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Background Pesticide residues are known to cause serious problems to human health. Although the detection of pesticides in fruit and fruit juice has been traditionally attempted using chromatographic techniques, surface-enhanced Raman spectroscopy (SERS) has recently arisen as a suitable alternative for the detection of organic compounds in biological matrices. Scope and approach All reported methods for the detection of pesticides in fruit and fruit juice, based on SERS enhanced with gold and silver nanoparticles, are covered for the first time. The detection parameters obtained using different experimental conditions are compared throughout the manuscript. The achievements and limitations of this technique for the detection of pesticides in fruit and fruit juice are discussed. Key findings and conclusions A variety of sample preparation steps, scaffolds for the deposition of nanoparticles, nanoparticles with different shapes and decorations, and metal combinations were screened across the reports. The decoration of the nanoparticles with organic structures, such as mercaptooctanone and polyvinyl alcohol, and combinations with WO3, WS2 and MoS2 provided high sensitivity and stability. The developed methods were used for the detection and quantification of numerous pesticides in different matrices and showed similar limits of detection in comparison with traditional chromatographic methods. Interestingly, SERS allowed the detection of cations and organometallic structures that are difficult to detect with other techniques. In contrast with traditional methods, methods based on Raman spectroscopy allow the detection of only one or a few pesticides simultaneously, and the simultaneous quantification of several pesticides requires the introduction of a preliminary separation step.

Recent advances in mass spectrometry (MS)-based proteomics allow the measurement of turnover rates of thousands of proteins using dynamic labeling methods, such as pulse stable isotope labeling by amino acids in cell culture (pSILAC). However, when applying the pSILAC strategy to multicellular animals (e.g., mice), the labeling process is significantly delayed by native amino acids recycled from protein degradation in vivo, raising a challenge of defining accurate protein turnover rates. Here, we report JUMPt, a software package using a novel ordinary differential equation (ODE)-based mathematical model to determine reliable rates of protein degradation. The uniqueness of JUMPt is to consider amino acid recycling and fit the kinetics of the labeling amino acid (e.g., Lys) and whole proteome simultaneously to derive half-lives of individual proteins. Multiple settings in the software are designed to enable simple to comprehensive data inputs for precise analysis of half-lives with flexibility. We examined the software by studying the turnover of thousands of proteins in the pSILAC brain and liver tissues. The results were largely consistent with the proteome turnover measurements from previous studies. The long-lived proteins are enriched in the integral membrane, myelin sheath, and mitochondrion in the brain. In summary, the ODE-based JUMPt software is an effective proteomics tool for analyzing large-scale protein turnover, and the software is publicly available on GitHub (https://github.com/JUMPSuite/JUMPt) to the research community.

Single-crystal Ni-rich cathode material LiNi0.88Co0.09Al0.03O2 (SC) was synthesized by a high-temperature solid-state calcination method. Physicochemical properties of primary and delithiated SC samples were investigated by X-ray diffractometry, X-ray photoelectron spectroscopy, and transmission electron microscopy. Electrochemical performance was characterized by long-term cycling, cyclic voltammetry, and in-situ impedance spectroscopy. The results indicated that high temperature rendered layered oxides to lose lithium/oxygen in the interior and exterior, and induced cationic disordering. Besides, the solid-phase synthesis process promoted phase transformation for electrode materials, causing the coexisting multi-phase in a single particle. High temperature can foster the growth of single particles, but it caused unstable structure of layered phase.

Vinylpyrazine compounds are widely present in foods, especially in hot-processed foods, as a class of flavor compounds; however, their formation mechanism in food systems is still unclear. Therefore, in this study, 2-vinylpyrazine and 2-vinyl-6-methylpyrazine were identified in the Maillard model reaction of D-glucose and glycine. The Maillard model reaction of glucose–glycine was constructed to explore the effects of reaction parameters on vinylpyrazines and the related products. The Maillard reaction of [U-13C6] glucose and glycine was established, and alkylpyrazines and formaldehyde were determined via isotope tracing technique as the precursors of vinylpyrazines. The formation of vinylpyrazines was verified by building a model reaction between alkylpyrazines and formaldehyde. The H/D exchange experiment confirmed that the active site of alkylpyrazines was on the methyl group, which was the reaction site for the condensation reaction of alkylpyrazines with formaldehyde. Results suggest that vinylpyrazines are formed by the condensation reaction of alkylpyrazines and formaldehyde.

Background Study shows that signal transducer and activator of transcription 3 (STAT3) can increase the Warburg effect by stimulating hexokinase 2 in breast cancer and upregulate lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 in myeloma. STAT3 and pyruvate kinase M2 (PKM2) can also be activated and enhance the Warburg effect in hepatocellular carcinoma. Precancerous lesions are critical to human and rodent hepatocarcinogenesis. However, the underlying molecular mechanism for the development of liver precancerous lesions remains unknown. We hypothesized that STAT3 promotes the Warburg effect possibly by upregulating p-PKM2 in liver precancerous lesions in rats. Aim To investigate the mechanism of the Warburg effect in liver precancerous lesions in rats. Methods A model of liver precancerous lesions was established by a modified Solt-Farber method. The liver pathological changes were observed by HE staining and immunohistochemistry. The transformation of WB-F344 cells induced with N-methyl-N'-nitro-N-nitrosoguanidine and hydrogen peroxide was evaluated by the soft agar assay and aneuploidy. The levels of glucose and lactate in the tissue and culture medium were detected with a spectrophotometer. The protein levels of glutathione S-transferase-π, proliferating cell nuclear antigen (PCNA), STAT3, and PKM2 were examined by Western blot and immunofluorescence. Results We found that the Warburg effect was increased in liver precancerous lesions in rats. PKM2 and p-STAT3 were upregulated in activated oval cells in liver precancerous lesions in rats. The Warburg effect, p-PKM2, and p-STAT3 expression were also increased in transformed WB-F344 cells. STAT3 activation promoted the clonal formation rate, aneuploidy, alpha-fetoprotein expression, PCNA expression, G1/S phase transition, the Warburg effect, PKM2 phosphorylation, and nuclear translocation in transformed WB-F344 cells. Moreover, the Warburg effect was inhibited by stattic, a specific inhibitor of STAT3, and further reduced in transformed WB-F344 cells after the intervention for PKM2. Conclusion The Warburg effect is initiated in liver precancerous lesions in rats. STAT3 activation promotes the Warburg effect by enhancing the phosphorylation of PKM2 in transformed WB-F344 cells.

Heart failure (HF) is a clinical syndrome in the late stage of cardiovascular disease and is associated with high prevalence, mortality and rehospitalisation rate. The pathophysiological mechanisms of HF have experienced the initial ‘water-sodium retention’ mode to ‘abnormal hemodynamics’ mode, and subsequent to ‘abnormal activation of neuroendocrine’ mode, which has extensively promoted the reform of HF treatment and updated the treatment concept. Since the Human Microbiome Project commencement, the study on intestinal microecology has swiftly developed, providing a new direction to reveal the occurrence of diseases and the mechanisms behind drug effects. Intestinal microecology comprises the gastrointestinal lumen, epithelial secretion, food entering the intestine, intestinal flora and metabolites. Choline and L-carnitine in the diet are metabolised to trimethylamine (TMA) by the intestinal micro-organisms, with TMA being absorbed into the blood. TMA then enters the liver through the portal vein circulation and is oxidised to trimethylamine oxide (TMAO) by the hepatic flavin-containing mono-oxygenase (FMO) family, especially FMO3. The circulating TMAO levels are associated with adverse outcomes in HF (mortality and readmission), and lower TMAO levels indicate better prognosis. As HF progresses, the concentration of TMAO in patients gradually increases. Whether the circulating TMAO level can be decreased by intervening with the intestinal microflora or relevant enzymes, thereby affecting the prognosis of patients with HF, has become a research hotspot. Therefore, based on the HF intestinal hypothesis, exploring the treatment strategy for HF targeting the TMAO metabolite of the intestinal flora may update the treatment concept in HF and improve its therapeutic effect.

