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AbstractThis article mainly considers the parameter estimation problem for the Gaussian Vasicek process defined as dXt=(α−βXt)dt+σtdGt, t≥0 with unknown parameters α∈ℝ and β < 0, where Gt is a continuous centered Gaussian process. The volatility parameter σt is allowed to vary with time t. Based on the time-continuous observations and least squares method, the Least squares estimations of drift parameters for the non ergodic Gaussian Vasicek model with time-varying volatility are obtained. The strong consistency and asymptotic distributions of proposed estimations are verified under some sufficient conditions. Finally, we verify that the results are still valid under different forms of the volatility function when Gt is fractional Brownian motion, sub-fractional Brownian motion, and bi-fractional Brownian motion, respectively. In some sense, our results extend the findings of El Machkouri, Es-Sebaiy, and Ouknine (2016) and Es-Sebaiy and Sebaiy (2021). [ABSTRACT FROM AUTHOR]

• A new method for isolating novel flavonoid glycosides was developed. • Flavonoids were separated on polar-modified RP and zwitterionic HILIC modes. • Nine flavonoid glycosides were obtained, including seven novel compounds. • Their bioactivities were evaluated via label-free cell phenotypic assays. • Four novel flavonoid glycosides displayed agonistic activities at GPR35. Flavonoid glycosides are widespread in herbs and often used as medicines and nutraceuticals because of good bioactivities and low toxicities. However, due to their structural complexity and diversity, isolation of flavonoid glycosides and evaluation of their bioactivities are still highly challenging. To solve this problem, a new method for separation and preparation of novel flavonoid glycosides from Lobelia chinensis Lour (L. chinensis) was developed. To avoid the interference of non-flavonoids, a solid phase extraction method was used to selectively enrich the flavonoids from the total extract. Based on hydrophilic and hydrophobic properties of the flavonoid chemical structure consisting of sugar residue and diphenylpropane (C 6 C 3 C 6) skeleton, a structure-guided method development strategy was employed to design a 2D-HILIC × RPLC system in the first time. After optimization of chromatographic conditions, high selectivity and symmetric peaks of flavonoids were obtained on a zwitterionic Click XIon column and a polar-modified Atlantis T3 column. Based on these two columns, a 2 D-HILIC × RPLC system was constructed and successfully enlarged from the analytical level to the preparative level. In the first dimension, 20 fractions were obtained with good peak shapes at high sample loading. In the second-dimensional preparation, nine compounds were isolated and identified. Seven of them were novel flavonoid glycosides, lobelitin A-G, and two other known compounds were linatin and diosmin, respectively. Their target activities were evaluated via label-free cell phenotypic assays. Four novel flavonoid glycosides lobelitin A-D were found to have agonistic activities at G protein-coupled receptor 35 (GPR35). These results demonstrated that this method was effective to orthogonally separate flavonoids at the preparative level, especially for novel active flavonoid glycosides. The discovery of flavonoid glycosides with novel agonistic activity on GPR35 also sheds light on the mechanisms of action of L. chinensis relevant to its clinical application. [ABSTRACT FROM AUTHOR]

Using first principles calculations based on spin-polarized density functional theory, the magnetic behavior of Mn-doped GaN (1[formula]00) film is studied. The doping Mn atoms have an attractive pair interaction. Our results give the ground state with antiferromagnetic coupling for Mn-doped GaN (1[formula]00) film when the nearest neighbor Ga atoms on the surface layer are replaced by Mn atoms, which is contrary to the ferromagnetic coupling when Mn is doped in the bulk GaN. However, in-plane tension and hole doping can switch the magnetic ordering from antiferromagnetism to ferromagnetism, which is important for application in semiconductor spintronics. [ABSTRACT FROM AUTHOR]

