Preparation of mixed-mode weak cation exchange magnetic solid-phase extraction sorbent and its application in the extraction of 21 illicit drugs from wastewater.

The detection of illicit drugs in wastewater can effectively monitor and evaluate the trend of illicit drug abuse. A novel mixed-mode cation exchange magnetic sorbent Fe3O4 @poly(ST/DVB/MA-COOH) was prepared and firstly applied as magnetically dispersed solid phase extraction material to efficiently, rapidly, and selectively extract 21 illicit drugs from wastewater. The selectivity of the sorbent was mainly attributed to the electrostatic interaction. The effects of Fe3O4 @poly(ST/DVB/MA-COOH) preparation and extraction conditions on the adsorption performance were thoroughly discussed. Among the 21 illicit drugs, the absolute extraction recovery values for 19 illicit drugs were greater than 80 % and the entire adsorption process could be achieved in one minute. Subsequently, the Fe3O4 @poly(ST/DVB/MA-COOH) sorbent combined with UHPLC-MS/MS was used to establish a quantitative method for the effectively extracted 19 illicit drugs in wastewater. The method had a good determination coefficient in the range of 0.2-200 ng/L and the limits of detection of the method were 0.03-0.67 ng/L. The spiked recovery values were in the range of 87.0-119.6 %. Finally, the method was successfully applied to the detection of 19 illicit drugs in wastewater samples and also compared with the commonly used SPE method. The obtained results indicate that Fe3O4 @poly(ST/DVB/MA-COOH) has great advantages in the detection of illicit drugs in wastewater.

Study on the Mass Spectrometry Fragmentation Patterns for Rapid Screening and Structure Identification of Ketamine Analogues in Illicit Powders.

Ketamine analogues have been emerging in recent years and are causing severe health and social problems worldwide. Ketamine analogues use 2-phenyl-2-aminocyclohexanone as the basic structure and achieve physiological reactions similar to or even more robust than the prototype of ketamine by changing the substituents on the benzene ring (R1 and R2) and amine group (RN1). Therefore, the mass spectrometry (MS) fragmentation pathways and fragments of ketamine analogues have certain regularity. Eight ketamine analogues are systematically investigated by GC-QTOF/MS and LC-Q-Orbitrap MS/MS with the positive mode of electrospray ionization. The MS fragmentation patterns of ketamine analogues are summarized according to high-resolution MS data. The α-cleavage of carbon bond C1-C2 in the cyclohexanone moiety and further losses of CO, methyl radical, ethyl radical and propyl radical are the characteristic fragmentation pathways of ketamine analogues in EI-MS mode. The loss of H2O or the sequential loss of RN1NH2, CO and C4H6 are the distinctive fragmentation pathways of ketamine analogues in ESI-MS/MS mode. Moreover, these MS fragmentation patterns are first introduced for the rapid screening of ketamine analogues in suspicious powder. Furthermore, the structure of the ketamine analogue in suspicious powder is 2-(Methylamino)-2-(o-tolyl)cyclohexan-1-one, which is further confirmed by NMR. This study contributes to the identification of the chemical structure of ketamine analogues, which can be used for the rapid screening of ketamine analogues in seized chemicals.

Rapid Simultaneous Determination of Three Synthetic Cannabinoids in Urine and Plasma of Rats Using Ultra-High Performance Liquid Chromatography Tandem Mass Spectrometry.