Indole-3-butyric acid (IBA) is widely used to encourage root development in cuttings of general field crops, vegetables, forest trees, fruit trees, and flowers. However, previous studies reported that IBA inhibited the germination of citrus buds via an unknown molecular mechanism. This study aimed to unravel the regulatory mechanisms underlying this inhibition. Citrus apical buds were sprayed with 100 mg ⋅ L−1 IBA. Subsequently, the plant hormone levels were analyzed, and transcriptomic analysis was performed. The results identified 3325 upregulated genes and 2926 downregulated genes in the citrus apical buds. The gene set enrichment analysis method was used to determine the Gene Ontology related to the treatment. Genes were enriched into 157 sets, including 17 upregulated sets and 140 downregulated sets, after indole butyric acid treatment. The upregulated gene sets were related to glucose import, sugar transmembrane transporter activity, and photosynthesis. The downregulated genes were mainly related to the ribosomal subunit and cell cycle process under butyric acid treatment. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed the enrichment of 11 pathways. Of note, genes related to the ribosome and proteasome pathways were significantly downregulated. Only one pathway was significantly upregulated: the autophagy pathway. Overall, these results provided insights into the molecular mechanisms underpinning the IBA-mediated inhibition of citrus bud germination inhibition. Also, the study provided a large transcriptomics dataset that could be used for further research.

2-Acetylthiazole possesses a nutty, cereal-like and popcorn-like aroma and a low odor threshold, and this compound has been identified in some processed foods, while the formation pathway of 2-acetylthiazole has not been clearly elucidated. Here, a model reaction of d-glucose and l-cysteine was constructed to investigate the formation pathway of 2-acetylthiazole. l-Cysteine, d-glucose and the corresponding intermediates, namely, dicarbonyl compounds (DCs), were involved in the formation of 2-acetylthiazole and detected by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS), high-performance ion chromatography (HPIC) and HPLC, respectively. The carbon module labeling (CAMOLA) technique revealed that the C-4 and C-5 of 2-acetylthiazole were derived from the carbons of glucose. The potential of glyoxal, which is degraded by glucose, to form 2-acetylthiazole was revealed for the first time. A novel route to form 2-acetylthiazole by the reaction of glyoxal and methylglyoxal produced by d-glucose with H2S and NH3 produced by l-cysteine was proposed.

Soil salinity is a serious abiotic stress worldwide. Pecan plants (Carya illinoensis K. Koch) have been suggested for cultivation in soils with high levels of salinity owing to their huge demand. To understand the potential molecular mechanisms in pecan in response to salt stress, RNA-sequencing technology was used to compare the transcriptomes of pecan plants treated with 0, 0.3 %, or 0.6 % NaCl solutions. The results indicated that 170,086 unigenes were obtained from pecan leaf cDNA samples. Based on the assembled de novo transcriptome, 53, 535, and 7358 differentially expressed genes (DEGs) were detected between untreated and salt-treated leaves at 8, 24, and 48 h, respectively. Because of the large number of DEGs across different contrasts, a Gene Set Enrichment Analysis was selected to identify gene pathways associated with salt treatment. A total of 1858 DEGs were enriched in 66 gene sets, including 22 up-regulated and 47 down-regulated gene sets in the salt treatment groups, compared with those in the control groups. The up-regulated gene sets were mainly involved in the response to salicylic acid; the regulation of the jasmonic acid-mediated signalling pathway during the short-term treatment (8 h); and the cellular response to hypoxia, cellular respiration, and RNA modification during the long-term treatment (24-48 h). The down-regulated gene sets were predominately associated with photosynthesis, water transport, and the metabolic biosynthetic process under salt stress. Genes related to the Really Interesting New Gene superfamily protein and F-box domain protein in the ubiquitin-dependent degradation pathway were significantly up-regulated or down-regulated in different periods of the regulating process. Overall, these results not only enrich genomic resources but also provide insights into the molecular mechanism in pecan under salt stress.

l -asparaginase (EC 3.5.1.1) needs to endure high temperatures during applications in food processing. We here improved the thermal stability of Bacillus subtilis 168 l -asparaginase by regulating both the kinetic and thermodynamic states of the enzyme. According to the molecular dynamics simulation for l -asparaginase, 10 flexible residues potentially affecting the kinetic stability were individually subjected to saturation mutagenesis, generating two highly stabilized mutants, S180N and D289T. As predicted by Discovery Studio, eight residues of l -asparaginase formed multiple unfavourable charge–charge interactions adversely affecting thermodynamic stability. Single-site saturation mutagenesis on these residues resulted in two thermodynamically stabilized mutants, E260F and E292S. Using these mutants, we constructed a further stabilized quadruple mutant NTFS (S180N/D289T/E260F/E292S). Compared with the wild-type enzyme, NTFS exhibited an 8.1-fold increase in half-life at 65 °C and a 5.56 °C increase in melting temperature. NTFS also showed a substantial increase in the transition state energy barrier (ΔΔGtransition = 5.27 KJ/mol) and a clear decrease in folding free energy (ΔΔGfolding = −19.12 kcal/mol) relative to the wild-type enzyme. These results indicated that simultaneous regulation of both the kinetic and thermodynamic states of an enzyme represents an efficient strategy for enhancing thermal stability. The highly stable NTFS described here might be beneficial for industrial application.

Osteolysis at the tendon-bone interface can impair pullout strength during tendon-bone healing and lead to surgery failure, but the effects of clinical treatments are not satisfactory. Mesenchymal stem cell (MSC)-derived exosomes have been used as potent and feasible natural nanocarriers for drug delivery and have been proven to enhance tendon-bone healing strength, indicating that MSC-derived exosomes could be a promising therapeutic strategy. In this study, we explored Scleraxis (Scx) dynamically expressed in PDGFRα(+) bone marrow-derived mesenchymal stem cells (BMMSCs) during natural tendon-bone healing. Then, we investigated the role of PDGFRα(+) BMMSCs in tendon-bone healing after Scx overexpression as well as the underlying mechanisms. Our data demonstrated that Scx-overexpressing PDGFRα(+) BMMSCs (BMMSCScx) could efficiently inhibit peritunnel osteolysis and enhance tendon-bone healing strength by preventing osteoclastogenesis in an exosomes-dependent manner. Exosomal RNA-seq revealed that the abundance of a novel miRNA, miR-6924-5p, was highest among miRNAs. miR-6924-5p could directly inhibit osteoclast formation by binding to the 3'-untranslated regions (3'UTRs) of OCSTAMP and CXCL12. Inhibition of miR-6924-5p expression reversed the prevention of osteoclastogenic differentiation by BMMSCScx derived exosomes (BMMSCScx-exos). Local injection of BMMSCScx-exos or miR-6924-5p dramatically reduced osteoclast formation and improved tendon-bone healing strength. Furthermore, delivery of miR-6924-5p efficiently inhibited the osteoclastogenesis of human monocytes. In brief, our study demonstrates that BMMSCScx-exos or miR-6924-5p could serve as a potential therapy for the treatment of osteolysis during tendon-bone healing and improve the outcome.