Abstract This paper is dedicated to the study of continuous-time mean–variance optimal portfolio selection problem with non-linear wealth equations under non-extensive statistical mechanics for the time-varying stochastic differential equation model. Firstly, we allow the returns and variance of risky assets are time-varying functions, which can fit the financial data better. Secondly, we consider an investor with the non-linear wealth equation. In fact, the wealth equations are not linear in many cases. The investor has to pay some taxes, which leads to a non-linear wealth equation. Moreover, since the return of the stocks price may be affected by a large investors portfolio selection, the wealth equation is non-linear in this case. Thirdly, the non-linear wealth equation driven by Tsallis distribution is constructed under non-extensive statistical mechanics, which can capture the characteristics of fat tails and aiguilles of the risky asset's return. The viscosity solution of the HJB equation for the portfolio problem is proposed by the optimal stochastic control theory and Lagrange multiplier method. Finally, the efficient portfolio strategy and efficient frontier under non-extensive statistical mechanics are obtained. Furthermore, numerical analysis and real data study are discussed to show our results. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A multi-component bioactivity and structure-guided method was used to screen drugs. • SSD was identified as the most effective anti-TNBC compound from Radix Bupleuri. • SSD induced TNBC cell apoptosis via inhibiting Wnt/β-catenin signaling. • SSD did not act on EGFR and NTSR1targets. Abstract Background Triple-negative breast cancer (TNBC) is one of the most aggressive and poor prognosis breast cancers. Currently, chemotherapy with conventional cytotoxic agents is the only available option to treat TNBC. Hence, we identified new therapeutic agents against TNBC from traditional Chinese medicine Radix Bupleuri and unveiled the molecule mechanism of anti-TNBC effects. Methods Multi-component bioactivity and structure-guided methods were used to identify the most effective anti-TNBC compound Saikosaponin D (SSD) from Radix Bupleuri. Cell viability and apoptosis assays were employed to demonstrate the effect of SSD on the proliferation and apoptosis of TNBC cells. Dynamic mass redistribution assay, TopFlash assay, western blotting, and special agonist were applied to dissect the potential molecular mechanisms of SSD. Results We screened twenty fractions in Radix Bupleuri and identified SSD as the most effective component to inhibit the proliferation of TNBC cells. Investigating the interaction of SSD with the frequently overexpressed targets in TNBC led to the identification that it markedly suppressed Wnt/β-catenin signaling, but did not act on epidermal growth factor receptor and neurotensin receptor-1. Moreover, we demonstrated that SSD significantly repressed β-catenin and its downstream target genes, resulting in TNBC cell apoptosis. Specifically, docking of SSD to the crystal structure of β-catenin suggested that SSD interacted with β-catenin via hydrogen bonds and hydrophobic interaction. Conclusion We identified the most effective component SSD from Radix Bupleuri in inhibiting the proliferation of TNBC cells by targeting β-catenin signaling. Given the important role of Wnt/β-catenin signaling in breast cancer, SSD may present an opportunity to discover new therapeutics for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Highlights • The combining of label-free cell phenotypic assay with 2DLC. • D1 activity location and D2 activity tracking obtained three β 2 -AR agonists. • The first time to discover diarylheptanoids with the β 2 -AR agonistic activity. • Providing possible explanation for the anti-asthmatic effect of C. zedoaria. Abstract Traditional Chinese Medicines (TCMs) have been widely used in clinical practice, and provided a rich source for discovering new drug leads. However, efficient identification of active molecules responsible for the therapeutic effects of complex TCMs is still highly challenging. Here, we combined label-free cell phenotypic assay with two dimensional liquid chromatography (2DLC) to identify potential β 2 -adrenoceptor (β 2 -AR) agonists related to anti-asthmatic effect of Curcuma zedoaria Rosc (C.zedoaria), a commonly used TCM. The ethyl acetate extract of C.zedoaria was first fractionated into 26 fractions. Label-free cell phenotypic profiling was then used to locate the active sites. Orthogonal second-dimensional (D2) separation was performed on two fractions displaying agonistic effect at the β 2 -AR, combined with screening of the D2 fractions to track the activity. Finally, this approach led to the isolation of three known diarylheptanoids, among which diarylheptanoid b exhibited the most potent agonistic activity with an EC 50 value of 5.93 μM. This result was further demonstrated through the chemical synthesis of diarylheptanoid b. It is the first time to discover that diarylheptanoids could activate the β 2 -AR, which may be responsible for the anti-asthmatic effect of C.zedoaria observed traditionally and in clinical application. This study also demonstrates the potential of this integrated strategy for identifying active ingredients and determining the basis of therapeutic materials in complex TCMs. [ABSTRACT FROM AUTHOR]

