Search

Glomerella leaf spot (GLS) caused by Glomerella cingulata is a newly emerging disease that results in severe defoliation and fruit spots in apples. In China, the compound of pyraclostrobin and tebuconazole was registered to control GLS in 2018 and has achieved excellent control efficiency. In this study, we showed that the high-level resistant isolates of G. cingulata to pyraclostrobin, caused by the point mutation at codon 143 (GGT→GCT, G143A) in the cytochrome b gene, has appeared in apple orchards in Shandong Province in 2020, and the resistance frequency was 4.8%. Based on the genotype of the resistant isolates, we developed a loop-mediated isothermal amplification (LAMP) assay for detection of the pyraclostrobin resistance. The LAMP assay was demonstrated to have good specificity, sensitivity, and repeatability, and it exhibited high accuracy in detecting pyraclostrobin resistance in the field. This study reported the resistance status of GLS to pyraclostrobin in Shandong Province and developed a molecular tool for the detection of pyraclostrobin resistance, which is of practical significance for the scientific control of GLS.

Farnesyl/geranylgeranyl diphosphate synthases (FPPS/GGPPS) as the short-chain prenyltransferases catalyze the formation of the acyclic precursors (E)-FPP and (E)-GGPP for isoprenoid biosynthesis. Here, we first cloned the cDNAs encoding FPPS and GGPPS in the vetch aphid Megoura viciae (designated as MvFPPS and MvGGPPS). They had an open reading frame of 1185 bp and 930 bp in length, encoding 395 and 309 amino acids, with a theoretical isoelectric point of 6.52 and 6.21, respectively. Sequence alignment and phylogenetic analysis showed that MvFPPS and MvGGPPS shared the conserved aspartate-rich motifs characterized by all prenyltransferases identified to date and were clustered with their homologues in two large clades. RNA interference (RNAi) combined with gas chromatography/mass spectrometry (GC-MS) analysis showed that both MvFPPS and MvGGPPS were involved in the biosynthesis of alarm pheromone. Spatiotemporal expression profiling showed that the expression of MvFPPS and MvGGPPS was significantly higher in embryos than in other tissues. RNAi and GC-MS performed specifically in embryos corroborated the function of MvFPPS and MvGGPPS. In vitro enzymatic activity assay and product analysis demonstrated that MvFPPS could catalyzed the formation of (E)-FPP using DMAPP or (E)-GPP as the allylic cosubstrates in the presence of IPP, while MvGGPPS could only use (E)-GPP or (E)-FPP as cosubstrates. Functional interaction analysis using RNAi revealed that MvGGPPS exerts a unidirectional functional compensation for MvFPPS. Moreover, it can regulate the biosynthesis of alarm pheromone by imposing a negative feedback regulation on MvFPPS. Our study helps to understand the molecular regulatory mechanism of terpenoid biosynthesis in the aphid. This article is protected by copyright. All rights reserved.

Oxalate-induced nephropathies comprise a range of kidney disorders, for which there are no efficient pharmacological treatments. Hydroxycitric acid (HCA) is a derivative of citric acid with a variety of pharmacological activities including reducing body weight and calcium salt deposition. However, the specific mechanism of inhibition of oxalate nephropathies by this compound is not well understood. In this study, we successfully applied bioinformatics-based and simulated drug molecular docking approaches to predict potential targets of HCA. Subsequently, we explored the molecular mechanisms of HCA inhibition of renal calcium oxalate (CaOx) deposition and nephrotoxicity in an oxalate-induced NRK-52E cell model and an oxalate nephropathy rat model. HCA could effectively inhibit CaOx crystal deposition and reduce crystal adhesion and oxidative damage, effectively inhibit lipid deposition caused by high oxalate, and reduce lipid nephrotoxicity. HCA is more effective than traditional stone medications in inhibiting CaOx deposition and kidney damage. Further cellular transcriptomic analysis and in vitro results showed that HCA could stably bind peroxisome proliferator-activated receptor α (PPARα) and promote PPARα-RXR heterodimer formation, thus promoting the expression of downstream oxidative stress molecules (Nrf2, HO-1, SOD) and inhibiting calcium ion release and mitochondrial dysfunction, thus reducing oxalate-induced renal lipid peroxidation damage. Therefore, HCA, a novel drug with the ability to modulate lipid metabolism and inhibit CaOx formation, may be a therapeutic option for the treatment of oxalate nephropathies.

High-performance AlGaN/GaN lateral Schottky barrier diodes (SBDs) with recess structure and dual metal nitride anodes were demonstrated. With high work-function and nonrecess structure, a NiN anode enhances the breakdown voltage (BV), while a TiN anode reduces the turn-on voltage ( ${V}_{ \mathrm{\scriptscriptstyle ON}}$ ) due to its low work-function and contact to the two-dimensional electron gas (2DEG) layer directly on a recess structure. As the length of the NiN anode ( ${L}_{r}$ ) on the nonrecess region decreases from 75 to 3 $\mu \text{m}$ , ${V}_{ \mathrm{\scriptscriptstyle ON}}$ is reduced from 0.56 to 0.30 V, while the reverse leakage current slightly increases from ${3} \times {10}^{-{4}}$ to ${2} \times {10}^{-{3}}$ A/cm2 at the bias of −10 V. The lateral AlGaN/GaN SBD with a ${L}_{r}$ of 3 $\mu \text{m}$ at a distance of cathode–anode ( ${L}_{\text {AC}}$ ) of 20 $\mu \text{m}$ achieves a high BV of 1.62 kV, an ultralow ${V}_{ \mathrm{\scriptscriptstyle ON}}$ of 0.30 V and a small capacitance of 6.0 pF at zero bias with little degradation on ON-resistance, indicating superior potential application in high-frequency and high-power devices.