Citrus plants are sensitive to waterlogging because it frequently causes root zone hypoxia (RZH), a serious abiotic stress to its growth. As root is the first organ to be affected by hypoxia stress, its ability to sense and respond to hypoxia stress is crucial to survive. In this study, the response of citrus plant to RZH stress was investigated at morphological, physiological and molecular levels. Our data showed that RZH stress significantly decreased root length, dry weight, and the number of root tips, and not obviously affected shoot growth. Under RZH stress, the malondialdehyde (MDA) contents in leaf and root increased, and the enzyme activities of SOD, POD and APX significantly enhanced in root, while in leaf just POD activity increased with an opposite trend to CAT. RZH stress increased IAA and decreased ABA contents in root, and in leaf all hormones including IAA, ABA and GAs were increased. Despite the leaf chlorophyll content unchanged, several photosynthesis-related parameters were significantly affected by RZH stress, including ABS/RC, TRo/RC and DIo/RC etc. The root soluble sugar and lignin contents were remarkably decreased and increased by RZH stress, respectively. Besides these, RZH stress also reduced nutrient uptake, reflecting in the root decreased Fe, Mn and Zn contents. RNA-Seq analysis revealed that most of the genes were up-regulated by RZH stress, and the differentially expressed genes (DEGs) mainly linked to carbon metabolism, reactive oxygen species scavenging, nutrient uptake and transport, and hormone synthesis/signaling. Taken together, our data obtained in this study will be helpful in further studies regarding hypoxia tolerance in citrus or other crops.

A novel Gram-staining positive, moderately halophilic, endospore-forming, motile, rod-shaped and strictly aerobic strain, designated YIM 93565T, was isolated from a salt lake in Xinjiang province of China and subjected to a polyphasic taxonomic study. Strain YIM 93565T grew in the range of pH 6.0–9.0 (optimum pH 7.0), 10–45 °C (optimum 35–40 °C) and at salinities of 2–24% (w/v) NaCl (optimum 7–10%). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain YIM 93565T clustered with members of the genera Gracilibacillus and form a clade with Gracilibacillus bigeumensis KCTC 13130T (95.6% similarity) and Gracilibacillus halophilus DSM 17856T (94.9%), which was well separated from others. The DNA G + C content of this novel strain was 36.8 mol%. The major fatty acids were anteiso-C15:0, iso-C15:0, C16:0 and anteiso-C17:0 and its polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, one unidentified glycolipid and two unidentified phospholipids. The predominant menaquinone was MK-7. The cell-wall peptidoglycan was based on meso-diaminopimelic acid. Based on the results of phylogenetic, physiological and chemotaxonomic comparative analyses, the isolate is assigned to a novel species of the genus Gracilibacillus, for which the name Gracilibacillus eburneus sp. nov. is proposed, with the type strain YIM 93565T (= DSM 23710T = CCTCC AB 2013249T).

Atherosclerosis (AS) is a progressive disease of multifactorial origin, which occurs in response to endothelial injury. Increased homocysteine (Hcy) is considered a major cause of endothelial dysfunction, oxidative stress and DNA methylation; however, the mechanisms remain to be fully elucidated. The aim of the present study was to investigate whether Hcy causes injury to endothelial cells (ECs) by the effect of lectin‑like oxidized‑low density lipoprotein receptor‑1 (LOX‑1) DNA methylation through toll‑like receptor 4(TLR4)/nuclear factor (NF)‑κB/DNA methyltransferase (DNMT)1. The ECs were treated with different concentrations of Hcy, and it was found that Hcy promoted the expression of TLR4, leading to EC injury. The effect of oxidative stress was analyzed by measuring superoxide dismutase, malondialdehyde and hydrogen peroxide in the ECs. In addition, the association between NF‑κB and DNMT1 was examined by treatment of the ECs with pyrrolidine dithiocarbamate (PDTC). The results suggested that Hcy induced LOX‑1 DNA hypomethyaltion to promote the expression levels of LOX‑1. Taken together, Hcy injured the ECs through the effect of methylation and trans‑sulfuration metabolism of LOX‑1 through TLR4/NF‑κB/DNMT1. Following injury to the ECs, lipids, particularly ox‑LDL, accumulated in the sub‑endothelial layer to promote the formation of AS.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. The formation of amyloid plaques by aggregated amyloid beta (Aβ) peptides is a primary event in AD pathology. Understanding the metabolomic features and related pathways is critical for studying plaque-related pathological events (e.g., cell death and neuron dysfunction). Mass spectrometry imaging (MSI), due to its high sensitivity and ability to obtain the spatial distribution of metabolites, has been applied to AD studies. However, limited studies of metabolites in amyloid plaques have been performed due to the drawbacks of the commonly used techniques such as matrix-assisted laser desorption/ionization MSI. In the current study, we obtained high spatial resolution (∼17 μm) MS images of the AD mouse brain using the Single-probe, a microscale sampling and ionization device, coupled to a mass spectrometer under ambient conditions. The adjacent slices were used to obtain fluorescence microscopy images to locate amyloid plaques. The MS image and the fluorescence microscopy image were fused to spatially correlate histological protein hallmarks with metabolomic features. The fused images produced significantly improved spatial resolution (∼5 μm), allowing for the determination of fine structures in MS images and metabolomic biomarkers representing amyloid plaques.

The flavor release mechanism related to the interaction of aroma compounds with proteins is still unclear. In this study, the interaction of protein with pyrazine homologues, such as 2-methylpyrazine (MP), 2,5-dimethylpyrazine (DP), 2,3,5-trimethylpyrazine (TRP) and 2,3,5,6-tetramethylpyrazine (TEP), was investigated to elucidate the effect of alkyl distribution in a pyrazine ring on its flavor release in bovine serum albumin (BSA) solution (pH 7.4). The results of SPME-GC-MS indicated that methyl distribution in a pyrazine ring significantly affected its release from BSA solution. The pyrazines released from BSA solution with an increasing order of MP, DP, TRP and TEP. The inhibition mechanism of alkyl-pyrazine release was further elucidated by the interaction between alkyl-pyrazines and BSA using multiple spectroscopic methods. The non-covalent interaction between alkyl-pyrazines and BSA was confirmed as the main interaction force by the value of the bimolecular quenching constant (Kq > 2 × 1010 L mol−1 s−1). A decrease in the hydrophobicity of the microenvironment between the alkyl-pyrazine and BSA was detected by synchronous fluorescence spectra, which revealed that alkyl-pyrazines were mainly bound on the sites of tyrosine and tryptophan in BSA. The UV-vis absorption spectra and circular dichromatic (CD) spectrum revealed that alkyl-pyrazines could induce polarity and conformation change of BSA. The above results indicated that the structure of the flavor homologues can affect their release in food matrices.