GPR35, a class A G-protein-coupled receptor, is considered an orphan receptor; the endogenous ligand and precise physiological function of GPR35 remain obscure. GPR35 is expressed relatively highly in the gastrointestinal tract and immune cells. It plays a role in colorectal diseases like inflammatory bowel diseases (IBDs) and colon cancer. More recently, the development of GPR35 targeting anti-IBD drugs is in solid request. Nevertheless, the development process is in stagnation due to the lack of a highly potent GPR35 agonist that is also active comparably in both human and mouse orthologs. Therefore, we proposed to find compounds for GPR35 agonist development, especially for the human ortholog of GPR35. As an efficient way to pick up a safe and effective GPR35 targeting anti-IBD drug, we screened Food and Drug Administration (FDA)-approved 1850 drugs using a two-step DMR assay. Interestingly, we found aminosalicylates, first-line medicine for IBDs whose precise target remains unknown, exhibited activity on both human and mouse GPR35. Among these, pro-drug olsalazine showed the most potency on GPR35 agonism, inducing ERK phosphorylation and β-arrestin2 translocation. In dextran sodium sulfate (DSS)-induced colitis, the protective effect on disease progression and inhibitory effect on TNFα mRNA expression, NF-κB and JAK-STAT3 pathway of olsalazine are compromised in GPR35 knock-out mice. The present study identified a target for first-line medicine aminosalicylates, highlighted that uncleaved pro-drug olsalazine is effective, and provided a new concept for the design of aminosalicylic GPR35 targeting anti-IBD drug. [ABSTRACT FROM AUTHOR]

[Display omitted] • Inspired by two active natural products, a series of 2-(2,2-diarylethyl)-cyclamine derivatives were designed and synthesized for screening M3 mAChR antagonists. • Compound 5b-C1 exhibited the highest M3 antagonistic activity with an IC 50 value of 3 nM, and the most of compound 6 displayed inactivity against histamine H1 receptor closely related to M3. • In in vitro and in vivo evaluations of tracheo-relaxation function, some compounds even showed good safety and comparable activity to tiotropium bromide, a known blockbuster drug for COPD. Muscarine acetylcholine receptors (mAChRs) regulate a variety of central and peripheral physiological functions and emerge as important therapeutic targets for a number of diseases including chronic obstructive pulmonary disease (COPD). Inspired by two active natural products, we designed and synthesized a series of 2-(2,2-diarylethyl)-cyclamine derivatives for screening M3 mAChR antagonists. On this skeleton, the structural units including N heterocycle, aryl groups and its substituents on aryl were examined and resulted in a clear structure–activity relationships on the M3 mAChR. In general, these 2-(2,2-diarylethyl)-cyclamine derivatives exhibited good to excellent M3 antagonistic potency and receptor selectivity. The most active 5b-C1 had an IC 50 value of 3 nM and the most of compound 6 displayed inactivity against histamine H1 receptor closely related to M3. In in vitro and in vivo evaluations of tracheo-relaxation function, some compounds even showed comparable activity to tiotropium bromide, a known blockbuster drug for COPD. Such excellent properties made these novel compounds potential candidates for COPD drug development. [ABSTRACT FROM AUTHOR]

Nowadays more and more hydrophilic interaction liquid chromatography (HILIC) columns with diverse functional groups have become commercially available, which pose a challenge to select an appropriate one. However, there is no universal model to provide guidance for selecting HILIC columns. To handle this problem, a retention model named “hydrophilic-subtraction model” was developed to characterize and compare HILIC columns. The hydrophilic-subtraction model, which was designed based on the widely recognized HILIC retention mechanisms including hydrophilic partitioning, hydrogen-bonding and electrostatic interactions, was established by the retention of 41 solutes with various properties on 8 representative HILIC columns. High correlation coefficients ( R 2 ≥ 0.990) and small standard deviations ( SD ≤ 0.041) indicated that this model correlated effectively the retention with solute descriptors and column parameters. To evaluate reliability of the model, the model was further applied to characterize 15 additional HILIC columns using 41 solutes. The results of multiple linear regression confirmed the significance of the model. The regression coefficients of the model were used to investigate retention mechanisms occurring in different chromatographic systems. Based on these regression coefficients, selectivities of HILIC stationary phases were exhibited intuitively by an angle graph and a spider diagram, which could be used as guidance for researchers to select appropriate columns for HILIC separation. Additionally, a rapid and convenient procedure was proposed for characterizing HILIC columns. [ABSTRACT FROM AUTHOR]

