N-Ethylnorketamine has anesthetic and analgesic effects with abuse liability.

Arylcyclohexylamines is an ever-growing class of new psychoactive substances, including an increasing number of ketamine analogs. N-Ethylnorketamine (NENK) is a new synthetic ketamine analog that has emerged as an abused drug, but little is known about the pharmacological profile of NENK. In this study, we investigated the anesthetic and analgesic activity, abuse liability of NENK compared with ketamine. The ED50 values of anesthetic activity for NENK and ketamine were 96.9, 69.4 mg/kg, respectively. The ED50 values of analgesic activity for NENK and ketamine were 45.9 and 23.6 mg/kg, respectively. NENK induced significant conditioned place preference at a minimum dose of 10.0 mg/kg in mice, an effect comparable to that of ketamine (3.0 mg/kg). Acute injections of NENK or ketamine at 30.0 mg/kg enhanced locomotor activity, and repeated treatments with this dose induced locomotor sensitization after withdrawal. Taken together, these results clearly demonstrated that NENK has lower anesthetic and analgesic activity compared to ketamine, but has significant abuse liability.

2-Fluorodeschloroketamine has similar abuse potential as ketamine.

2-Fluorodeschloroketamine (2-FDCK) as a substitute for ketamine has emerged among drug abusers in recent years. However, 2-FDCK has not been controlled or regulated in many countries, which may be partly related to the lack of evidence on its abuse potential. In this study, we evaluated the abuse potential of 2-FDCK via the tests of the conditioned place preference (CPP), locomotor sensitization, drug self-administration and drug discrimination using ketamine as a reference. 2-FDCK induced significant CPP at a minimum dose of 3 mg/kg in mice, an effect comparable with that of ketamine (3 mg/kg). Acute injections of 2-FDCK or ketamine at 30 mg/kg enhanced locomotor activity. Repeated treatments with this dose of 2-FDCK and ketamine induced locomotor sensitization after withdrawal. 2-FDCK readily induced self-administration with 0.5 mg/kg/infusion, the same dose for ketamine, and induced the highest seeking response at 1 mg/kg. Drug discrimination test showed that 2-FDCK dose-dependently substitute for ketamine with comparable ED50 to ketamine in substitution testing. Taken together, these results strongly suggested that 2-FDCK has an abuse potential comparable with ketamine.

Cultivated human intestinal fungus Candida metapsilosis M2006B attenuates colitis by secreting acyclic sesquiterpenoids as FXR agonists.

OBJECTIVE: Dysbiosis of the intestinal fungal community has been observed in inflammatory bowel disease (IBD); however, its potential role in IBD development and prevention remains unclear. Here, we explored the biological effects and molecular mechanisms of intestinal fungi isolated from human faeces on colitis in mice. DESIGN: Intestinal fungal strains with differential abundance in IBD were cultivated in human faeces and their effects on various mouse models of experimental colitis were evaluated. In addition, the bioactive metabolites secreted by the target fungus were accurately identified and their pharmacological effects and potential molecular targets were investigated in vitro and in vivo. RESULTS: The abundance of Candida spp was significantly higher in patients with IBD. After large-scale human intestinal fungal cultivation and functional analysis, Candida metapsilosis M2006B significantly attenuated various models of experimental colitis in wild-type, antibiotic-treated, germ-free, and IL10-/- mice by activating farnesoid X receptor (FXR). Among the seven acyclic sesquiterpenoids (F1-F7) identified as major secondary metabolites of M2006B, F4 and F5 attenuated colitis in mice by acting as novel FXR agonists. The therapeutic effects of M2006B and its metabolites on colitis via specific FXR activation were confirmed in Fxr -/- mice. CONCLUSION: This study revealed that C. metapsilosis M2006B significantly attenuated colitis in mice and identified two acyclic sesquiterpenoids (F4 and F5) as major active metabolites of M2006B. Notably, these metabolites were able to effectively treat experimental colitis by selectively activating FXR. Together, this study demonstrates that M2006B could be a beneficial intestinal fungus for treating and preventing IBD.

Nucleosides and amino acids, isolated from Cordyceps sinensis, protected against cyclophosphamide-induced myelosuppression in mice.