Synthetic cannabinoids, a class of psychoactive compounds, are controlled as new psychoactive substances (NPSs) identified by the early warning system (EWS) of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). At present, several new synthetic cannabinoids have appeared in the illegal drug market, including 4-methylnaphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-122), methyl (1-(5-fluoropentyl)-1H-indazole-3-carbonyl)-L-valinate (5F-AMB), and methyl 2-(1-(4-fluorobenzyl)-1Hindazole-3-carboxamido)-3-methylbutanoate (AMB-FUBINACA). A convenient, rapid, and highly sensitive analytical method was developed to determine three synthetic cannabinoids in rat plasma and urine. The liquid chromatography tandem mass spectrometry (LC-MS/MS) method was optimized and validated to analyze the three synthetic cannabinoids in rat plasma and urine. The method identified intra-assay precision (1.3-9.0% and 2.8-6.7%), inter-assay precision (3.0-8.6% and 3.9-8.8%), limits of detection (0.003-0.004 ng/mL and 0.00125-0.002 ng/mL) and quantification (0.012-0.016 ng/mL and 0.003-0.005 ng/mL), recovery (95.4-106.8% and 92.0-106.8%) for rat plasma and urine, and the matrix effect (93.4-118.0%) for rat urine, and the correlation coefficients were above 0.99 in the linear range. The established LC-MS/MS method was successfully used to simultaneously detect the JWH-122 and 5F-AMB in rat plasma and JWH-122, 5F-AMB, and AMB-FUBINACA in rat urine. The present study provides methodological support for internal exposure assessment of three synthetic cannabinoids and promotes the quantitative analysis and technical supervision of synthetic cannabinoids.

The effects of genetic distance, nutrient conditions, and recognition ways on outcomes of kin recognition in Glechoma longituba.

Kin recognition might help plants decrease competitive cost and improve inclusive fitness with close genes; thus it might interact with environmental factors to affect communities. Whether and how various factors, such as the genetic distance of neighbors, environmental stressors, or the way a plant recognizes its neighbors, might modify plant growth strategies remains unclear. To answer these questions, we conducted experiments in which ramets of a clonal plant, Glechoma longituba, were grown adjacent to different genetically related neighbors (clone kin / close kin / distant kin) in different nutrient conditions (high / medium / low), or with only root exudates from pre-treatment in culture solution. By comparing competitive traits, we found that: (1) kin recognition in G. longituba was enhanced with closer genetic distance; (2) the outcomes of kin recognition were influenced by the extent of nutrient shortage; (3) kin recognition helped to alleviate the nutrient shortage effect; (4) kin recognition via root exudates affected only below-ground growth. Our results provide new insights on the potential for manipulating the outcome of kin recognition by altering neighbor genetic distance, nutrient conditions and recognition ways. Moreover, kin recognition can help plants mitigate the effects of nutrient shortage, with potential implications in agricultural research.

Detection of 3,4-Methylene Dioxy Amphetamine in Urine by Magnetically Improved Surface-Enhanced Raman Scattering Sensing Strategy.

Abuse of illicit drugs has become a major issue of global concern. As a synthetic amphetamine analog, 3,4-Methylene Dioxy Amphetamine (MDA) causes serotonergic neurotoxicity, posing a serious risk to human health. In this work, a two-dimensional substrate of ITO/Au is fabricated by transferring Au nanoparticle film onto indium-tin oxide glass (ITO). By magnetic inducing assembly of Fe3O4@Au onto ITO/Au, a sandwich-based, surface-enhanced Raman scattering (SERS) detection strategy is designed. Through the use of an external magnet, the MDA is retained in the region of hot spots formed between Fe3O4@Au and ITO/Au; as a result, the SERS sensitivity for MDA is superior compared to other methods, lowering the limit of detection (LOD) to 0.0685 ng/mL and attaining a corresponding linear dynamic detection range of 5-105 ng/mL. As an actual application, this magnetically improved SERS sensing strategy is successfully applied to distinguish MDA in urine at trace level, which is beneficial to clinical and forensic monitors.

Preparation and application of polystyrene-divinylbenzene sorbent with weak cation-exchange character for the selective extraction of illicit drugs in environmental water.

