) model suitable for multiple chemical substances and whole species is constructed by using optimized 4-MLP machine learning algorithm with selected molecular and bioactivity descriptors. The constructed model significantly improves the prediction accuracy of BCF. The R2 of verification set and test set are 0.8575 and 0.7924, respectively, and the difference between predicted BCF and measured BCF is mostly less than 1.5 times. Then, BCF of BTEX in Chinese common aquatic products is predicted using the constructed QSAR-QSIIR model, and the HHAWQC of BTEX in China are derived using the predicted BCF, which provides a valuable reference for establishment of China's BTEX water quality standards.

Reference dose prediction by using CDK molecular descriptors: A non-experimental method.

Reference dose (RfD) is an estimate of a daily dose that individual can be exposed chronically without obvious deleterious effects during a lifetime. In the area of toxicology, researchers always use the traditional approach by employing NOAEL/LOAEL or the benchmark dose (BMD) and other dose-response approaches to estimate RfD. These methods have, despite their typicalness, certain limitations. In this study, we present a novel method of the estimation of reference dose without experiments. The information of the organic chemicals is available from the Integrated Risk Information System (IRIS) of USEPA. Molecular descriptors for each molecular structure were calculated by an integrated platform, and the chemicals were classified into four categories based on molecular similarity: 128 contained benzene rings, 47 were heteroaromatics, 104 contained halogen substituents and 44 were halogenated aliphatic hydrocarbons. The predictive model of RfD was constructed by the multiple linear stepwise regression (MLR) method. Approximately 95% and 82% of the data points differ by less than 10-fold and 5-fold between the predicted values and the true values respectively. The non-experimental method improves the estimation efficiency and has a certain reference value to predict.

2,2'-((1R,3R,4S)-4-methyl-4-vinylcyclohexane-1,3-diyl) bis(prop-2-en-1-amine), a bisamino derivative of ß-Elemene, inhibits glioblastoma growth through downregulation of YAP signaling.

ß-Elemene, a compound extracted from Chinese herb Curcuma wenyujin, has been demonstrated with antitumor effects in various cancers, including glioblastoma (GBM), a primary brain tumor with high morbidity and mortality. In this study, we reported a bisamino derivative of ß-Elemene, 2, 2'-((1R, 3R, 4S)-4-methyl-4-vinylcyclohexane-1, 3-diyl) bis(prop-2-en-1-amine) (compound 1), displayed a better anti-GBM effect than ß-Elemene with lower concentration. GBM cell lines (C6 and U87) were treated with compound 1 and subsequently analyzed by several assays. Compound 1 significantly inhibited the migration of C6 and U87 cells based on wound healing assay, transwell assay and inverted migration assay. Furthermore, colony formation assay, immunostaining and flow cytometry assays revealed that compound 1 significantly inhibited the proliferation of GBM cells. In addition, compound 1 induced the apoptosis of GBM cells. Mechanistically, we found Yes-associated protein (YAP) was down-regulated in compound 1-treated GBM cells, and the overexpression of YAP partially rescued the anti-GBM effects of compound 1. Finally, compound 1 suppresses the GBM growth in xenograft model through inactivation YAP signaling. Taken together, these results reveal that a novel derivative of ß-Elemene, compound 1, exhibits more potent anti-GBM activity than ß-Elemene through inactivating YAP signaling pathway, which will provide novel strategies for the treatment of GBM.

Generation of Indoles with Agrochemical Significance through Biotransformation by Chaetomium globosum.

Six new (1-6) and two known (7 and 8) indole alkaloids were produced by the marine fish-derived fungus Chaetomium globosum 1C51 through biotransformation. The structures of these alkaloids were elucidated by a combination of MS, NMR, and X-ray crystallography analyses. Chaetoindolone A (1) was shown to inhibit the growth of the rice-pathogenic bacteria Xanthomonas oryzae pv. oryzae (xoo) both in vitro and in vivo. Chaetogline A (7) was found to be fungicidal against Sclerotinia sclerotiorum, a pathogen causing rape sclerotinia rot. Collectively, this work provides access to new indole alkaloids with potential agrochemical significance.

Nigrosporanenes C and D, two new cyclohexene derivatives from the enphytic fungus Nigrospora oryzae S4.

Two new cyclohexene derivatives, nigrosporanenes C and D (1 and 2), together with three known compounds (3-5), were isolated from the culture of an endophyte Nigrospora oryzae S4. Their structures were characterized by a combination of detailed spectroscopic analysis and comparison of their NMR data with those reported in the literature. All compounds were tested for anti-phytopathogenic activity, however, none of them showed activity at a concentration of 20 µM.

Osseointegration of three-dimensional designed titanium implants manufactured by selective laser melting.

The selective laser melting (SLM) technique is a recent additive manufacturing (AM) technique. Several studies have reported success in the SLM-based production of biocompatible orthopaedic implants and three-dimensional bone defect constructs. In this study, we evaluated the surface properties and biocompatibility of an SLM titanium implant in vitro and compared them with those of a machined (MA) titanium control surface. In addition, we evaluated the osseointegration capability of the SLM implants in vivo and compared it with those of MA and Nobel-speedy (Nobel-S) implants. SLM microtopographical surface analysis revealed porous and high roughness with varied geometry compared with a smooth surface in MA Ti samples but with similar favourable wettability. Osteoblast proliferation and alkaline phosphatase activity were significantly enhanced on the SLM surface. Histological analysis of the bone-implant contact ratio revealed no significant difference among SLM, MA, and Nobel-S implants. Micro-CT assessment indicated that there was no significant difference in bone volume fraction around the implant among SLM implants and other types of surface modification implants. The removal torque value measurement of SLM implants was significantly lower that of than Nobel-S implants P < 0.001 and higher than that of MA implants. The study demonstrates the capability of SLM implants to integrate with living bone. The SLM technique holds promise as a new dental implant manufacturing technique.