The material basis of Cordyceps sinensis (Berk.) Sacc has not yet been well understood and natural C. sinensis resources are very rare. The present study aimed to clarify the substance basis and compare the protective effect of natural and artificially-cultivated C. sinensis against cyclophosphamide (CTX)-induced myelosuppression. Both natural and artificially-cultivated C. sinensis effectively improved CTX-induced decrease of peripheral blood counts and hemopoietic growth factors, pathological changes, and apoptosis of bone marrow. Importantly, artificially-cultivated C. sinensis showed similar capacity compared with natural C. sinensis. Uridine (1), adenosine (2), L-pyroglutamic acid (3), lysinonorleucine (4), 1,3,5-trimethoxybenzene (5), D-mannitol (6), L-pyroglutamic acid methyl ester (7), tryptophan (8), and phenylalanine (9) were isolated from bioactivity-guided fraction and identified to attenuate CTX-induced myelosuppression in mice. In conclusions, nucleosides and amino acids represented the effective chemical components in C. sinensis. Artificial cultivation can be used as an effective substitute for natural C. sinensis.

Uncaria rhynchophylla ameliorates unpredictable chronic mild stress-induced depression in mice via activating 5-HT1A receptor: Insights from transcriptomics.

BACKGROUND: Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain. PURPOSE: The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE). STUDY DESIGN AND METHODS: A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT1A receptor was assayed by dual-luciferase reporter system. RESULTS: URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT1A signaling pathway 5-HT1A, CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT1A receptor with an EC50 value of 17.42 µg/ml. CONCLUSION: U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT1A receptor.

Flavonoids Regulate Inflammation and Oxidative Stress in Cancer.

Cancer is the second leading cause of death globally. Millions of persons die due to cancer each year. In the last two decades, the anticancer effects of natural flavonoids have become a hot topic in many laboratories. Meanwhile, flavonoids, of which over 8000 molecules are known to date, are potential candidates for the discovery of anticancer drugs. The current review summarizes the major flavonoid classes of anticancer efficacy and discusses the potential anti-cancer mechanisms through inflammation and oxidative stress action, which were based on database and clinical studies within the past years. The results showed that flavonoids could regulate the inflammatory response and oxidative stress of tumor through some anti-inflammatory mechanisms such as NF-κB, so as to realize the anti-tumor effect.

Exploring the Therapeutic Composition and Mechanism of Jiang-Suan-Chu-Bi Recipe on Gouty Arthritis Using an Integrated Approach Based on Chemical Profile, Network Pharmacology and Experimental Support Using Molecular Cell Biology.

BACKGROUND: Gouty arthritis is a common metabolic disease caused by long-term purine metabolic disorder and elevated serum uric acid. Jiang-Suan-Chu-Bi recipe (JSCBR), a traditional Chinese herbal formula prescribed according to utilization frequency and cluster analysis, has been clinically validated remedy for gouty arthritis. However, its therapeutic composition and mechanism remains unclear. METHODS: In the present study, a simple, rapid, and sensitive ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS)-based chemical profiling was firstly established for comprehensively identifying the major constituents in JSCBR. A phytochemistry-based network pharmacology analysis was further performed to explore the potential therapeutic targets and pathways involved in JSCBR bioactivity. Finally, THP-1 cell model was used to verify the prediction results of network pharmacology by western blot analysis. RESULTS: A total of 139 compounds containing phenolic acids, flavonoids, triterpenoid saponins, alkaloids, amino acids, fatty acids, anthraquinones, terpenes, coumarins, and other miscellaneous compounds were identified, respectively. 175 disease genes, 51 potential target nodes, 80 compounds, and 11 related pathways based on network pharmacology analysis were achieved. Among these pathways and genes, NOD-like receptor signaling pathway may play an important role in the curative effect of JSCBR on gouty arthritis by regulation of NRLP3/ASC/CASP1/IL1B. The results of cellular and molecular experiments showed that JSCBR can effectively reduce the protein expression of ASC, caspase-1, IL-1ß, and NRLP3 in monosodium urate-induced THP-1 cells, which indicated that JSCBR mediated inflammation in gouty arthritis by inhibiting the activation of NOD-like receptor signaling pathway. CONCLUSION: Thus, the integrated approaches adopted in the present study could contribute to simplifying the complex system and providing directions for further research of JSCBR.