The dispersion solid-phase microextraction (DSPE) combined with dispersion liquid–liquid microextraction (DLLME) was developed as a rapid, simple and effective pretreatment method for the determination of flavor enhancers (maltol, ethyl maltol, vanillin, methyl vanillin, ethyl vanillin) of ready-to-eat seafood products (dried squid, baked squid, fried fish, steamed abalone). Under the optimized DSPE–DLLME method, the developed method exhibited low limits of quantitation (0.20–0.50 μg g−1) and excellent linearity (R2 ≥ 0.995). The recoveries of flavor enhancers in the actual samples were 83.7%–114.9%. Compared with traditional pretreatment methods, the developed DSPE–DLLME method was rapid (17 min) and easy to determine the flavor enhancers by high performance liquid chromatography with photodiode array detector (HPLC-PDA). In the actual samples, creamy compounds such as vanillin, methyl vanillin and ethyl vanillin were hardly found. However, the flavor compounds produced by thermal reactions such as maltol (except for dried squid 3) and ethyl maltol were present in all samples.

The current study developed a cheap and effective method for the simultaneous extraction of 14 heterocyclic aromatic amines (HAAs) in food matrix. Core-shell Fe3O4@PDA nanoparticles were constructed and acted as the magnetic solid-phase extraction adsorbent to separate and purify HAAs from meat products for the first time. Then, UPLC-MS/MS technique was employed to identify and quantify the HAAs easily. Fe3O4@PDA nanoparticles were synthesized and characterized successfully. Totally 14 HAAs were completely separated in 19.99 min with good regression coefficients. LODs and LOQs were in the range of 0.013–0.247 ng/g and 0.056–0.803 ng/g, respectively. The intra-day precisions and inter-day precisions were below 9%. Except for IQ[4,5-b], Phe-p-1, PhIP, other 11 types of HAAs (DMIP, 1,5,6-TMIP, IQ, IQx, MeIQ, MeIQx, 7,8-DiMeIQx, AαC, MeAαC, Harman, Norharman) could acquire relatively high recoveries (71.06%–108.49%). The proposed method was successfully devoted to the evaluation of HAAs levels in 8 commercial meat products to verify the adaptability.

Extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) is an Epstein-Barr virus (EBV)-associated lymphoma with a strong tendency relapse or be refractory in response to chemotherapy. Development of a new strategy for NKTCL treatment is still quite necessary. In this study, we found that aspirin treatment suppresses VEGF expression in NKTCL SNK-6 cells. Further investigation showed that aspirin treatment increases histone methylation in the range of −100~0 that is proximal to the transcription start site on the VEGF promoter, subsequently decreasing the binding ability of Sp1 to the VEGF promoter with VEGF suppression. Furthermore, aspirin treatment modulates mitochondrial function with increased ROS formation and apoptosis in NKTCL cells. Aspirin treatment alone slightly inhibits NKTCL SNK-6 tumor growth and EBV replication; while in the presence of histone deacetylase inhibitor (HDACi) chidamide (CDM), aspirin significantly suppresses the VEGF signaling pathway with increased ROS overgeneration and EBV inhibition. We also showed that with the addition of chidamide, aspirin significantly suppresses NKTCL tumor growth in both in vitro cell culture and in vivo mouse model with prolonged mouse survival. This is the first time that the potential mechanism for aspirin-mediated VEGF suppression and anti-tumor effect has been discovered, and this study provides a new strategy for anti-tumor drug development for NKTCL treatment based on aspirin-mediated targeting of the VEGF signaling pathway and ROS formation.

Dried Lentinus edodes (Berk.) sing stipe (LES) is mostly discarded owing to its high fibre content and bad palatability, causing significant waste of resources. The aim of this study is to sustainably use LES for the production of flavour soybean oil using the supercritical CO2 fluid extraction (SFE) method. The quality properties of the obtained soybean oil flavoured by LES (OFLS) were evaluated in this study. Profiles obtained with an electronic nose and gas chromatography results obtained by quadrupole time-of-flight mass spectrometry and with a mass-selective detector indicated that mushroom-like aroma compounds were mainly concentrated into the OFLSs from separation kettle A (9 MPa). Interestingly, off-flavour compounds from soybean oil, such as o-xylene and trans-2-nonenal, were mostly distilled into separation kettle B (4 MPa). More importantly, the developed SFE method effectively improved the colour quality of the OFLSs. Additionally, the decrease of the viscosity of the OFLSs indicated that the thermal stability of the edible oil could be improved. In summary, the OFLSs prepared by the green and sustainable SFE method significantly improved the quality of the edible oil.

Background Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERβ knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERβ expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERβ activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERβ and its target genes by demethylation of DNA and histone on the ERβ promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application. Electronic supplementary material The online version of this article (10.1186/s13229-018-0225-5) contains supplementary material, which is available to authorized users.

l -Asparaginase (ASN; EC 3.5.1.1) shows great commercial value because of its ability to reduce toxic levels of acrylamide in foods. To achieve high-efficiency production of l -asparaginase, an open reading frame of 978 bp encoding asparaginase (BcA) was amplified from Bacillus cereus BDRD-ST26, followed by its expression in Bacillus subtilis WB600, with the highest yield of 374.9 U/ml obtained using an amyE-signal peptide. A four-step purification protocol was used to purify BcA, resulting in a 15.1-fold increase in purification yield, with a specific activity of purified BcA at 550.8 U/mg and accompanied by detection of minimal l -glutaminase activity. Maximum BcA activity was detected at 50°C and pH 9.0 in 20 mM Tris–HCl buffer, with a half-life at 50°C of 17.35 min and a Km and kcat of 9.38 mM and 63.6 s−1, respectively. Compared with untreated potato strips, 72% acrylamide (2.35 mg/kg) was removed from potato strips pretreated with BcA. These results indicated that this novel BcA variant represents a potential candidate for application in the food-processing industry.

Elevated homocysteine (Hcy) levels have been reported to be involved in liver injury, and autophagy plays an important role in normal hepatic physiology and pathophysiology, but the mechanism underlying Hcy regulated autophagy is currently unknown. In this study, CBS+/- mice were fed with regular diet for 12 weeks to establish a hyperhomocysteinemia (HHcy) model and HL-7702 cells were treated with Hcy, we found that Hcy increases autophagy and aggravates liver injury by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo and in vitro. Overexpression of CFTR inhibited the formation of autophagosomes and the expression of autophagy-related proteins BECN1, LC3-II/I and Atg12, while the expression of p62 increased in Hcy-treated hepatocytes and CBS+/- mice injected with lentivirus expressing CFTR. Further study showed that CFTR expression is regulated by the interaction of DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2), which, respectively, regulate DNA methylation and histone H3 lysine 27 trimethylation (H3K27me3). In conclusion, our study showed that Hcy activates autophagy by inhibition of CFTR expression via interaction between H3K27me3 and DNA methylation in the mouse liver. These findings provide new insight into the mechanism of Hcy-induced autophagy in liver injury.

Exercise reduces the risk of developing a number of neurological disorders and increases the efficiency of cellular energy production. However, overly strenuous exercise produces oxidative stress. Proper oxygenation is crucial for the health of all tissues, and tight regulation of cellular oxygen is critical to balance O2 levels and redox homeostasis in the brain. Hypoxia Inducible Factor (HIF)1α and HIF2α are transcription factors regulated by cellular oxygen concentration that initiate gene regulation of vascular development, redox homeostasis, and cell cycle control. HIF1α and HIF2α contribute to important adaptive mechanisms that occur when oxygen and ROS homeostasis become unbalanced. It has been shown that preconditioning by exposure to a stressor prior to a hypoxic event reduces damage that would otherwise occur. Previously we reported that 3months of exercise protects SNpc dopaminergic (DA) neurons from toxicity caused by Complex I inhibition. Here, we identify the cells in the SNpc that express HIF1α and HIF2α and show that running exercise produces hypoxia in SNpc DA neurons, and alters the expression of HIF1α and HIF2α. In mice carrying a conditional knockout of Hif1α in postnatal neurons we observe that exercise alone produces SNpc TH+ DA neuron loss. Loss of HIF1α also abolishes exercise-induced neuroprotection. In mice lacking Hif2α in postnatal neurons, the number of TH+ DA neurons in the adult SNpc is diminished, but 3months of exercise rescues this loss. We conclude that HIF1α is necessary for exercise-induced neuroprotection and both HIF1α and HIF2α are necessary for the survival and function of adult SNpc DA neurons.