Rhizoma Anemarrhenae is a well-known herbal medicine with saponins as its commonly regarded major bioactive components. It is essential to classify the properties of saponins which are associated with their toxicity and efficacy. In this study, 25 compounds were identified by HPLC-Q-TOF/MS in the extract of Rhizoma Anemarrhenae and 8 saponins were detected in rat plasma by HPLC-MS/MS after oral administration of this extract. These were neomangiferin, mangiferin, timosaponin E1, timosaponin E, timosaponin B-II, timosaponin B-III, timosaponin A-III and timosaponin A-I. A sensitive and accurate HPLC-MS/MS method was developed and successfully applied to a pharmacokinetic study of the abovementioned eight saponins after oral administration of the Rhizoma Anemarrhenae extract to rats. The method validation, including specificity, linearity, precision, accuracy, recovery, matrix effect and robustness, met the requirements of the intended use. The pharmacokinetic parameter, T max value, ranged from 2 to 8 h for these eight saponins whereas their elimination half-life (t 1/2) ranged from 4.06 to 9.77 h, indicating slow excretion. The plasma concentrations of these eight saponins were all very low, indicating a relatively low oral bioavailability. All these results provide support for further clinical studies.

Background: Timosaponin A-III is one of the most promising active saponins from Anemarrhena asphodeloides Bge. As an oral chemotherapeutic agent, there is an urgent need to clarify its biopharmaceutics and pharmacokinetics to improve its development potential. Objective: This research explores the bioavailability of timosaponin A-III and clarifies its absorption and metabolism mechanisms by a sensitive and specific HPLC-MS/MS method. Methods: Pharmacokinetics and bioavailability studies of timosaponin A-III were performed in Sprague- Dawley rats by oral (20 mg/kg) and intravenous administration (2 mg/kg). Control group was given the same volume of normal saline. The absorption of timosaponin A-III was investigated in a rat intestinal perfusion model in situ and a Caco-2 cell transport model in vitro. The metabolic rate of timosaponin A-III was determined in a rat liver microsome incubation system. Results: After the oral administration, timosaponin A-III reached Cmax of 120.90 ± 24.97 ng/mL at 8 h, and the t1/2 was 9.94 h. The absolute oral bioavailability of timosaponin A-III was 9.18%. The permeability coefficients of timosaponin A-III in four intestinal segments ranged from 4.98 to 5.42 × 10-7 cm/s, indicating a difficult absorption. A strikingly high efflux transport of timosaponin A-III was found, PappBA 3.27 ± 0.64 × 10−6 cm/s, which was abolished by a P-gp inhibitor. Rat liver microsome incubation studies showed that timosaponin A-III could hardly be metabolized, with a t1/2 of over 12 h. In addition, the solubility test showed a low solubility in PBS solution, i.e. 30.58 μg/mL. Conclusion: Timosaponin A-III exhibited low oral bioavailability by oral and intravenous administration, which was probably caused by its low permeability and solubility. This study may provide a reference for its rational clinical use and further study on the pharmacology or toxicology of timosaponin A-III.

Pancreatic cancer (PC) is highly malignant and has a high mortality with a 5-year survival rate of less than 8%. As a member of the roundabout immunoglobulin superfamily of proteins, ROBO1 plays an important role in embryogenesis and organogenesis and also inhibits metastasis in PC. Our study was designed to explore whether ROBO1 has effects on the proliferation of PC and its specific mechanism. The expression of ROBO1 was higher in cancer tissues than in matched adjacent tissues by immunohistochemistry (IHC) and qRT-PCR. Low ROBO1 expression is associated with PC progression and poor prognosis. Overexpression of ROBO1 can inhibit the proliferation of PC cells in vitro, and the S phase fraction can also be induced. Further subcutaneous tumor formation in nude mice showed that ROBO1 overexpression can significantly inhibit tumor growth. YY1 was found to directly bind to the promoter region of ROBO1 to promote transcription by a luciferase reporter gene assay, a chromatin immunoprecipitation (ChIP) and an electrophoretic mobility shift assay (EMSA). Mechanistic studies showed that YY1 can inhibit the development of PC by directly regulating ROBO1 via the CCNA2/CDK2 axis. Taken together, our results suggest that ROBO1 may be involved in the development and progression of PC by regulating cell proliferation and shows that ROBO1 may be a novel and promising therapeutic target for PC.