Simultaneous Determination of 15 Flavonoids in Scutellaria barbata-Hedyotis diffusa Herb Pair by HPLC Q-TOF MS.

Background: The Scutellaria barbata-Hedyotis diffusa herb pair has appeared in classical prescriptions and has usually been used for the treatment of cancer and inflammatory conditions. Objective: For quality control of this herb pair, a rapid and reliable HPLC-quadrupole-time-of-flight(Q-TOF)-MS method was used for the simultaneous determination of alpinetin, apigenin-7-O-ß-D-glucopyranoside, scutellarein, apigenin, quercetin-3-O-ß-D-glucopyranoside, wogonoside, quercetin, amentoflavone, wogonin, chrysin, luteolin, rutin, naringenin, baicalein, and baicalin in the S. barbata-H. diffusa herb pair. Methods: LC-MS analysis was performed on a Shimadzu HPLC 20ADXR LC system in-line with an AB-SCIEX 5600 Triple TOF mass spectrometer. Results: The calibration curves showed good linearity in a relatively wide concentration range (r >0.996). The LOD and LOQ were less than 20 and 68 ng/mL, respectively. The relative standard deviation (RSD) values of intraday and inter-day precision were <3.31% for all the analytes. The recoveries of the method were in the range of 94.6-106.0%, with RSD <4.72%. The RSD values of peak areas in the stability study were not more than 4.28% for all analytes within 2 days. These results revealed that the method exhibited good sensitivity, precision, accuracy, and stability. Conclusions: This method could be applied to the quantitative determination of 15 flavonoids in the S. barbata - H. diffusa herb pair. Highlights: (1) The established method of HPLC-Q-TOF-MS is simple, fast, sensitive, and reliable. (2) 15 Flavonoids in the S. barbata-H. diffusa herb pair were simultaneous determined.

Di-n-but-yl[4-hy-droxy-N'-(3-meth-oxy-2-oxido-benzyl-idene-κO (2))benzo-hydrazidato-κ(2) N,O]tin(IV).

In the title compound, [Sn(C4H9)2(C15H12N2O4)], the Sn(IV) atom is coordinated by the N, O and O' atoms from the tridentate Schiff base dianion in an overall cis-C2SnNO2 trigonal-bipyramidal geometry. Adjacent mol-ecules are linked by O-H⋯O hydrogen bonds, forming a chain running along [001].

{4-Chloro-N'-[(2-oxidonaphthalen-1-yl-κO)methyl-idene]benzohydrazidato-κ(2) N',O}di-methyl-tin(IV).

In the title complex, [Sn(CH3)2(C18H11ClN2O2)], the Sn(IV) ion is coordinated by two O atoms and an N atom from a 4-chloro-N'-[(2-oxidonaphthalen-1-yl)methyl-idene]benzohydrazidate ligand and two C atoms from two methyl ligands in a distorted trigonal-bipyramidal geometry [Sn-O = 2.092 (3) and 2.144 (3) Å; Sn-N = 2.160 (4) Å]. The dihedral angle between the naphthalene ring system and the benzene ring is 8.6 (2)°. In the crystal, adjacent mol-ecules are linked by weak C-H⋯O hydrogen bonds, forming a chain along the b-axis direction.

trans-Tris(4-bromo-phen-yl)dichlorido-antimony(V).

The Sb(V) atom in the title compound, [SbCl2(C6H4Br)3], has an almost regular trigonal-bipyramidal geometry with the equatorial plane made up of three C atoms of the bromo-phenyl groups and the axial positions occupied by two Cl(-) ions in a trans configuration. In the crystal, C-H⋯Br hydrogen bonds link the mol-ecules into zigzag chains along the b-axis direction. Pairs of C-H⋯Cl hydrogen bonds further link mol-ecules into cyclic dimers with R2(2)(10) ring motifs, generating a three-dimensional network.