Characterization of reverse-phase column selectivity is helpful for chromatographers to select an optimal column. A novel method, based on linear solvation energy relationships (LSERs) combined with fundamental retention equations, was developed to characterize and compare reversed-phase column selectivity. The retention times of 25 elaborately selected solutes on 12 reversed-phase columns were determined in three linear gradient elutions. Using these retention times, fundamental retention equations were acquired by a complex sample analysis software system (CSASS). When 0%, 10%, 20%, 30%, 40% and 50% acetonitrile were introduced into the fundamental retention equations, the corresponding retention factors were predicted and used to obtain LSER equations by multiple linear regression. In the gradient elution, the retention times of solutes could be accurately determined and the excessively long or short analysis time could be avoided. As the retention factor (ln k w ) at a hypothetical 0% organic modifier closely reflected properties of columns, coefficients of LSERs equations obtained based on ln k w were employed to discuss the properties of different stationary phases. An angle and a spider diagram based on solvation energy vectors were used to compare selectivity differences between stationary phases, which provided a visual means for users to select appropriate columns with orthogonal or similar selectivity. These results of column selectivities were compared with those obtained by geometric orthogonality approach, and a consistent result was acquired. Finally, Click TE-CD and XCharge C18PN with highest difference in column selectivity were applied to the separation of Psoralea corylifolia extraction. [ABSTRACT FROM AUTHOR]

Ionic liquids are potential media/solvents for asymmetric synthesis when combined with chiral catalysts, while most reported catalysts are homogenous, making them difficult to separate from the reaction systems. Herein, chiral porous poly(ionic liquid)s (CPPILs) containing chiral salen Mn(III) complex have been successfully synthesized through a simple and one-pot route involving simultaneously occurred Friedel-Crafts alkylation and quaternization. These CPPILs possess large specific surface area, plentiful micro/meso-porosity, and abundant ionic active sites. Consequently, CPPILs can serve as highly efficient heterogeneous catalysts for asymmetric epoxidation of styrene. Excellent catalytic performance with yield of epoxides and enantiomeric excess value comparable with or even higher than that of the homogeneous system was achieved. The high catalytic activity can be further expanded to various substrates of unfunctionalized olefins. These catalysts are stable and could be recycled at least five times without significant loss of reactivity and enantioselectivity. [Display omitted] • Chiral porous poly(ionic liquid)s were synthesized by one-step Friedel-Crafts reaction combined with quaternization. • The porous structure and chemical composition of CPPILs can be easily adjusted by the molar ratios of reactants. • CPPILs could catalyze asymmetric epoxidation of olefins with performance comparable with the homogeneous catalyst. • TOF values of CPPILs are higher than most reported chiral salen Mn(III) complex-based catalysts. [ABSTRACT FROM AUTHOR]

Highlights: [•] A novel method was firstly developed for the extraction and cleanup of triptorelin from plasma. [•] The performance of the new sorbent Click XIon was excellent and satisfactory in terms of the matrix effect, recovery and overall process efficiency at the low, middle and high concentration levels of triptorelin. [•] The method was validated and successfully applied to determine triptorelin in rat plasma. [Copyright &y& Elsevier]

In the drug discovery field, the binding affinities and binding kinetics of drug candidates are very important. Angiotensin II type 1 (AT1) receptor antagonists, e.g., candesartan, telmisartan, irbesartan, losartan and valsartan, show high affinities and long-lasting bindings to the receptor, making them preferred medications for hypertension treatment. However, the molecular binding properties of AT1 receptor antagonists are controversial. In this work, we established a profile to study the phenotypic properties of AT1 receptor antagonists with label-free dynamic mass redistribution (DMR) assays in native human cells. With noninvasive features, DMR assay were conducted in multiple formats. Eleven antagonists were systematically evaluated with angiotensin II as an agonist probe in the Hep G2 cell line, which endogenously expresses the AT1 receptor. The IC 50 values to the AT1 receptor of individual antagonist varied with different incubation times. The antagonists showed competitive behavior with angiotensin II. Schild analysis was used to analyze the competitive behavior of the antagonist. All of the antagonist showed long-lasting possession of the AT1 receptor, except telmisartan. The systematic evaluation of the antagonists implied that 11 antagonists showed high binding affinity but distinct binding modes to AT1 receptor. This study demonstrated that the DMR assay has great potential for determining the pharmacological parameters of ligands. This work may serve as guidance for other receptor and ligand assays. • The first time to systematically characterize AT1 receptor antagonists. • The first time to combine label-free DMR technology with AT1 receptor and antagonists. • AT1 receptor models were established on endogenous cell lines. • Multiple DMR assay formats were conducted to characterize AT1 receptor antagonists. • The DMR data analysis methods are improved with the help of classical analytical methods. [ABSTRACT FROM AUTHOR]