Aims The emerging of drug resistant Pseudomonas aeruginosa is a critical challenge and renders an urgent action to discover innovative antimicrobial interventions. One of these interventions is to disrupt the pseudomonas quinolone signal (pqs) quorum sensing (QS) system, which governs multiple virulence traits and biofilm formation. This study aimed to investigate the QS inhibitory activity of a series of new PqsR inhibitors bearing a quinoline scaffold against Ps. aeruginosa. Methods and Results The results showed that compound 1 suppressed the expression of QS-related genes and showed the best inhibitory activity to the pqs system of wild-type Ps. aeruginosa PAO1 with an IC50 of 20.22 μmol L−1. The virulence factors including pyocyanin, total protease, elastase and rhamnolipid were significantly suppressed in a concentration-dependent manner with the compound. In addition, compound 1 in combination with tetracycline inhibited synergistically the bacterial growth and suppressed the biofilm formation of PAO1. The molecular docking studies also suggested that compound 1 could potentially interact with the ligand-binding domain of the Lys-R type transcriptional regulator PqsR as a competitive antagonist. Conclusions The quinoline-based derivatives were found to interrupt the quorum sensing system via the pqs pathway and thus the production of virulence factors was inhibited and the antimicrobial susceptibility of Ps. aeruginosa was enhanced. Significance and Impact of Study The study showed that the quinoline-based derivatives could be used as an anti-virulence agent for treating Ps. aeruginosa infections.

Xin-Yuan Sun,1,* Hui Zhang,2,* Ji-Wang Deng,1,* Bang-Xian Yu,1 Yi-Han Zhang,1 Jian-Ming Ouyang2 1Department of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510230, People’s Republic of China; 2Department of Chemistry, Institute of Biomineralization and Lithiasis Research, Jinan University, Guangzhou, 510632, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin-Yuan SunDepartment of Urology, Guangzhou Institute of Urology, Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510230, People’s Republic of ChinaEmail sunxinyuan1985@163.comJian-Ming OuyangDepartment of Chemistry, Institute of Biomineralization and Lithiasis Research, Jinan University, Guangzhou, 510632, People’s Republic of ChinaTel +86-20-85223353Email toyjm@jnu.edu.cnBackground: The interaction between urinary microcrystals and renal epithelial cells is closely related to kidney stone formation. However, the mechanism of cell state changes that affect crystal–cell interaction remains unclear.Methods: This study investigated the relationship between the sulfate group (–OSO3−) content in Porphyra yezoensis polysaccharide (PYP) and the ability to repair damaged cells, as well as the changes in cell adhesion and endocytosis of nano-calcium oxalate monohydrate (COM) crystals before and after PYP repair of damaged renal tubular epithelial cells. The sulfur trioxide–pyridine method was used to sulfate PYP (–OSO3− content of 14.14%), and two kinds of sulfated PYPs with –OSO3− content of 20.28% (SPYP1) and 27.14% (SPYP2) were obtained. The above three PYPs were used to repair oxalate-damaged human proximal tubular epithelial cells (HK-2), and the changes in the biochemical indicators of the cells before and after the repair and the changes in cell adhesion and endocytosis of nano-COM crystals were detected.Results: After repair by PYPs, the cell viability increased, the number of reactive oxygen species decreased, and the reduction of mitochondrial membrane potential and the release of intracellular Ca2+ were suppressed. The cells repaired by PYPs inhibited the adhesion of nano-COM crystals while promoting the endocytosis of the adhered crystals. The endocytosed crystals mainly accumulated in the lysosome. The ability of PYPs to repair cell damage, inhibit crystal adhesion, and promote crystal endocytosis was enhanced when the –OSO3− content increased. Among them, SPYP2 with the highest –OSO3− content showed the best biological activity.Conclusion: SPYP2 showed the best ability to repair damaged cells, followed by SPYP1 and PYP. SPYP2 may become a potential green drug that inhibits the formation and recurrence of calcium oxalate stones.Keywords: Porphyra yezoensis polysaccharide, polysaccharide sulfation, cell repair, adhesion and endocytosis, kidney stone

Previous studies pointed out that a variety of microRNAs (miRNAs) are involved in the pathogenesis of neonatal acute respiratory distress syndrome (NARDS) and play different roles in the pathological process. However, there have been few studies reporting the connection between circular RNA (circRNA) and NARDS, so the expression profile of circRNAs in newborns with acute respiratory distress syndrome remains largely unknown. In the present study, 10 samples obtained from remaining clinical blood samples of newborns hospitalized in a neonatal ward of the First Affiliated Hospital of Nanjing Medical University from January 2020 to October 2020 were divided into the “NARDS” group and “non-NARDS” group according to the Montelux standard and then were analyzed in microarray, and 10 other samples collected from the same place and from January 1, 2021 to August 31, 2021, were used to do RT-qPCR experiment. circRNA expression profiles, in which 741 circRNAs were downregulated and 588 were upregulated, were screened with circRNA high-throughput sequencing. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of parent genes of the differentially expressed circRNAs revealed that these circRNAs may be related to the process of protein synthesis and metabolism in NARDS. Moreover, five circRNAs—hsa_circ_0058495, hsa_circ_0000367, hsa_circ_0005389, hsa_circ_0059571, and hsa_circ_0006608—were selected randomly among the top 10 circRNAs of the downregulated or upregulated expression profiles. Then, bioinformatics tools were used to predict correlative miRNA and its target genes, which were also subjected to the same bioinformatics analysis for further study. The top 30 enriched KEGG pathway analyses of the 125 target genes suggested that these target genes are widely involved in the synthesis and secretion of endocrine hormones, and the top 30 enriched GO terms based on the 125 target genes are also focused on the protein and DNA processing. Thus, the present results show that circRNAs could promote the inflammation of NARDS which may provide a new therapeutic direction and it can be used as molecular markers for early diagnosis of NARDS, but further molecular biology verification is needed to define the specific role of differentially expressed circRNAs in NARDS.