[2-(4-Chloro-phen-yl)-1,3-selenazol-4-yl]methanol.

In the title compound, C10H8ClNOSe, the dihedral angle between benzene and selenazole rings is 11.4 (3)° and the hy-droxy-methyl group is bent from the selenazole ring, making a dihedral angle of 63.8 (3)°. In the crystal, mol-ecules are linked into inversion dimers by pairs of O-H⋯N hydrogen bonds. Roof-tile-like stacking of the mol-ecules along [010] [b = 4.5707 (4) Å] is observed, with the benzene and selenazole rings separated by a face-to-face distance of 3.57 Šand a mutual slippage of 2.85 Å.

(E)-4-[2-(2-Hy-droxy-benzo-yl)-hydra-zin-ylidene]penta-noic acid.

The title mol-ecule, C(12)H(14)N(2)O(4), adopts a trans configuration with respect to the C=N double bond. The amino group is involved in an intra-molecular N-H⋯O hydrogen bond. In the crystal structure, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into doubled sheets parallel to the (101) plane.

Enhanced fluorescence anisotropy assay for human cardiac troponin I and T detection.

Human cardiac troponin I (hcTnI) and troponin T (hcTnT) are the biomarkers of choice for the diagnosis of cardiac diseases. In an effort to improve assay sensitivity, in this study we developed a novel approach to simultaneously detect hcTnI and hcTnT in homogenous solutions by monitoring enhanced-fluorescence-anisotropy changes. Specifically, our design was based on a competition assay by measuring anisotropy change of fluorophore-labeled peptides bound to primary monoclonal antibodies in the presence of nano-gold-modified secondary antibody in response to the presence of target proteins. Enhanced-fluorescence-anisotropy resulted from interaction between the primary antibody and the nano-gold-labeled secondary antibody, which significantly increased the size and decreased tumbling motion of the complex of peptide-antibodies. The measurements were performed to detect hcTnI and hcTnT either individually or simultaneously in a homogenous buffer solution and in the solutions containing human plasma. Our results showed that when fluorescence emission was monitored at a single wavelength selected by a monochromator the assay at all experimental conditions had excellent linear response to the target proteins within the concentration range of 0.5-40 nM. The detection limit is 0.5 nM for both hcTnI and hcTnT in the presence of human plasma. However, when fluorescence emission was monitored using a cutoff filter, the linear response of the assay to the target proteins is within 15-500 pM. The detection limit is 15 pM which is close to the recommended 99th percentile cutoff point for concentrations of hcTnI and hcTnT tests to discriminate healthy and diseased conditions. Homogenous nature, rapid response time, and easy implementation of our assay design make it a useful tool for disease biomarker and protein sensing.

{1-[(2-Oxidonaphthalen-1-yl)methylidene]thiosemicarbazidato-κN,O,S}diphenyl-tin(IV).

The asymmetric unit of the title compound, [Sn(C(6)H(5))(2)(C(12)H(9)N(3)OS)], contains two independent mol-ecules with almost identical configurations. In each mol-ecule, the Sn(IV) atom is coordinated by O, N and S atoms from a (2-oxido-1-naph-thaldehyde)-thio-semicarbazonato ligand and two C atoms from phenyl rings in a distorted trigonal-bipyramidal geometry. Weak inter-molecular N-H⋯O and N-H⋯S hydrogen bonds link four mol-ecules into a centrosymmetric tetra-mer. The crystal packing exhibits short inter-molecular S⋯S contacts of 3.335 (3) Å.

Development of a rapid resolution liquid chromatographic method for simultaneous analysis of four alkaloids in Rhizoma coptidis under different cultivation conditions.