In order to develop anion exchange membranes (AEMs) with high ionic conductivity, low swelling ratio (SR) and long-term alkaline stability, a series of crosslinked polybenzimidazole-based AEMs (FPBI-QPVC x) were prepared. We herein demonstrated that the integration of a partially fluorinated polybenzimidazole and quaternized poly(vinylbenzyl chloride) benefits the fabrication of the AEMs with well-defined hydrophilic/hydrophobic phase-segregated structure, leading to a relative high hydroxide conductivity of 91.7 mS cm−1 at 80 °C for FPBI-QPVC 2.5. The existence of a crosslinking structure endowed the as-prepared AEMs with relatively low water uptake and SR. Besides, the FPBI-QPVC x AEMs also have robust mechanical properties, high thermal decomposition temperature and good alkaline stability. Only 10.7% of conductivity loss was observed after soaking the ether-bond-free AEMs into 1 M a.q. KOH at 80 °C for 480 h. A maximum power density of 197.5 mW cm−2 was determined by a single cell using FPBI-QPVC 2.5 AEM. Image 1 • Novel crosslinked polybenzimidazole-based AEMs were prepared. • The AEMs exhibited well-defined micro-phase separation structures. • The crosslinking structure constrained the water swelling behavior of the AEMs. • The ether-bond-free backbone improved the alkaline stability of the AEMs. • The highest conductivity of 91.7 mS cm−1 was obtained. [ABSTRACT FROM AUTHOR]

This paper is dedicated to the study of the geometric average Asian call option pricing under non-extensive statistical mechanics for a time-varying coefficient diffusion model. We employed the non-extensive Tsallis entropy distribution, which can describe the leptokurtosis and fat-tail characteristics of returns, to model the motion of the underlying asset price. Considering that economic variables change over time, we allowed the drift and diffusion terms in our model to be time-varying functions. We used the I t o ^ formula, Feynman–Kac formula, and P a d e ´ ansatz to obtain a closed-form solution of geometric average Asian option pricing with a paying dividend yield for a time-varying model. Moreover, the simulation study shows that the results obtained by our method fit the simulation data better than that of Zhao et al. From the analysis of real data, we identify the best value for q which can fit the real stock data, and the result shows that investors underestimate the risk using the Black–Scholes model compared to our model. [ABSTRACT FROM AUTHOR]