Improved bioactivity of selective laser melting titanium: Surface modification with micro-/nano-textured hierarchical topography and bone regeneration performance evaluation.

Selective laser melting (SLM) titanium requires surface modification to improve its bioactivity. The microrough surface of it can be utilized as the micro primary substrate to create a micro-/nano-textured topography for improved bone regeneration. In this study, the microrough SLM titanium substrate was optimized by sandblasting, and nano-porous features of orderly arranged nanotubes and disorderly arranged nanonet were produced by anodization (SAN) and alkali-heat treatment (SAH), respectively. The results were compared with the control group of an untreated surface (native-SLM) and a microtopography only surface treated by acid etching (SLA). The effects of the different topographies on cell functions and bone formation performance were evaluated in vitro and in vivo. It was found that micro-/nano-textured topographies of SAN and SAH showed enhanced cell behaviour relative to the microtopography of SLA with significantly higher proliferation on the 1st, 3rd, 5th and 7th day (P<0.05) and higher total protein contents on the 14th day (P<0.05). In vivo, SAN and SAH formed more successively regenerated bone, which resulted in higher bone-implant contact (BIC%) and bone-bonding force than native-SLM and SLA. In addition, the three-dimensional nanonet of SAH was expected to be more similar to native extracellular matrix (ECM) and thus led to better bone formation. The alkaline phosphatase activity of SAH was significantly higher than the other three groups at an earlier stage of the 7th day (P<0.05) and the BIC% was nearly double that of native-SLM and SLA in the 8th week. In conclusion, the addition of nano-porous features on the microrough SLM titanium surface is effective in improving the bioactivity and bone regeneration performance, in which the ECM-like nanonet with a disorderly arranged biomimetic feature is suggested to be more efficient than nanotubes.

Sustained dual release of placental growth factor-2 and bone morphogenic protein-2 from heparin-based nanocomplexes for direct osteogenesis.

OBJECTIVE: To compare the direct osteogenic effect between placental growth factor-2 (PlGF-2) and bone morphogenic protein-2 (BMP-2). METHODS: Three groups of PlGF-2/BMP-2-loaded heparin-N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) nanocomplexes were prepared: those with 0.5 µg PlGF-2; with 1.0 µg BMP-2; and with 0.5 µg PlGF-2 combined with 1.0 µg BMP-2. The loading efficiencies and release profiles of these growth factors (GFs) in this nanocomplex system were quantified using enzyme-linked immunosorbent assay, their biological activities were evaluated using cell counting kit-8, cell morphology, and cell number counting assays, and their osteogenic activities were quantified using alkaline phosphatase and Alizarin Red S staining assays. RESULTS: The loading efficiencies were more than 99% for the nanocomplexes loaded with just PlGF-2 and for those loaded with both PlGF-2 and BMP-2. For the nanocomplex loaded with just BMP-2, the loading efficiency was more than 97%. About 83%-84% of PlGF-2 and 89%-91% of BMP-2 were stably retained on the nanocomplexes for at least 21 days. In in vitro biological assays, PlGF-2 exhibited osteogenic effects comparable to those of BMP-2 despite its dose in the experiments being lower than that of BMP-2. Moreover, the results implied that heparin-based nanocomplexes encapsulating two GFs have enhanced potential in the enhancement of osteoblast function. CONCLUSION: PlGF-2-loaded heparin-HTCC nanocomplexes may constitute a promising system for bone regeneration. Moreover, the dual delivery of PlGF-2 and BMP-2 appears to have greater potential in bone tissue regeneration than the delivery of either GFs alone.

Functional mimicry of the active site of glutathione peroxidase by glutathione imprinted selenium-containing protein.

For imitating the active site of antioxidant selenoenzyme glutathione peroxidase (GPx), an artificial enzyme selenosubtilisin was employed as a scaffold for reconstructing substrate glutathione (GSH) specific binding sites by a bioimprinting strategy. GSH was first covalently linked to selenosubtilisin to form a covalent complex GSH-selenosubtilisin through a Se-S bond, then the GSH molecule was used as a template to cast a complementary binding site for substrate GSH recognition. The bioimprinting procedure consists of unfolding the conformation of selenosubtilisin and fixing the new conformation of the complex GSH-selenosubtilisin. Thus a new specificity for naturally occurring GPx substrate GSH was obtained. This bioimprinting procedure facilitates the catalytic selenium moiety of the imprinted selenosubtilisin to match the reactive thiol group of GSH in the GSH binding site, which contributes to acceleration of the intramolecular catalysis. These imprinted selenium-containing proteins exhibited remarkable rate enhancement for the reduction of H2O2 by GSH. The average GPx activity was found to be 462 U/micromol, and it was approximately 100 times that for unimprinted selenosubtilisin. Compared with ebselen, a well-known GPx mimic, an activity enhancement of 500-fold was observed. Detailed steady-state kinetic studies demonstrated that the novel selenoenzyme followed a ping-pong mechanism similar to the naturally occurring GPx.