A novel mixed-mode weak cation-exchange sorbent (PS-DVB-WCX-II) was prepared by the modification of polystyrene-divinylbenzene with mercaptosuccinic acid for the selective extraction of illicit drugs in environmental water. The PS-DVB-WCX-II was synthesized through the Friedel-Crafts acylation reaction on the surface of polystyrene-divinylbenzene, followed by nucleophilic substitution reaction and thiol-ene click reaction. The sorbent can selectively absorb illicit drugs through the reverse-phase interactions provided by benzene ring on the polymer backbone and the ion-exchange interactions provided by functional group (-COOH). As compared with the extraction performance of three commercial SPE cartridges, it was found that the prepared sorbent had better adsorption performance with the recovery values between 84.1% and 106.0% for the selected 11 illicit drugs under the optimized SPE conditions. Illicit drugs in environmental water were extracted by the sorbent, prior to the detection of UHPLC-MS/MS. Two quantitative methods were established respectively for the detection of 11 illicit drugs in different matrices of river water and wastewater. Both methods had good determination coefficient (r2>0.992) in the range of 0.5-50 ng/L, 2.5-250 ng/L, 5-500 ng/L, and low limits of detection (S/N = 3) of 0.17-1.67 ng/L. In the real wastewater samples, the concentration of morphine was 18.3-126.3 ng/L, and the methamphetamine was 12.7-27.4 ng/L. Meanwhile, PS-DVB-WCX-II was compared with Oasis MCX and Oasis HLB in the detection of real wastewater samples. The results revealed that PS-DVB-WCX-II and Oasis MCX had better performance in absorbing methamphetamine than Oasis HLB, and PS-DVB-WCX-II had better ability to remove the matrix. The results suggested that the prepared weak cation-exchange sorbent had the potential in the application of illicit drug detection in environmental water.

Development of a fragmentation pattern of synthetic cannabinoids based on electrospray ionization mass spectrometry in positive ion mode to screen synthetic cannabinoids in illicit products.

To explore the MS fragmentation pattern of synthetic cannabinoids by electrospray ionization mass spectrometry, twenty-seven synthetic cannabinoids were systematically investigated by liquid chromatography coupled to high-resolution quadrupole Orbitrap mass spectrometry(LC-Q-Orbitrap/MS)with positive mode of electrospray ionization. Based on tandem multistage MS and high resolution MS data, MS fragmentation pattern of synthetic cannabinoids was summarized. The cleavage of CC bonds next to the oxygen at the side chain on the C-3 position of synthetic cannabinoids was the characteristic fragmentation pathway of synthetic cannabinoids in the positive mode of electrospray ionization. When the synthetic cannabinoids with a 3-carbamoylpropyl-indole/indazole structure, NH3, CO, NH2CHO and CH2(CH3)2 were easy to lose to form different ions. While when the synthetic cannabinoids with a 3-carboxamide-indole/indazole structure, the side chain on the C-3 position was susceptible to γ-cleavage. In addition, this MS fragmentation pattern was applied to quickly screen whether electronic cigarette oil and tobacco from drug cases contain synthetic cannabinoids. This kind of compounds had strong fragmentation pattern, which provided new evidence for the rapid structure identification of synthetic cannabinoids.

Determination of ketamine, methamphetamine and 3,4-methylenedioxymethamphetamine in human hair by flash evaporation-gas chromatography/mass spectrometry.

A rapid and sensitive method utilizing flash evaporation-gas chromatography/mass spectrometry (FE-GC/MS) has been developed. The method is applicable to determine ketamine (KET), methamphetamine (MAMP) and 3,4-methylenedioxymethamphetamine (MDMA) in human hair. Cut and weighted hair (0.30 mg) was heated at the flash evaporation temperature of 350 °C. KET, MAMP and MDMA were released into a capillary column for GC/MS analysis and produced fragment ions in SIM mode. Validation of the method included evaluation of linearity, sensitivity, accuracy, precision and repeatability. Linearity ranged from 2 to 300 ng/mg for KET in hair and 2 to 200 ng/mg for MAMP and MDMA in hair with the correlation coefficients all greater than 0.998. Limits of detection were 0.7 ng/mg and limits of quantification were 2.0 ng/mg of hair for KET, MAMP and MDMA. The precision ranged from 1.57% to 7.75% for KET, 1.49% to 7.10% for MAMP and 1.84% to 8.31% for MDMA. The recovery ranged from 102.1% to 110.9% for KET, 99.3% to 108.0% for MAMP and 89.5% to 112.6% for MDMA. Six authentic hair samples from known drug abusers and three drug-free hair samples from volunteers who had never used drugs were successfully analyzed. Compared with traditional time-consuming and hair-comsuming pretreatment method, FE-GC/MS was a faster, simpler and low sample consumption method for the determination of KET, MAMP and MDMA in human hair.

Synthesis and biological evaluation of moxifloxacin-acetyl-1,2,3-1H-triazole-methylene-isatin hybrids as potential anti-tubercular agents against both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains.