CC chemokine receptor 3 (CCR3) plays important roles in atopic dermatitis (AD) and other related allergic diseases. Activation of CCR3 receptor signaling pathways regulates the recruitment of eosinophils to related tissues, releasing inflammatory mediators and causing inflammatory responses. However, none of the known CCR3 antagonists exhibit promising efficacy in clinical trials. In this work, we sought new natural CCR3 antagonists for drug development. To construct a high-throughput screening model, we established a stably transfected CHO-K1-Gα15-CCR3 cell line, and receptor expression was demonstrated by real-time quantitative PCR , confocal detection and flow cytometry analysis. Then, we applied a label-free cell phenotyping technique to profile and deconvolute CCR3 target pathways in CHO-K1-Gα15-CCR3 cells and found that activation of CCR3 triggered the Gq-PLC-Ca2+ and MAPK-P38-ERK pathways. By in vitro and in silico experiments, we discovered a novel CCR3 antagonist emodin, with an IC 50 value of 27.28 ± 1.71 μM out of 266 compounds that were identified in 15 traditional Chinese medicines used in the clinical treatment of skin diseases. Molecular docking graphically presented the binding mode of emodin on CCR3. This work reports a new approach for CCR3 antagonist screening and pathway detection and identifies a new antagonist that would benefit future drug development. • Our study provided a different screening technique for active CCR3 compounds than traditional ones. • Activation of CCR3 receptors led to activation of Gq-PLC-Ca2+ and MAPK-P38-ERK pathways. • Emodin had obvious inhibitory effect on CCR3. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicines have been widely used to prevent and cure diseases for thousands of years. For the purpose of better understanding the extremely complicated traditional Chinese medicines, powerful separation techniques are essential. Two‐dimensional liquid chromatography has been proven to be more powerful for the separation of complex traditional Chinese medicines due to its enhanced peak capacity and resolution compared with one‐dimensional liquid chromatography. Enormous efforts have been made on the coupling of independent separation mechanisms to improve the resolving power for complex traditional Chinese medicine samples, including the development and introduction of novel stationary phases. This review aims to give an overview on the applications of two‐dimensional liquid chromatography in traditional Chinese medicine research since 2008, including comprehensive two‐dimensional liquid chromatography, heart‐cutting two‐dimensional liquid chromatography both in on‐line, and off‐line mode. Different couplings of separation modes were respectively discussed based on specific studies, with emphasis on the applications of novel stationary phases in the two‐dimensional liquid chromatography. [ABSTRACT FROM AUTHOR]

Anion exchange membrane (AEM) fuel cells have received significant attention due to their low fuel permeability and the use of non-platinum catalysts. However, the development of AEMs with robust chemical stability and high conductivity is still a great challenge. Herein, we prepare a new type of partially fluorinated backbone bearing pendent N-spirocyclic quaternary ammonium (QA) cations via a facile Williamson reaction, which displays great potential for fuel cells. The integration of the two substructures (a fluorinated moiety into a polymer backbone and a pendent cation structure) is beneficial for the fabrication of a well-defined micro-phase separation structure, thereby facilitating the construction of a highly-efficient ion transporting pathway. Correspondingly, the resulting AEM (PAENQA-1.0), despite its a relatively low ionic exchange capacity (0.93 meq g−1) demonstrates a conductivity of 63.1 mS cm−1 (80 °C). Meanwhile, the constrained ring conformation of N-spirocyclic QA results in improved stability of the AEMs. Image 1 • Novel side-chain-type AEMs bearing N-spirocyclic cations were prepared. • The synthesized procedure was performed at mild condition. • The AEM demonstrated well-developed micro-phase separation. • The AEM exhibited high conductivity at low water uptake. • High retention rate of conductivity was achieved after alkaline treatment. [ABSTRACT FROM AUTHOR]

Polar compounds are abundant in the water decoction of Traditional Chinese Medicines (TCMs) and possess important biological activities. However, purifying these compounds has faced great difficulties largely due to poor retention and insufficient selectivity. To solve this problem, an offline orthogonal 2-D RPLC coupled with hydrophilic interaction chromatography (HILIC) method was developed to achieve purification of polar compounds from Caulis Polygoni Multiflori. A polar-copolymerized XAqua C18 column and a zwitterionic Click XIon column exhibited satisfactory retention and separation for polar compounds. Therefore, they were adopted to construct the offline 2-D LC system. Furthermore, the method presented a high orthogonality, which was calculated to be 72%. The XAqua C18 column was used in the first dimension to fractionate the 5.1 g polar fraction with a recovery of 85% within 10 h. In the second dimension, three representative fractions were purified using the Click XIon column. Finally, three compounds with purity higher than 95% were identified for the first time from this plant. This offline 2-D RPLC/HILIC method was shown to be an effective approach to purifying polar compounds from Caulis Polygoni Multiflori. • An offline 2-D RPLC/HILIC method was developed to purify polar compounds. • A polar-copolymerized XAqua C18 and zwitterionic Click XIon column were selected and combined. • The orthogonality was 72% in the separation of Caulis Polygoni Multiflori. • Three polar compounds with high purity were first purified from this plant. [ABSTRACT FROM AUTHOR]