The discovery of small molecular inhibitors targeting essential and conserved bacterial drug targets such as FtsZ protein is a promising approach to fight against multi-drug resistant bacteria. In the present study, two new series of FtsZ inhibitors based on a 1-methylquinolinium scaffold were synthesized. The inhibitors possess a variety of substituent groups including the cyclic or linear amine skeleton at the 2- and 4-position of the quinolinium ring for structure-activity relationship study. In general, the inhibitors bearing a cyclic amine substituent at the 4-position of the quinolinium ring showed better antibacterial activity (MIC down to 0.25 μg/mL) than that at the 2-position, especially against Gram-positive bacteria. Among the twenty FtsZ inhibitors examined in various assays, A3 was identified to exhibit excellent antibacterial activity against S. aureus (MIC = 0.5-1 μg/mL), S. epidermidis (MIC = 0.25 μg/mL) and E. faecium (MIC = 1-8 μg/mL). More importantly, A3 showed low hemolytic toxicity (IC

Background Circular RNAs (circRNAs) are becoming a unique member of non-coding RNAs (ncRNAs) with emerging evidence of their regulatory roles in various cancers. However, with regards to pancreatic ductal adenocarcinoma (PDAC), circRNAs biological functions remain largely unknown and worth investigation for potential therapeutic innovation. Methods In our previous study, next-generation sequencing was used to identify differentially expressed circRNAs in 3 pairs of PDAC and adjacent normal tissues. Further validation of circRHOBTB3 expression in PDAC tissues and cell lines and gain-and-loss function experiments verified the oncogenic role of circRHOBTB3. The mechanism of circRHOBTB3 regulatory role was validated by pull-down assays, RIP, luciferase reporter assays. The autophagy response of PANC-1 and MiaPaca-2 cells were detected by mCherry-GFP-LC3B labeling and confocal microscopy, transmission electron microscopy and protein levels of LC3B or p62 via Western blot. Results circRHOBTB3 is highly expressed in PDAC cell lines and tissues, which also promotes PDAC autophagy and then progression in vitro and in vivo. Mechanistically, circRHOBTB3 directly binds to miR-600 and subsequently acts as a miRNA-sponge to maintain the expression level of miR-600-targeted gene NACC1, which facilitates the autophagy response of PDAC cells for adaptation of proliferation via Akt/mTOR pathway. Moreover, the RNA-binding protein FUS (FUS) directly binds to pre-RHOBTB3 mRNA to mediate the biogenesis of circRHOBTB3. Clinically, circRHOBTB3, miR-600 and NACC1 expression levels are correlated with the prognosis of PDAC patients and serve as independent risk factors for PDAC patients. Conclusions FUS-mediated circRHOBTB3 functions as a tumor activator to promote PDAC cell proliferation by modulating miR-600/NACC1/Akt/mTOR axis regulated autophagy.

Background A growing number of studies have focused on investigating circRNAs as crucial regulators in the progression of multiple cancer types. Nevertheless, the biological effects and underlying mechanisms of circRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Methods Differentially expressed circRNAs between cancerous tissue and adjacent normal tissues were identified by RNA sequencing in PDAC. Subsequently, in vitro and in vivo functional experiments were performed to investigate the functional roles of circNEIL3 in PDAC tumour growth and metastasis. Furthermore, RNA pull-down, dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, fluorescent in situ hybridization (FISH) and Sanger sequencing assays were performed to examine the circular interaction among circNEIL3, miR-432-5p and adenosine deaminases acting on RNA 1 (ADAR1). Results CircNEIL3 was upregulated in PDAC and promoted the progression of PDAC cells both in vitro and in vivo. Mechanistically, circNEIL3 was shown to regulate the expression of ADAR1 by sponging miR-432-5p to induce RNA editing of glioma-associated oncogene 1 (GLI1), ultimately influencing cell cycle progression and promoting epithelial-to-mesenchymal transition (EMT) in PDAC cells. Moreover, we discovered that the circNEIL3/miR-432-5p/ADAR1 axis was correlated with the PDAC clinical stage and overall survival of PDAC patients, while ADAR1 may reduce the biogenesis of circNEIL3. Conclusions Our findings reveal that circNEIL3 facilitates the proliferation and metastasis of PDAC through the circNEIL3/miR-432-5p/ADAR1/GLI1/cell cycle and EMT axis and that its expression is regulated by ADAR1 through a negative feedback loop. Therefore, circNEIL3 may serve as a prognostic marker and a therapeutic target for PDAC.