Herein, synthesis and biological evaluation of fourteen moxifloxacin-acetyl-1,2,3-1H-triazole-methylene-isatin hybrids as potential anti-tubercular agents against both drug-susceptible (MTB H37Rv), rifampicin-resistant and multidrug-resistant Mycobacterium tuberculosis strains were reported, and cytotoxicity towards VERO cells as well as inhibitory activity against MTB DNA gyrase were also discussed in this paper. The structure-activity relationship and structure-cytotoxicity relationship demonstrated that substituents on the C-3 and C-5/C-7 positions of isatin framework were closely related with the anti-mycobacterial activity and cytotoxicity. The most active hybrids 8h and 8l (MIC: 0.12-0.5 µg/mL) showed excellent activity which was no inferior to the parent moxifloxacin against the tested drug-susceptible, rifampicin-resistant and multidrug-resistant Mycobacterium tuberculosis strains, demonstrating their potential application as novel anti-tubercular candidates.

On the combination of luminescent rare earth MOF and rhodamine dopant with two sensing channels for picric acid.

The present paper reported a hybrid structure for the optical recognition of PA (picric acid). This dye-MOF structure, named as R6h@EuBTC, consisted of a supporting matrix based on rare earth MOF and a sensing probe based on rhodamine dye, which was confirmed using XRD, IR, thermal and photophysical analysis. R6h@EuBTC's rhodamine absorption in visible region was enhanced by increasing PA concentrations, showing obvious color change and consequently colorimetric sensing. R6h@EuBTC's rhodamine emission component was increased by increasing PA concentrations, while its Eu emission component was slightly quenched by increasing PA concentrations, which offered self-calibrated sensing signals for ratiometric fluorescent sensing. Linear response and good selectivity were observed for both sensing channels with LOD of 3.9 µM. R6h@EuBTC's sensing mechanism towards PA was the combination of two procedures, which were the emission turn on effect of rhodamine component triggered by PA-released protons and the emission turn off effect of Eu component caused by its electron transfer procedure to PA, respectively. R6h@EuBTC's novelty was its two sensing channels and the practicability of naked eye detection.

Quinolone derivatives and their activities against methicillin-resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus (MRSA) is the most common pathogen both in hospital and community settings, and is capable of causing serious and even fatal infections. Several antibiotics have been approved for the treatment of infections caused by MRSA, but MRSA has already developed resistance to them. More than ever, it's imperative to develop novel, high effective and fast acting anti-MRSA agents. Quinolones are one of the most common antibiotics in clinical practice used to treat various bacterial infections, and some of them displayed excellent in vitro and in vivo anti-MRSA activities, so quinolone derivatives are one of the most promising candidates. This review summarizes the recent developments of quinolone derivatives with potential activity against MRSA, and the structure-activity relationship is also discussed.

Design, synthesis and evaluation of oxime-functionalized nitrofuranylamides as novel antitubercular agents.

A series of oxime-functionalized nitrofuranylamides were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against MTB H37Rv and drug-resistant clinical isolates. Among them, two compounds 7a and 7b exhibited excellent activity against the three tested strains. Both of them were comparable to the first-line anti-TB agents INH and RIF against MTB H37Rv, and were far more potent than INH and RIF against MDR-TB 16833 and 16995 strains. Thus, both of them could act as leads for further optimization.

Recent advances of imidazole-containing derivatives as anti-tubercular agents.

Tuberculosis still remains one of the most common, communicable, and leading deadliest diseases known to mankind throughout the world. Drug-resistance in Mycobacterium tuberculosis which threatens to worsen the global tuberculosis epidemic has caused great concern in recent years. To overcome the resistance, the development of new drugs with novel mechanisms of actions is of great importance. Imidazole-containing derivatives endow with various biological properties, and some of them demonstrated excellent anti-tubercular activity. As the most emblematic example, 4-nitroimidazole delamanid has already received approval for treatment of multidrug-resistant tuberculosis infected patients. Thus, imidazole-containing derivatives have caused great interests in discovery of new anti-tubercular agents. Numerous of imidazole-containing derivatives were synthesized and screened for their in vitro and in vivo anti-mycobacterial activities against both drug-sensitive and drug-resistant Mycobacterium tuberculosis pathogens. This review aims to outline the recent advances of imidazole-containing derivatives as anti-tubercular agents, and summarize the structure-activity relationship of these derivatives. The enriched structure-activity relationship may pave the way for the further rational development of imidazole-containing derivatives as anti-tubercular agents.