Ziziphi spinosae semen has been widely used to treat insomnia and anxiety. To profile its chemical components, an online comprehensive two‐dimensional liquid chromatography‐mass spectrometry was developed. In this two‐dimensional liquid chromatography system, a novel phthalic anhydride‐bonded stationary phase column was combined with a C18 column. As a result, this new stationary phase exhibited remarkable differences in separation selectivity from C18, achieving a good orthogonality of 83.3%. Moreover, this new stationary phase with weaker hydrophobicity than C18 realized solvent compatibility in the online configuration. Coupled with tandem MS, 154 compounds were identified, including 51 unreported compounds. Compared with one‐dimensional liquid chromatography‐mass spectrometry, this online two‐dimensional liquid chromatography‐mass spectrometry system exhibited a much higher resolving power in isomer separation. This work provided an effective separation and characterization method for the material basis of Ziziphi spinosae semen. This strategy provides ideas for the material basis research of other traditional Chinese medicines. [ABSTRACT FROM AUTHOR]

In this paper we consider pricing problems of the geometric average Asian options under a non-Gaussian model, in which the underlying stock price is driven by a process based on non-extensive statistical mechanics. The model can describe the peak and fat tail characteristics of returns. Thus, the description of underlying asset price and the pricing of options are more accurate. Moreover, using the martingale method, we obtain closed form solutions for geometric average Asian options. Furthermore, the numerical analysis shows that the model can avoid underestimating risks relative to the Black-Scholes model. [ABSTRACT FROM AUTHOR]

Curcuma kwangsiensis, one species of Curcumae zedoaria Ros. c, is a commonly used traditional Chinese medicine (TCM) for treating cardiovascular disease, cancer, asthma and inflammation. Polar compounds are abundant in water decoction, which would be responsible for critical pharmacological effects. However, current research on polar compounds in Curcumae zedoaria Ros. c remains scarce. In this study, the polar fraction from Curcuma kwangsiensis was firstly profiled on G protein-coupled receptor 109A (GPR109A), β2-adrenergic receptor (β2-AR), neurotensin receptor (NTSR), muscarinic-3 acetylcholine receptor (M3) and G protein-coupled receptor 35 (GPR35), which were involved in its clinical indications and exhibited excellent β2-AR and GPR109A receptor activities. Then, an offline two-dimensional reversed-phase liquid chromatography (RPLC) coupled with the hydrophilic interaction chromatography (HILIC) method was developed to separate polar compounds. By the combination of a polar-copolymerized XAqua C18 column and an amide-bonded XAmide column, an orthogonality of 47.6% was achieved. As a result of coupling with the mass spectrometry (MS), a four-dimensional data plot was presented in which 373 mass peaks were detected and 22 polar compounds tentatively identified, including the GPR109A agonist niacin. Finally, molecular docking of these 22 identified compounds to β2-AR, M3, GPR35 and GPR109A receptors was performed to predict potential active ingredients, and compound 9 was predicted to have a similar interaction to the β2-AR partial agonist salmeterol. These results were supplementary to the material basis of Curcuma kwangsiensis and facilitated the bioactivity research of polar compounds. The integration of RPLC×HILIC-MS and molecular docking can be a powerful tool for characterizing and predicting polar active components in TCM. [ABSTRACT FROM AUTHOR]

ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism and its aberrantly high expression is closely associated with various cancers, hyperlipemia and atherosclerotic cardiovascular diseases. Prospects of ACLY inhibitors as treatments of these diseases are excellent. To date, flavonoids have not been extensively reported as ACLY inhibitors. In our study, 138 flavonoids were screened and 21 of them were subjected to concentration–response curves. A remarkable structure–activity relationship (SAR) trend was found: ortho-dihydroxyphenyl and a conjugated system maintained by a pyrone ring were critical for inhibitory activity. Among these flavonoids, herbacetin had a typical structure and showed a non–aggregated state in solution and a high inhibition potency (IC50 = 0.50 ± 0.08 μM), and therefore was selected as a representative for the ligand–protein interaction study. In thermal shift assays, herbacetin improved the thermal stability of ACLY, suggesting a direct interaction with ACLY. Kinetic studies determined that herbacetin was a noncompetitive inhibitor of ACLY, as illustrated by molecular docking and dynamics simulation. Together, this work demonstrated flavonoids as novel and potent ACLY inhibitors with a remarkable SAR trend, which may help design high–potency ACLY inhibitors. In–depth studies of herbacetin deepened our understanding of the interactions between flavonoids and ACLY. [ABSTRACT FROM AUTHOR]