The emergence of worldwide spreading drug-resistant bacteria has been a serious threat to public health during the past decades. The development of new and effective antibacterial agents to address this critical issue is an urgent action. In the present study, we investigated the antibacterial activity of two 9,10-dihydroacridine derivatives and their mechanism. Both compounds were found possessing strong antibacterial activity against some selected Gram-positive bacteria including MRSA, VISA and VRE. The biological study suggests that the compounds promoted FtsZ polymerization and also disrupted Z-ring formation at the dividing site and consequently, the bacterial cell division is interrupted and causing cell death.

A small-sized c-MYC promoter G-quadruplex selective fluorescent BZT-Indolium binding ligand was demonstrated for the first time as a highly target-specific and photostable probe for in vitro staining and live cell imaging and it was found to be able to inhibit the amplification of the c-MYC G-rich sequence (G-quadruplex) and down-regulate oncogene c-MYC expression in human cancer cells (HeLa).

Pancreatic cancer (PC) is a malignant cancer with high mortality and poor prognosis. In this study, we found that Linc01232 was significantly upregulated in PC tissues and cells and higher Linc01232 expression was associated with poorer prognosis. Linc01232 overexpression promoted and Linc01232 knockdown inhibited the migration and invasion of PC cells. The results of RNA pull-down, RNA Binding Protein Immunoprecipitation (RIP) assays revealed that Linc01232 physically interacted with Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2B1) (680–890 nt fragment with the RNA recognition motif 2 domain) to inhibit its ubiquitin-mediated degradation in PC cells. RNA sequencing was performed to obtain the transcriptional profiles regulated by Linc01232 and we further demonstrated that Linc01232 participated in the alternative splicing of A-Raf by stabilizing HNRNPA2B1 and subsequently regulated the MAPK/ERK signaling pathway. Collected, our study showed that Linc01232/HNRNPA2B1/A-Raf/MAPK axis participated in the progression of PC and provided a potential therapeutic target for PC.

Pancreatic cancer (PC) is a malignant tumor with a poor prognosis and high mortality. However, the biological role of miR-548t-5p in PC has not been reported. In this study, we found that miR-548t-5p expression was significantly decreased in PC tissues compared with adjacent tissues, and that low miR-548t-5p expression was associated with malignant PC behavior. In addition, high miR-548t-5p expression inhibited the proliferation, migration, and invasion of PC cell lines. Regarding the molecular mechanism, the luciferase reporter gene, chromatin immunoprecipitation (ChIP), and functional recovery assays revealed that YY1 binds to the miR-548t-5p promoter and positively regulates the expression and function of miR-548t-5p. miR-548t-5p also directly regulates CXCL11 to inhibit its expression. A high level of CXCL11 was associated with worse Tumor Node Metastasis (TNM) staging in patients with PC, enhancing proliferation and metastasis in PC cells. Our study shows that the YY1/miR-548t-5p/CXCL11 axis plays an important role in PC and provides a new potential candidate for the treatment of PC.

Background Rhizoma Anemarrhenae (RA) has been conventionally used for treatment of Alzheimer's disease (AD) in Traditional Chinese Medicine, and thus, the active components from RA can be screened. Purpose This research aimed to identify the active components of RA and their targets and further clarify the molecular mechanisms underlying its anti-AD activity. Methods First, the potential active compounds from RA were screened by neurocyte extraction and micro-dialysis methods. Second, the potential targets were predicted by a chemogenomics target knowledgebase and further explored by surface plasmon resonance and enzyme activity assays. Third, the pharmacological effects were evaluated by employing APP/PS1 transgenic mice and SH-SY5Y-APP cells. ELISAs and Western blot analyses were used to evaluate the expression of key molecules in the amyloidogenic and NMDAR/ERK pathways. Results Timosaponin A-III (TA-III) was screened and identified as a potential active component for the anti-AD activity, and BACE1 was proven to be a potential high-affinity target. Enzyme kinetic analysis showed that TA-III had strong noncompetitive inhibitory activity against BACE1. The in vitro and in vivo assays indicated that TA-III had pharmacological effects through improving memory impairment, reducing Aβ aggregation via the amyloidogenic pathway and preventing neuronal impairment through downregulating the NMDAR/ERK signaling pathway. Conclusion TA-III targets BACE1 to reduce Aβ aggregation through down-regulating the NMDAR/ERK pathway for treating AD.

Transition-metal-catalyzed C–H functionalization is already a useful tool in organic synthesis, whilst the rapid development of photoredox catalysis provides new pathways for C–H functionalization with high selectivity and efficiency under mild reaction conditions. In this review, recent advances in C–H functionalization through merging transition­-metal catalysis with photoredox catalysis are discussed.1 Introduction2 Merging Nickel Catalysis with Photoredox Catalysis3 Merging Palladium Catalysis with Photoredox Catalysis4 Merging Cobalt Catalysis with Photoredox Catalysis5 Merging Photoredox Catalysis with Other Transition-Metal Catalysis­6 Conclusions

A selective oxy-difluoroalkylation of allylamines with carbon dioxide (CO2) via visible-light photoredox catalysis is reported. These multicomponent reactions are efficient and environmentally friendly to generate a series of important 2-oxazolidinones with functionalized difluoroalkyl groups. The good functional group tolerance, broad substrate scope, easy scalability, mild reaction conditions, and facile functionalization of products provide great potential for application in organic synthesis and pharmaceutical chemistry.