Poly(propylene carbonate) (PPC) was melt blended in a batch mixer with poly(butylene carbonate) (PBC) in an effort to improve the toughness of the PPC without compromising its biodegradability and biocompatibility. DMA results showed that the PPC/PBC blends were an immiscible two-phase system. With the increase in PBC content, the PPC/PBC blends showed decreased tensile strength, however, the elongation at break was increased to 230% for the 50/50 PPC/PBC blend. From the tensile strength experiments, the Pukanszky model gave credit to the modest interfacial adhesion between PPC and PBC, although PPC/PBC was immscible. The impact strength increased significantly which indicated the toughening effects of the PBC on PPC. SEM examination showed that cavitation and shear yielding were the major toughening mechanisms in the blends subjected the impact tests. TGA measurements showed that the thermal stability of PPC decreased with the incorporation of PBC. Rheological investigation demonstrated that the addition of PBC reduced the value of storage modulus, loss modulus and complex viscosity of the PPC/PBC blends to some extent. Moreover, the addition of PBC was found to increase the processability of PPC in extrusion. The introduction of PBC provided an efficient and novel toughened method to extend the application area of PPC.

Metal–organic nanotubes (MONTs) have great potential for solid phase microextraction (SPME) on account of high specific surface area, tunable pore sizes, and exceptional thermal and chemical stability. In this work, zinc (II)-based metal–organic nanotubes (Zn-MONTs) were used as an adsorbent for the SPME of nitro-polycyclic aromatic hydrocarbons (NPAHs) at trace levels from environmental water samples. Gas chromatography–mass spectrometry was used for sample analysis and key factors were investigated and optimized. Under optimal parameters, the developed method achieved low limits of detection (1.4–7.3 ng L−1), wide linear range (10–5000 ng L−1), and high enrichment factors (1510−17,684). In comparison to the PDMS and DVB/CAR/PDMS fiber for potential commercial use, the Zn-MONTs fiber obtained MS responses 2–9 times as high as those achieved by the commercial 100 µm PDMS and 0.2–2.3 times higher than 50/30 µm DVB/CAR/PDMS fiber did. The proposed method was successfully used in the analysis of NPAHs at trace levels in environmental samples.

Vascular smooth muscle cell (VSMC) proliferation is a primary pathological event in the development of atherosclerosis (AS), and the presence of homocysteine (Hcy) acts as an independent risk factor for AS. However, the underlying mechanisms remain to be elucidated. Phosphatase and tensin homologue on chromosome 10 (PTEN), is endogenously expressed in VSMCs and induces multiple signaling networks involved in cell proliferation, survival and inflammation, however, the specific role of PTEN is still unknown. The present study detected the proliferation ratio of VSMCs following treatment with Hcy and Resveratrol (RSV). In the 100 µM Hcy group, the proliferation ratio increased, and treatment with RSV decreased the proliferation ratio induced by Hcy. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to analyze PTEN expression, RSV treatment was associated with decreased PTEN expression levels in VSMCs. PTEN levels were decreased in Hcy treated cells, and the proliferation ratio of VSMCs were increased following treated with Hcy. To study the mechanism of regulation of PTEN by Hcy, the present study detected PTEN methylation levels in VSMCs, and PTEN DNA methylation levels were demonstrated to be increased in the 100 µM Hcy group, whereas treatment with RSV decreased the methylation status. DNA methyltransferase 1 is important role in the regulation of PTEN methylation. Overall, Hcy impacts the methylation status of PTEN, which is involved in cell proliferation, and induces the proliferation of VSMCs. This effect is alleviated by treatment with RSV, which exhibits an antagonistic mechanism against Hcy.

One new tirucallane-type nortriterpenoid Nortirucallane A (1), together with Chrysoeriol (2) and Isorhamnetin (3), was isolated from the methylene chloride part of Lonicerae japonicae flos. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. Compound 3 was isolated from the genus of Lonicera for the first time. The significance of 1 for the study of phytochemical taxonomy was discussed.

Ethnopharmacological relevance Mistletoe ( Viscum coloratum (Kom.) Nakai ) has long been categorized as a traditional herbal medicine in Asia. In addition to its application in cancer therapy, mistletoe has also been used in the treatment of chronic hepatic disorders in China. In the present study, we investigated the antifibrotic effect and mechanisms of action of mistletoe extracts in a rat model of carbon tetrachloride (CCl 4 )-induced hepatotoxicity. Materials and methods An experimental model of hepatic fibrosis was established by intraperitoneal injection of rats with CCl 4 for 8 weeks. Rats were subsequently treated with a mistletoe alkaloid fraction preparation via oral administration (120 mg/kg daily for 8 weeks) or with distilled water as a control. Histopathological changes were observed by hematoxylin and eosin staining and Masson׳s trichrome staining. The expression of markers relevant to hepatic stellate cell (HSC) activation in the liver was assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry and western blotting. The anti-fibrosis activity and mechanisms of action of mistletoe alkaloid fractions were further investigated in the HSC-T6 HSC line, following treatment with mistletoe alkaloid fractions (12 mg/ml) for 48 h. Results Hepatic fibrosis decreased markedly in CCl 4 -treated animals following treatment with mistletoe alkaloid fractions , compared to controls. The mRNA levels of transforming growth factor-β1 (TGF-β1), procollagen I and tissue inhibitors of metalloproteinases (TIMPs) were significantly downregulated, by about 40%, 40% and 45%, respectively, in liver tissues from rats treated with mistletoe alkaloid fractions . Furthermore, significant downregulation of TGF-β1, TGF-β1 receptor, phosphorylated Smad 2 and alpha smooth muscle actin (α-SMA) proteins, by about 45%, 30% and 40%, respectively, was also observed in liver tissues from mistletoe alkaloid fractions -treated rats. In contrast, Smad 7 levels were significantly increased by about 30% in mistletoe alkaloid fractions -treated rats. Treatment of HSC-T6 cells with mistletoe alkaloid fractions significantly induced Smad 7 expression and inhibited the expression of α-SMA, TGFβ1, TGF-β1 receptor, Smad 2 and TIMP-1, in vitro. Conclusion We demonstrate that mistletoe alkaloid fractions decrease extracellular matrix accumulation by inhibiting HSC activation. Mechanistically, this may occur via inhibition of TGF-β1/Smad 2 and Smad 7 signal transduction, thereby blocking the synthesis of procollagen I and TIMP-1. These findings suggest that mistletoe alkaloid fractions may be a potential therapeutic agent for the treatment of hepatic fibrosis.