A sensitive and specific method using rapid resolution liquid chromatography coupled with UV-Vis detection was developed for fingerprint analysis of Rhizoma coptidis and simultaneous determination of 4 alkaloids: jatrorrhizine, coptisine, palmatine, and berberine. Samples of R. coptidis grown under different cultivation conditions and from different habitats were analyzed. The analysis was performed using a reversed-phase octylsilyl (C8) column and gradient elution. The mobile phase consisted of acetonitrile and 20 mmol/L KH2PO4. Each analysis was completed within 3.5 min. The method showed good linearity within test ranges of 4.75-47.50 microg/mL for jatrorrhizine, 20.60-164.80 microg/mL for coptisine, 18.07-180.73 microg/mL for palmatine, and 89.70-717.57 microg/mL for berberine. The method showed good precision, repeatability, and stability for quantification of the 4 alkaloids. The lower limit of detection was 0.19 ng for jatrorrhizine, 0.21 ng for coptisine, 0.15 ng for palmatine, and 0.14 ng for berberine. The lower limit of quantification was 0.57 ng for jatrorrhizine, 0.82 ng for coptisine, 0.55 ng for palmatine, and 0.27 ng for berberine. The overall recovery ranged from 96.30 to 104.10% for the 4 alkaloids. The method is accurate, rapid, and convenient, and it is suitable for routine quality control of R. coptidis.

A rapid resolution liquid chromatographic method for fingerprint analysis of raw and processed caowu (Aconitum kusnezoffii).

A sensitive and reliable rapid resolution liquid chromatographic (RRLC) method coupled with diode array detection has been developed for the fingerprint analysis of raw and processed caowu (Aconitum kusnezoffii). The RRLC fingerprints were established with a Zorbax Extend C18 analytical column (4.6 x 50 mm, 1.8 microm) and gradient elution. Analysis run time was <10 min. The method displayed good precision, stability, and repeatability in fingerprint analysis. Characteristic RRLC fingerprints of caowu were generated and used to assess the consistency and differences in the products. Raw and processed caowu from different sources were analyzed under the developed RRLC conditions, yielding contrasting RRLC fingerprints. Comparison of the RRLC fingerprints of processed and raw caowu indicated that the major constituents changed during processing. Meanwhile, a peak area ratio analysis method was applied to assess their chromatographic fingerprints. In characterizing the constituents of caowu, 11 major chromatographic peaks were identified by mass spectrometry and compared with reference standards and reference data. In summary, RRLC fingerprinting is a rapid and useful way to evaluate the quality of raw and processed caowu.

catena-Poly[[triphenyl-tin(IV)]-µ-2-(2-picolinoylhydrazono)propanoato-κO:O].

In the title polymeric coordination compound, [Sn(C(6)H(5))(3)(C(9)H(8)N(3)O(3))](n), the Sn(IV) atom is in a distorted trigonal-bipyramidal geometry, being coordinated by two O atoms from two 2-(2-picolinoylhydrazono)propanoate ligands and three phenyl groups. Adjacent Sn atoms are bridged by the 2-(2-picolinoylhydrazono)propanoate ligand through one carbonyl O atom and one carboxyl-ate O atom, forming a chain structure propagating parallel to [100]. An intra-molecular N-H⋯O hydrogen bond is observed.

2,2'-[Pyridine-2,6-diylbis(carbonyl-hydrazono)]dipropanoic acid N,N-dimethyl-formamide disolvate.

The complete molecule of the title compound, C(13)H(13)N(5)O(6)·2C(3)H(7)NO, is generated by crystallographic twofold rotation with an N and a C atom lying on the axis. The structure is stabilized by inter-molecular O-H⋯O hydrogen bonds.

[4-Chloro-N'-(3-meth-oxy-2-oxidobenzyl-idene)benzohydrazidato]dimethyl-tin(IV).

In the title mol-ecule, [Sn(CH(3))(2)(C(15)H(11)ClN(2)O(3))], the two benzene rings form a dihedral angle of 6.37 (2)°. The Sn atom is coordinated by one N [Sn-N = 2.187 (3) Å], two O [Sn-O = 2.123 (3) and 2.174 (3) Å] and two C [Sn-C = 2.096 (4) and 2.101 (4) Å] atoms in a distorted trigonal-bipyramidal geometry. The crystal packing exhibits weak inter-molecular C-H⋯O hydrogen bonds, which link the mol-ecules into centrosymmetric dimers with an Sn⋯Sn separation of 4.330 (6) Å, and π-π inter-actions [centroid-centroid distance of 3.690 (5) Šbetween the benzene rings of neighbouring mol-ecules].