The transition-metal-free lactonization of heteroaryl and alkenyl C–H bonds with carbon dioxide is reported to synthesize important coumarin derivatives in moderate to excellent yields. These redox-neutral reactions feature a broad substrate scope, good functional group tolerance, facile scalability, and easy product derivatization.

The effect of liver dysfunction on target-controlled infusion (TCI) of propofol remains poorly documented. The pharmacodynamic performance of propofol TCI was evaluated in a cohort of Chinese patients with hepatic insufficiency. Fifty-three patients with hepatic insufficiency were enrolled in the current prospective, observational study. Anesthesia was induced with propofol via TCI to a plasma concentration of 3 µg/ml. Following loss of consciousness (LOC), fentanyl and cisatracurium were administered. Pharmacodynamic parameters were recorded during TCI, including time to LOC, bispectral index (BIS), heart rate (HR) and blood pressure. Patients were divided into two groups based on model of end stage liver disease (MELD) score: Those with a MELD score of ≤9 and those with a MELD score of ≥10. BIS, mean arterial pressure and HR were demonstrated to vary according to time, but were not affected by liver dysfunction. Hypotension was prominent in patients with a MELD score of ≥10 30 min after induction. The proportion of bradycardia and hypotension at the other time points was not significantly different between MELD scores of ≤9 and ≥10. Notably, no bradycardia was observed in MELD of ≥10. Thus, bradycardia and hypotension was observed in patients with hepatic insufficiency over time, although patients with different severities of hepatic insufficiency did not present with different depths of anesthesia. TCI of propofol to 3 µg/ml may be not suitable for patients with hepatic insufficiency, particularly those with severe liver dysfunction. Predictive concentrations (Cp) of TCI propofol requires further investigation and adjustment in patients with hepatic insufficiency (trial registration no. ChiCTR-OCH-12002255).

Protein nitrosylation is a ubiquitous post-translational modification in almost all biological systems. However, its function on stem cell biology is so far incompletely understood. Here, we demonstrated that peroxiredoxin 2 (Prdx-2) nitrosylation was involved in cardiomyocyte differentiation of mouse embryonic stem (ES) cells induced by S-nitrosoglutathione (GSNO). We found that temporary GSNO exposure could promote ES cell-derived cardiomyogenesis. Using a stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics approach, coupled with biotin switch technique, a total of 104 nitrosylated proteins were identified. Specifically, one of the antioxidant enzymes, Prdx-2, was abundantly nitrosylated and temporarily reduced in antioxidant activity, causing transient endogenous hydrogen peroxide (H2O2) accumulation and subsequent X-box binding protein-1s/phosphatidylinositol 3-kinase pathway activation. The present study reveals the mechanism in which GSNO favors cardiomyocyte differentiation. Prdx-2 nitrosylation could be a potent strategy to affect the pluripotent stem cell-derived cardiomyogenesis.

A selective oxy-difluoroalkylation of allylamines with carbon dioxide (CO

The transition-metal-free lactonization of heteroaryl and alkenyl C-H bonds with carbon dioxide is reported to synthesize important coumarin derivatives in moderate to excellent yields. These redox-neutral reactions feature a broad substrate scope, good functional group tolerance, facile scalability, and easy product derivatization.

Zircon U-Pb ages, Hf isotope data and whole-rock major and trace element data for the Middle to Late Ordovician gabbros and granites in the Erguna Massif, NE China were presented in this paper. The petrogenesis of these rocks and the Early Paleozoic tectonic evolution of the massif were discussed. Zircons from the granites and gabbros are of magmatic origin based on their cathodoluminescence (CL) images. The 206Pb/238U ages obtained from 20 spots on zircons from the granites range from 446±9 to 464±10 Ma, yielding a weighted mean age of 455±10 Ma; and 16 spots on zircons from the gabbros range from 465±10 to 466±7 Ma, yielding a weighted mean age of 465±2 Ma. Chemically, the Late Ordovician granites in the Erguna Massif are weakly peraluminous and similar to A-type granites. The granites and gabbros are all enriched in light rare earth elements and large ion lithophile elements (e.g., Rb, K), and depleted in heavy rare earth elements and high field strength elements (e.g., Nb, Ta, and Ti); they all exhibit marked negative Eu anomalies. Their zircon ɛ Hf(t) values range mainly from +1.86 to +6.21 (for the granites) and +1.39 to +3.89 (for the gabbros), except for one spot with a value of −0.27 (for a gabbro). The T DM1 ages for the gabbros and T DM2 ages for the granites vary from 928 to 1 091 Ma and from 1 287 to 1 675 Ma, respectively. It is concluded that the primary magma of the granites could have been derived by partial melting of Mesoproterozoic newly accreted crustal material, whereas the primary magma of the gabbros originated by partial melting of a depleted mantle wedge that had been metasomatized by fluids derived from a subducted slab. These Middle-Late Ordovician granites and gabbros constitute a typical bimodal igneous rock association, implying an extensional environment that was probably related to the post-collisional development of the Erguna and Xing’an massifs in the early Early Paleozoic.