Glycidyl methacrylate-functionalized methyl methacrylate–butyl acrylate (GACR) core–shell structure copolymers were synthesized to toughen polylactide (PLA). With an increase in GACR content, the PLA/GACR blends showed decreased tensile strength and modulus; however, the elongation at break and the impact strength were significantly increased compared with that of PLA. The brittle fracture of neat PLA was gradually transformed into ductile fracture by the addiction of GACR. From dynamic mechanical analysis, the rigidity of the PLA/GACR blends was decreased with the increase of GACR content. The addition of GACR decreased the degree of crystallinity of PLA. The GACR was found to aggregate to form clusters with size increasing with increasing GACR content by transmission electron microscope analysis. The clusters dispersed in PLA matrix uniformly. It was found that PLA demonstrated large area, plastic deformation (shear yielding) and cavities in the blend upon being subjected the tensile and impact tests, which was an important energy-dissipation process and led to a toughened and transparent blend.

A Gram-negative, moderately halophilic, strictly aerobic strain, designated YIM 95345T, was isolated from a soil sample of a hypersaline mine in Yunnan province, PR China, and subjected to a polyphasic taxonomic study. Strain YIM 95345T grew at 15–45 °C (optimum 30–35 °C), 3.0–23.0 % (w/v) NaCl (optimum 10.0–11.0 %, w/v) and pH 6.0–9.0 (optimum pH 7.0–8.0). Phylogenetic analyses based on 16S rRNA gene sequences revealed that the organism belongs to the genus Aquisalimonas and exhibited sequence similarity of 96.6 % to the sole type strain Aquisalimonas asiatica CG12T. The predominant isoprenoid quinone was Q-8 and the major fatty acids were C16 : 0, C19 : 0 cyclo ω8c and C18 : 1ω7c. The polar lipids consisted of diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, three aminolipids and three unidentified phospholipids. The G+C content of the genomic DNA was 59.4 mol%. Based on the results of our comparative phylogenetic, chemotaxonomic and physiological analyses, the new isolate is assigned to a novel species of the genus Aquisalimonas , for which the name Aquisalimonas halophila sp. nov. is proposed, with the type strain YIM 95345T ( = DSM 25902T = CCTCC AB 2012043T).

A simple hydrothermal process followed by heat treatment was applied to the preparation of spinel Li1.05Mn1.95O4. In this process, electrolytic manganese dioxide (EMD) and LiOH·H2O were used as starting materials. The physiochemical properties of the synthesized samples were investigated by thermogravimetry-differential scanning calorimetry (TG-DSC), X-ray diffractometry (XRD), and scanning electronic microscopy (SEM). The results show that the hydrothermally synthesized precursor is an essential amorphous. The precursor can be easily transferred to spinel powders with a homogeneous structure and a regularly-shaped morphology by heat treatment. Li1.05Mn1.95O4 powder obtained by heat treating the precursor at 430 °C for 12 h and then calcining at 800 °C for 12 h shows an excellent cycling performance with an initial charge capacity of 118.2 mA·h·g−1 obtained at 0.5C rate and 93.8% of its original value retained after 100 cycles.

In this paper, a microwave-assisted method in the presence of an additive has been employed to quickly and prepare UIO-66 (MWHAc-UIO-66) in high yield. The microwave/additive method gives rise to a full octahedral morphology of ~250 nm particles and a highest surface area 1533.53 m2 g−1, which is confirmed by the surface area of MWBA-UIO-66 (1661.01 m2 g−1), prepared with benzoic acid as the additive. The adsorption results for a low-concentration of acid chrome blue K show that MW-UIO-66 and MWHAc-UIO-66 have excellent adsorption abilities (~98%), while HHAc-UIO-66 is also satisfactory (~85%), which are far better than activated carbon. Moreover, the saturated adsorption amount of acid chrome blue K for MWHAc-UIO-66 can be up to ~15%. The adsorption of different dyes shows that MWHAc-UIO-66 is attractive to charged dyes. Reusability experiments indicate that sulfuric acid can facilitate dye desorption from MWHAc-UIO-66 instead of a base or salt.

For the purpose of effective and economic desulfurization of flue-gas, the predominance area diagram of the Mn–S–O system at different temperatures was constructed based on the thermodynamic data obtained from the literatures. It is seen from this figure that flue-gas desulfurization by manganese oxides is feasible from the thermodynamic point of view. Additionally, the most appropriate temperature range for flue-gas desulfurization is between 600 and 800 K, and the reaction is strongly exothermic to maintain the heat balance. The natural manganese ores encompass large tunnels that exhibit large surface areas and highly chemical activity, which can provide a high enough SO 2 removing efficiency. From the superposition of the diagrams of Mn–S–O and Fe–S–O systems, it is found that there is a coexistent stability region of MnSO 4 and Fe 2 O 3 , which provides the possibility of desulfurization by selective sulfation without ferric sulfate forming. A multi-stage desulfurization system has been discussed briefly.

Background Casticin, the flavonoid extracted from Vitex rotundifolia L, exerts various biological effects, including anti-inflammatory and anti-cancer activity. The aim of this study is to investigate the effects and mechanisms of casticin in human gallbladder cancer cells. Methods Human NOZ and SGC996 cells were used to perform the experiments. CCK-8 assay and colony formation assay were performed to evaluate cell viability. Cell cycle analyses and annexin V/PI staining assay for apoptosis were measured using flow cytometry. Western blot analysis was used to evaluate the changes in protein expression, and the effect of casticin treatment in vivo was experimented with xenografted tumors. Results In this study, we found that casticin significantly inhibited gallbladder cancer cell proliferation in a dose- and time-dependent manner. Casticin also induced G0/G1 arrest and mitochondrial-related apoptosis by upregulating Bax, cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase expression, and by downregulating Bcl-2 expression. Moreover, casticin induced cycle arrest and apoptosis by upregulating p27 and downregulating cyclinD1/cyclin-dependent kinase4 and phosphorylated protein kinase B. In vivo, casticin inhibited tumor growth. Conclusion Casticin induces G0/G1 arrest and apoptosis in gallbladder cancer, suggesting that casticin might represent a novel and effective agent against gallbladder cancer.

A Gram-stain-negative, moderately halophilic, strictly aerobic bacterium, designated YIM 95161T, was isolated from brine of a salt well in Yunnan province, China, and subjected to a taxonomic study using a polyphasic approach. Cells of strain YIM 95161T were short rods, approximately 0.9–1.4 µm long and 0.4–0.6 µm wide. Strain YIM 95161T grew at 15–40 °C (optimum, 25–30 °C), 6–29 % (w/v) NaCl (optimum, 14–19 %) and at pH 5.0–8.0 (optimum, pH 7.0). The predominant isoprenoid quinone was Q-8. The major fatty acids (>10 %) were summed feature 8 (C18 : 1ω6c and/or C18 : 1ω7c) and C14 : 0. The polar lipids consisted of diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, one unknown phosphoglycolipid and two unknown lipids. The DNA G+C content was 69.5 %. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain YIM 95161T was a member of the genus Salinisphaera and exhibited sequence similarities of 96.7 %, 95.6 % and 95.4 % to Salinisphaera shabanensis E1L3AT, Salinisphaera dokdonensis CL-ES53T and Salinisphaera hydrothermalis EPR70T, respectively. On the basis of phylogenetic, physiological and chemotaxonomic analysis, strain YIM 95161T represents a novel species of the genus Salinisphaera , for which the name Salinisphaera halophila sp. nov. is proposed. The type strain is YIM 95161T ( = CCTCC AB 2011132T = JCM 17431T).