Long non-coding RNA 00312 downregulates cyclin B1 and inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo.

Long non-coding RNAs are dysregulated in human hepatocellular carcinoma (HCC). We tested the potential effect of long non-coding RNA 00312 ("Lnc00312") on human HCC cell behavior in vitro and in vivo. Forced-expression of Lnc00312 by a lentiviral vector induced proliferation inhibition and apoptosis in HepG2 cells and primary human HCC cells. Lnc00312 downregulated cyclin B1 and induced G2-M cell cycle arrest in HCC cells. Restoring cyclin B1 expression by a cyclin B1 cDNA construct inhibited Lnc00312-induced cytotoxicity against HCC cells. Conversely, siRNA-mediated knockdown of Lnc00312 increased cyclin B1 expression and promoted HepG2 cell proliferation. In vivo, the growth of HepG2 xenograft tumors in severe combined immunodeficient (SCID) mice was largely inhibited after expression of Lnc00312. Significantly, Lnc00312 is downregulated in human HCC tissues, which is negatively correlated with the tumor grade. Overall, Lnc00312 inhibits human HCC cell proliferation in vitro and in vivo. Cyclin B1 could be a key target protein of Lnc00312 in human HCC cells.

Fluoroquinolone derivatives and their anti-tubercular activities.

Tuberculosis (TB) remains one of the most widespread and leading deadliest diseases, around one-third of the world's population harbor a latent infection by Mycobacterium tuberculosis (MTB), and 5-10% eventually develop an active TB. The emergency of MTB new virulent forms as well as the co-infection between MTB and HIV alarming the serious problem in TB control and demanding the need for new drugs more potent than earlier with safe ADME profile. Fluoroquinolones are emerged as a large family of synthetic broad spectrum antibiotics, and some of them were recommended as the second-line agents for the treatment of TB mainly in cases involving resistance or intolerance to first-line anti-TB therapy by WHO. Numerous of FQs derivatives have been synthesized for seeking for new anti-TB agents, and some of them exhibited promising potency. This review aims to summarize the recent advances made towards the discovery of FQs derivatives as anti-TB agents and the structure-activity relationship of these derivatives.

Antiplasmodial and antimalarial activities of quinolone derivatives: An overview.

Malaria remains one of the most deadly infectious diseases globally. Considering the growing spread of resistance, development of new and effective antimalarials remains an urgent priority. Quinolones, which are emerged as one of the most important class of antibiotics in the treatment of various bacterial infections, showed potential in vitro antiplasmodial and in vivo antimalarial activities, making them promising candidates for the chemoprophylaxis and treatment of malaria. This review presents the current progresses and applications of quinolone-based derivatives as potential antimalarials to pave the way for the development of new antimalarials.

Network analysis reveals crosstalk between autophagy genes and disease genes.

Autophagy is a protective and life-sustaining process in which cytoplasmic components are packaged into double-membrane vesicles and targeted to lysosomes for degradation. Accumulating evidence supports that autophagy is associated with several pathological conditions. However, research on the functional cross-links between autophagy and disease genes remains in its early stages. In this study, we constructed a disease-autophagy network (DAN) by integrating known disease genes, known autophagy genes and protein-protein interactions (PPI). Dissecting the topological properties of the DAN suggested that nodes that both autophagy and disease genes (inter-genes), are topologically important in the DAN structure. Next, a core network from the DAN was extracted to analyze the functional links between disease and autophagy genes. The genes in the core network were significantly enriched in multiple disease-related pathways, suggesting that autophagy genes may function in various disease processes. Of 17 disease classes, 11 significantly overlapped with autophagy genes, including cancer diseases, metabolic diseases and hematological diseases, a finding that is supported by the literatures. We also found that autophagy genes have a bridging role in the connections between pairs of disease classes. Altogether, our study provides a better understanding of the molecular mechanisms underlying human diseases and the autophagy process.