In many plasma discharge applications, automatic control of discharge mode is very important to maintain the best effect of generated plasma on flows or processed materials. A fast feedback control method in RF plasma discharge system is proposed to keep plasma actuator in desired plasma mode, which includes RF amplifier, impedance matching circuit, plasma actuator, oscilloscope, and controlling computer. The experiment installation and feedback control scheme are presented in detail, and experiment results show that the proposed fast feedback control method in RF plasma discharge system is valid and reliable.

Here, we present the results of U–Pb dating of detrital zircons from the Ergunahe Group and the Wubinaobao Formation, within northeastern Inner Mongolia, NE China, with the aim of constraining the tectonic setting of the Erguna Massif. The majority of detrital zircons from five samples collected from the Ergunahe Group and the Wubinaobao Formation are magmatic, although some zircons have metamorphic growth rims. Zircons in two mica schists and in feldspar–quartz sandstone from the Ergunahe Group yield age populations that cluster around 738, 760, 792, 837, 890, 964, and 1050 Ma, whereas zircons from two quartz sandstones within the Wubinaobao Formation yield age populations that cluster at 466, 484, 515, 738, 795, 837, and 894 Ma. These data, combined with detrital zircon age populations (ca. 712 Ma) from the adjacent Xinghuadukou Group, and the fact that the Ergunahe Group intruded by Caledonian gabbros is overlain by upper Silurian units, indicate that the Ergunahe Group formed at 738–712 Ma (i.e. during the Neoproterozoic). In addition, the Wubinaobao Formation is subdivided into two units: a calcareous siltstone unit within the western part of the study area and a quartz sandstone within the eastern part. The calcareous siltstone formed at 712–795 Ma, similar to the Ergunahe Group, whereas the quartz sandstone formed between the 466 Ma and late Silurian. The age spectra of detrital zircons from the Ergunahe Group and the Wubinaobao Formation indicate that sediment in both of these units was derived from terranes that outcrop around the basin. The widespread occurrence of Neoproterozoic detrital zircons within both the Ergunahe Group and the Wubinaobao Formation suggests that Precambrian terranes are present within the Erguna Massif and that the massif has an affinity to the Siberian Craton.

In this paper, we present new zircon U–Pb dating, Hf isotope, major and trace elements, and Sr–Nd isotope data for Early–Middle Triassic intrusive rocks in the Erguna Massif of NE China, in the eastern segment of the Central Asian Orogenic Belt (CAOB). Our aim is to elucidate the tectonic evolution of the Mongol–Okhotsk Ocean and its influence on NE China. Zircons from five representative intrusions in the Erguna Massif are euhedral–subhedral in shape, display oscillatory growth zoning in CL images, and have Th/U ratios of 0.17–1.54, and in combination these features indicate that the zircons are of igneous origin. Zircon U–Pb dating results demonstrate that the Early–Middle Triassic magmatism in the Erguna Massif took place between 241 and 247 Ma. The Early–Middle Triassic rocks are composed mainly of a suite of diorites, quartz–diorites, granodiorites, monzogranites, and syenogranites. They have SiO 2 = 57.71–72.86 wt.%, Mg# = 19–52, Al 2 O 3 = 14.27–17.23 wt.%, and Na 2 O/K 2 O = 0.67–1.59. Chemically, they are metaluminous to peraluminous and belong to the high-K calc-alkaline series. Moreover, they are enriched in light rare earth elements and large ion lithophile elements, and depleted in heavy rare earth elements and high field strength elements (e.g., Nb, Ta, and Ti). The whole-rock e Nd (t) and zircon e Hf (t) values of these samples range from − 4.68 to − 3.42, and from − 2.0 to + 6.6, respectively, indicative of formation from primary magmas generated by partial melting of juvenile crustal material with a contribution from mantle-derived mafic magmas. These magmas subsequently underwent fractional crystallization, contamination, and magma mixing. Geochemically, these Early–Middle Triassic intrusive rocks have affinities with intrusive rocks from active continental margin settings. We conclude, therefore, that the Early–Middle Triassic magmatism in the Erguna Massif was generated within an active continental margin setting related to the southwards subduction of the Mongol–Okhotsk oceanic plate beneath the Erguna Massif. This conclusion is supported by the occurrence of Early Mesozoic porphyry and skarn deposits along the southeastern side of the Mongol–Okhotsk suture belt.