A Gram-positive, moderately halotolerant, rod-shaped bacterium, designated YIM 94025(T), was isolated from a soil sample from a salt lake in Xinjiang province, north-west China. Strain YIM 94025(T) was observed to grow at 25-45 °C (optimum 37 °C), 0-22 % NaCl (optimum 2-10 %) and pH 6.0-9.0 (optimum pH 8.0). Phylogenetic analyses based on 16S rRNA gene sequences revealed that the organism belongs to the genus Tenuibacillus and exhibited sequence similarity of 98.0 % to the closest type strain, Tenuibacillus multivorans AS 1.3442(T). The predominant menaquinone was found to be MK-7; the cell-wall peptidoglycan diamino acid was meso-diaminopimelic acid; the polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, an unidentified phospholipid and an unknown lipid; and the major fatty acids were found to contain iso-C(15:0), anteiso-C(15:0) and iso-C(16:0). The chemotaxonomic characteristics of strain YIM 94025(T) are consistent with those of the genus Tenuibacillus. The level of DNA-DNA relatedness value between YIM 94025(T) and T. multivorans AS 1.3442(T) was 36.6 ± 4.5 %. The G+C content of the strain YIM 94025(T) was determined to be 38.5 %. Based on the comparative analysis of physiological, biochemical and chemotaxonomic data, as well as DNA-DNA hybridization results, the isolate is considered to represent a novel species of the genus Tenuibacillus, for which the name Tenuibacillus halotolerans sp. nov., is proposed, with the type strain of YIM 94025(T) (=CCTCC AB 2012860(T) = KCTC 33046(T)).

Activation of FFA1 (GPR40), a member of G protein-coupling receptor family A, is mediated by medium- and long-chain fatty acids and leads to amplification of glucose-stimulated insulin secretion, suggesting a potential role for free fatty acid 1 (FFA1) as a target for type 2 diabetes. It was assumed previously that there is a single binding site for fatty acids and synthetic FFA1 agonists. However, using members of two chemical series of partial and full agonists that have been identified, radioligand binding interaction studies revealed that the full agonists do not bind to the same site as the partial agonists but exhibit positive heterotropic cooperativity. Analysis of functional data reveals positive functional cooperativity between the full agonists and partial agonists in various functional assays (in vitro and ex vivo) and also in vivo. Furthermore, the endogenous fatty acid docosahexaenoic acid (DHA) shows negative or neutral cooperativity with members of both series of agonists in binding assays but displays positive cooperativity in functional assays. Another synthetic agonist is allosteric with members of both agonist series, but apparently competitive with DHA. Therefore, there appear to be three allosterically linked binding sites on FFA1 with agonists specific for each of these sites. Activation of free fatty acid 1 receptor (FFAR1) by each of these agonists is differentially affected by mutations of two arginine residues, previously found to be important for FFAR1 binding and activation. These ligands with their high potencies and strong positive functional cooperativity with endogenous fatty acids, demonstrated in vitro and in vivo, have the potential to deliver therapeutic benefits.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose etiology is thought to have environmental (toxin) and genetic contributions. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) induces pathological features of PD including loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and striatal dopamine (DA) depletion. We previously described the striatal transcriptional response following acute MPTP administration in MPTP-sensitive C57BL/6J mice. We identified three distinct phases: early (5 h), intermediate (24 h) and late (72 h) and reported that the intermediate and late responses were absent in MPTP-resistant Swiss-Webster (SWR) mice. Here we show that C57BL/6J mice pre-treated with a single 40 mg/kg dose of MPTP and treated 9 days later with 4 × 20 mg/kg MPTP, display a striatal transcriptional response similar to that of MPTP-resistant SWR mice, i.e. a robust acute response but no intermediate or late response. Transcriptional refractoriness is dependent upon the dose of the priming challenge with as little as 10 mg/kg MPTP being effective and can persist for more than 28 days. Priming of SWR mice has no effect on their response to subsequent challenge with MPTP. We also report that paraquat, another free radical producer, also elicits striatal transcriptional alterations but these are largely distinct from those triggered by MPTP. Paraquat-induced changes are also refractory to priming with paraquat. However neither paraquat nor MPTP elicits cross-attenuation. Thus exposure to specific toxins triggers distinct transcriptional responses in striatum that are influenced by prior exposure to the same toxin. The prolonged refractory period described here for MPTP could explain at the molecular level the reported discrepancies between different MPTP administration regimens and may have implications for our understanding of the relationship between environmental toxin exposure and PD.

Structural modification of a series of dual LXRα/β agonists led to the identification of a new class of LXRβ partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRβ with a reversed orientation compared to 1.

The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also blinded to treatment, evaluated the SNpc and/or striatum for loss of TH+ neurons (SNpc) or terminals (striatum), cell death (as indicated by amino cupric silver uptake, TUNEL and/or caspase 3 staining) and neuroinflammation (as indicated by Iba-1 and/or GFAP staining). PQ, administered either once or twice weekly to 9- or 16-week old mice from two suppliers, had no effect on the number of TH+ neurons or microglia in the SNpc, as assessed by two groups, each blinded to treatment, using different stereological methods. PQ did not induce neuronal cell loss or degeneration in the SNpc or striatum. Additionally, there was no evidence of apoptosis, microgliosis or astrogliosis. In MPTP-treated mice, the number of TH+ neurons in the SNpc was significantly decreased and the number of activated microglia increased. Histopathological assessment found degenerating neurons/terminals in the SNpc and striatum but no evidence of apoptotic cell death. MPTP activated microglia in the SNpc and increased the number of astrocytes in the SNpc and striatum.

Parkinson's disease (PD) is a neurodegenerative disease whose hallmark pathological features include a selective loss of dopaminergic neurons in the midbrain. Recent studies have described the activation of a stress-induced signal cascade, c-Jun N-terminal kinase (JNK)-mediated activation of c-Jun, and an increase in the expression of a downstream effector, cyclooxygenase 2 (COX-2), in postmortem PD brains. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces selective neuronal loss in the midbrain similar to that seen in PD, also induces JNK-mediated activation of c-Jun and generates a COX-2 response in C57BL/6J mice. However, mice exhibit a strain-dependent susceptibility to MPTP. Identifying the point(s) of molecular divergence in the MPTP-induced response may provide insight into the cause of PD or a means to identify susceptibility to PD in humans. Here we examined JNK signaling and COX-2 induction in two strains of mice, the MPTP-sensitive C57BL/6J and the MPTP-resistant Swiss Webster (SW). We show that C57BL/6J and SW strains differ in JNK and c-Jun activation in response to MPTP. In addition, the MPTP-induced COX-2 response occurs exclusively in C57BL/6J mice. Furthermore, strain-specific responses to MPTP are not due to differences in MPP+ levels and are not secondary to cell death. These results provide evidence toward a mechanism of strain-dependent sensitivity to MPTP.

Background: MPTP and paraquat are two compounds that have been used to model Parkinson’s disease in mice. Previous studies in two non-traditional strains of mice have shown that a single dose of MPTP can induce changes in body temperature, while the effects of paraquat have not been examined. Examination of body temperature is important since small fluctuations in an animal’s core temperature can significantly affect drug metabolism, and if significant enough can even culminate in an animal’s death. Objective: To determine how external heating can alter the survival of C57BL/6J mice following MPTP administration. Methods: In this study, we examine the effects of MPTP (4×20 mg/kg, 2 hours apart) and paraquat (2×10 mg/kg/week for 3 weeks) on core temperature of C57BL/6J mice. Correlations of purine and catecholamine levels were also done in mice treated with MPTP. Results: We find that MPTP induces a significant hypothermia in C57BL/6J mice that reduces their core temperature below the limit of fatal hypothermia. Unlike MPTP, paraquat did not induce a significant hypothermia. Placement of animals on heating pads significantly abrogates the loss of core temperature. In both heated and non-heated conditions, mice treated with MPTP showed a significant depletion of ATP within 2 hours of administration in both striatum and SN that started to recover 2 hours after MPTP administration was complete. Striatal DA and DOPAC are significantly reduced starting 4–6 hours after MPTP. Conclusions: The fatal hypothermic effects of MPTP can be abrogated through use of external heating.