In this paper, we discuss new zircon U–Pb ages, major and trace element analyses, and Hf isotope data for Neoproterozoic intrusive rocks in the Erguna Massif of NE China, in the eastern segment of the Central Asian Orogenic Belt (CAOB). Our aim is to elucidate the tectonic origin of the Erguna Massif and its relationship to the breakup of the Rodinia supercontinent. Zircons collected from a gabbro and five granitoids are euhedral–subhedral, and display striped absorption or fine-scale oscillatory growth zoning in CL images, implying a magmatic origin. Zircon U–Pb dating demonstrates that these rocks were emplaced in four stages during the Neoproterozoic, as follows: (1) ∼851 Ma, an intrusive suite of syenogranites; (2) ∼792 Ma, a bimodal igneous rock association of gabbros and gabbro–diorites, together with syenogranites; (3) ∼762 Ma, a suite of granodiorites; and (4) ∼737 Ma, another suite of syenogranites. These magmatic events are similar time-wise to those in the Tuva–Mongolia Massif and the northern Baikal region of the southern Siberian Craton, suggesting an affinity between the Erguna Massif and the southern margin of the Siberian Craton. The Neoproterozoic granitoids in the Erguna Massif have SiO2 = 68.72–78.36 wt.%, Mg# = 17–33, Al2O3 = 11.66–14.79 wt.%, (Na2O + K2O) = 7.46–9.27 wt.%, and A/CNK = 0.95–1.14; they are metaluminous to peraluminous, and similar to A-type granites. Moreover, these Neoproterozoic granitoids are enriched in light rare earth elements (LREEs) and large ion lithophile elements (LILEs), and depleted in heavy rare earth elements (HREEs) and high field strength elements (HFSEs, Nb, Ta, and Ti). Their zircon ɛHf (t) values mainly range from +2.7 to +8.1, which implies that their primary magmas were derived from partial melting of a depleted lower crust. In contrast, the Neoproterozoic gabbros and gabbro–diorites in the Erguna Massif have low SiO2 (50.43–51.53 wt.%), relatively high Mg# (46–51), high Ni (22.5–23.8 ppm), Cr (41.5–72.2 ppm), and Co contents (28.9–32.5 ppm), and are enriched in LILEs and LREEs but depleted in HREEs and HFSEs such as Nb and Ta. Their ɛHf (t) values range from +2.5 to +5.4. Together, these characteristics suggest the primary magmas of the gabbros and gabbro–diorites were derived by partial melting of a depleted mantle wedge that had been metasomatized by fluids derived from a subducted slab. In the context of the assembly and breakup of the Rodinia supercontinent, and Neoproterozoic magmatic events along the southern margin of the Siberian Craton, we conclude that the Neoproterozoic A-type granitoids, gabbros, and gabbro–diorites of the Erguna Massif formed in an extensional environment related to rifting, corresponding to the breakup of the Rodinia supercontinent.

Aristolochic acid I (AAI) existing in plant drugs from Aristolochia species is an environmental human carcinogen associated with urothelial cancer. Although gene association network analysis demonstrated gene expression profile changes in the liver of human TP53 knock-in mice after acute AAI exposure, to date, whether AAI causes hepatic tumorigenesis is still not confirmed. Here, we show that hepatic premalignant alterations appeared in canines after a 10-day AAI oral administration (3 mg/kg/day). We observed c-Myc oncoprotein and oncofetal RNA-binding protein Lin28B overexpressions accompanied by cancer progenitor-like cell formation in the liver by AAI exposure. Meanwhile, we found that forkhead box O1 (FOXO1) was robustly phosphorylated, thereby shuttling into the cytoplasm of hepatocytes. Furthermore, utilizing microarray and qRT-PCR analysis, we confirmed that microRNA expression significantly dysregulated in the liver treated with AAI. Among them, we particularly focused on the members in let-7 miRNAs and miR-23a clusters, the downstream of c-Myc and IL6 receptor (IL6R) signaling pathway linking the premalignant alteration. Strikingly, when IL6 was added in vitro, IL6R/NF-κB signaling activation contributed to the increase of FOXO1 phosphorylation by the let-7b inhibitor. Therefore, it highlights the new insight into the interplay of the network in hepatic tumorigenesis by AAI exposure, and also suggests that anti-premalignant therapy may be crucial for preventing AAI-induced hepatocarcinogenesis. Cancer Prev Res; 9(4); 324–34. ©2016 AACR.

To study the effect of steaming and baking process on contents of alkaloids in Aconite Lateralis Radix (Fuzi), 13 alkaloids were analyzed by UPLC-MS/MS equipped with ESI ion source in MRM mode. In steaming process, the contents of diester-diterpenoid alkaloids decreased rapidly, the contents of monoester-diterpenoid alkaloids firstly increased, reached the peak at 40 min, and then deceased gradually. The contents of aconine alkaloids (mesaconine, aconine and hypaconine) increased all the time during processing, while the contents of fuziline, songorine, karacoline, salsolionl were stable or slightly decreased. In baking process, dynamic variations of alkaloids were different from that in the steaming process. Diester-diterpenoid alkaloids were degraded slightly slower than in steaming process. Monoester-diterpenoid alkaloids, aconine alkaloids and the total alkaloids had been destroyed at different degrees, their contents were significantly lower than the ones in steaming Fuzi at the same processing time. This experiment revealed the dynamic variations of alkaloids in the course of steaming and baking. Two processing methods which can both effectively remove the toxic ingredients and retain the active ingredients are simple and controllable, and are valuable for popularization and application.