A Gram-negative, pink-coloured, rod-shaped, motile bacterium, designated YIM 93097T, was isolated from the desert soil collected from Xinjiang province of China. Strain YIM 93097T was found to grow at 20–45 °C (optimum 28–37 °C), pH 5.0–7.0 (optimum pH 7.0) and 0–8 % (w/v) NaCl (optimum 1 %, w/v). Based on 16S rRNA gene sequence similarity studies, it belongs to the genus Skermanella. The 16S rRNA gene sequence similarity was identified to be 98.7 % to Skermanella xinjiangensis CCTCC AB 207153T while the DNA–DNA hybridization value was found to be only 48.1 %. The predominant isoprenoid quinone was determined to be Q-10. The major fatty acids were identified to be C16:0, C18:1 ω7c and summed feature 4 (consisting of C17:1 anteiso B/iso I). The major polar lipids were identified as phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, two unidentified phospholipids and one unidentified aminolipid. The DNA G+C content was found to be 67.2 mol %. The analysis of the genotypic and phenotypic data indicated that strain YIM 93097T belongs to a novel species of the genus Skermanella, for which the name Skermanella rubra sp. nov. is proposed. The type strain is YIM 93097T (=DSM 21389T=CCTCC AB 2015161T).

Although the etiology of Parkinson's disease (PD) is not fully understood, there are numerous studies that have linked the increased risk for developing PD to pesticides exposure including paraquat (PQ). Moreover, the exposure to a combination of compounds or chemical mixtures has been suggested to further increase this risk. In the current study, the effects of PQ on the nigrostriatal dopaminergic system in male C57BL6 mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were examined to assess the impact of toxic substance mixtures exposure on neurochemical and behavioral changes. In this study, a low non-toxic dose of MPTP (10mg/kg) was injected once a day for 5 days and was followed by PQ (7 mg/kg) once a day for 6 days (subacute protocol) or once a week for 10 weeks (chronic protocol). The results from the subacute protocol showed that PQ reduced the turnover of dopamine (DA) as indicated by a 21% and a 22.3% decrease in dihydroxyphenyl acetic acid (DOPAC), homovanillic acid and increased S-adenosyl methionine/S-adenosyl homocysteine index (SAM/SAH) by 100%. However, the administration of PQ to MPTP primed mice resulted in the decrease of DOPAC, HVA, DA, by 35.8%, 35.2% and 22.1%, respectively. In addition, PQ decreased the total number of movements (TM) by 28% but MPTP plus PQ decreased TM by 41%. The SAM/SAH index showed that MPTP increased methylation by 33.3%, but MPTP plus PQ increased methylation by 81%. In the chronic protocol, the data showed that MPTP administration did not affect DA, DOPAC, and HVA levels. The administration of PQ led to significant decrease in DOPAC, HVA, and TD by 31.6%, 19.9%, and 21.2% respectively with no effect on DA levels. The MPTP plus PQ group showed reduced DA, DOPAC, HVA, and total distance traveled by 58.4%, 82.8%, 55.8%, and 83.9%, respectively. Meanwhile, PQ administration caused a reduction in tyrosine hydroxylase immunoreactivity in the substantia nigra, and this effect was more pronounced in MPTP pretreated mice. It was concluded from this study that prior treatment with MPTP potentiated the effects of PQ in reducing DA, DOPAC, HVA, TH immunoreactivity, locomotor activity, and increasing the methylation index. The enhanced effects of PQ following MPTP administration further support the role of toxic substance mixtures in causing Parkinson's disease.

Free radical damage has been shown to play a significant role in the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease. One model of experimental parkinsonism is the loss of substantia nigra cells following administration of MPTP. Previously, it has been shown that a number of inbred strains of mice have differential responses to this toxin, and this difference is dependent on glial cells. In this study, the number of glial cells in the substantia nigra pars compacta of C57Bl/6J (MPTP-sensitive) and Swiss Webster (MPTP-resistant) strains of mice was examined. The C57Bl/6J mice have an approximately 50% lower number of GFAP+ and S-100beta glial cells than the Swiss Webster mice. C57Bl/6J mice have a 25% increased number of resident nonactivated microglial cells. To determine whether this difference in cell number has functional significance, we used an in vitro SN culture system that allowed us to manipulate the number of glial cells. When C57Bl/6 neurons were grown on a glial mat plated with twice the number of cells, we were able to rescue the MPTP-sensitive neurons from toxin-induced cell death. This suggests that the number of glial cells in the SNpc may be an important factor in the survival of dopaminergic neurons following exposure to xenobiotics.

Summary Aims Stroke is a leading cause of disability. However, there is no pharmacological therapy available for promoting recovery. Although treatment of stroke with cystamine has gained increasing interest, the detailed mechanisms underlying this process remain elusive. Thus, our aim is to examine the effect of cystamine on the function recovery after stroke and investigate further cystamine mechanisms. Methods Adult male C57BL/6J mice were subjected to photothrombotic model of focal stroke or sham operation. Cystamine or saline was administered intraperitoneally at 24 h after stroke. Functional recovery was analyzed using behavioral tests; axon remodeling was analyzed using magnetic resonance diffusion tensor imaging (DTI) and histological assessment. ANA-12, an antagonist of tropomyosin-related kinase B (TrkB), was administrated to examine the mechanisms underlying the neuroprotection mediated by cystamine. Results Treatment with cystamine resulted in amelioration of impaired function with concomitant enhancement of axonal remodeling. Cystamine treatment significantly increased brain-derived neurotrophic factor (BDNF) levels and phosphorylation of TrkB in brain after stroke. Cystamine significantly enhanced neuronal progenitor cell proliferation, neuronal survival, and plasticity through BDNF/TrkB pathway. Conclusions These data provide evidence to investigate the promising utility of cystamine for therapy of stroke in a variety of ways, acting principally through BDNF/TrkB pathway.

A Gram-positive, facultative anaerobe microorganism, designated YIM 93067(T), was isolated from a salt lake in Xinjiang Province of China and subjected to a polyphasic taxonomic study. Strain YIM 93067(T) grew at 5-40 °C, 0-8.0 % (w/v) NaCl and pH 7.0-9.0. Phylogenetic analyses based on 16S rRNA gene sequences revealed that the organism belongs to the genus Jonesia and exhibited a sequence similarity of 98.8 % to the closely related type strain Jonesia quinghaiensis DSM 15701(T). The predominant menaquinone was MK-9 and the major fatty acids were anteiso-C15:0 and C16:0. The polar lipids consisted of diphosphatidylglycerol, glycolipid, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside and one unidentified phospholipid. The G+C content of the genomic DNA was 57.4 mol%. Based on the results of phylogenetic, physiological and chemotaxonomic comparative analyses, the isolate is assigned to a novel species of the genus Jonesia, for which the name Jonesia luteola sp. nov. is proposed, with the type strain YIM 93067(T) (=DSM 21367(T) = CCTCC AB 2014350(T)).