Neurotensin (NT), an endogenous peptide found in the central nervous system and in peripheral tissues, contributes to the pathophysiology of neurodegenerative and psychiatric diseases, cancer, inflammation, and immunomodulatory disease. NT exerts its physiological effects predominantly through its cognate high-affinity neurotensin receptor-1 (NTS1). NTS1 emerges as a druggable target; however, there are limited numbers of NTS1 active compounds reported to date. Here we reported a label-free cell phenotypic profiling model for screening NTS1 ligands and differentiating their biased agonism. Resonant waveguide grating enabled dynamic mass redistribution (DMR) assay was first optimized against cell confluency and then used to characterize the endogenous NTS1 in HT-29 cell using known agonists and antagonists. Pathway modulators were also used to deconvolute the signaling pathways of endogenous NTS1. Results showed that the NTS1 DMR assay is robust for screening and can differentiate biased agonism; and the activation of NTS1 in HT-29 triggers multiple pathways including G q signaling and epidermal growth factor receptor transactivation. This study highlighted the power of label-free DMR assay to characterize receptor signaling and pharmacology of distinct classes of ligands for NTS1, G protein-coupled receptors in general. [ABSTRACT FROM AUTHOR]

Prostatitis and benign prostatic hyperplasia (BPH) are inflammations of the prostate gland, which surrounds the urethra in males. Jinqiancao granules are a traditional Chinese medicine used to treat kidney stones and this medicine consists of four herbs: Desmodium styracifolium (Osbeck) Merr., Pyrrosia calvata (Baker) Ching, Plantago asiatica L. and stigma of Zea mays L. We hypothesized that Jinqiancao granules could be a potential therapy for prostatitis and BPH, and this work aimed to elucidate active compounds in Jinqiancao granules and their target mechanisms for the potential treatment of the two diseases. Jinqiancao granules were commercially available and purchased. Database-driven data mining and networking were utilized to establish a general correlation between Jinqiancao granules and the two diseases above. Ultra-performance liquid chromatography-mass spectrometry was used for compound separation and characterization. The characterized compounds were evaluated on four G-protein coupled receptors (GPCRs: GPR35, muscarinic acetylcholine receptor M3, alpha-1A adrenergic receptor α1A and cannabinoid receptor CB2). A dynamic mass redistribution technique was applied to evaluate compounds on four GPCRs. Nitric acid (NO) inhibition was tested on the macrophage cell line RAW264.7. Molecular docking was conducted on GPR35-active compounds and GPR35 crystal structure. Statistical analysis using GEO datasets was conducted. Seventy compounds were isolated and twelve showed GPCR activity. Three compounds showed potent GPR35 agonistic activity (EC 50 < 10 μM) and the GPR35 agonism action of PAL-21 (Scutellarein) was reported for the first time. Docking results revealed that the GPR35-targeting compounds interacted at the key residues for the agonist-initiated activation of GPR35. Five compounds showed weak antagonistic activity on M3, which was confirmed to be a disease target by statistical analysis. Seventeen compounds showed NO inhibitory activity. Several compounds showed multi-target properties. An experiment-based network reflected a pharmacological relationship between Jinqiancao granules and the two diseases. This study identified active compounds in Jinqiancao granules that have synergistic mechanisms, contributing to anti-inflammatory effects. The findings provide scientific evidence for the potential use of Jinqiancao granules as a treatment for prostatitis and BPH. [Display omitted] • Jinqiancao granules could be a potential treatment of prostatitis and BPH. • Compounds showed activity on four disease-related GPCRs and NO inhibition. • PAL-21 (Scutellarein) was a GPR35 agonist with an EC50 of 1.50 ± 0.18 μM. [ABSTRACT FROM AUTHOR]

[Display omitted] • An H4R target pathway model for high-throughput screening tests was developed. • Cryptotanshinone was a new H4R non-competitive antagonist. • Cryptotanshinone interacts with H4R at a novel allosteric binding site. Histamine 4 receptor (H4R), the most recently identified subtype of histamine receptor, primarily induces inflammatory reactions upon activation. Several H4R antagonists have been developed for the treatment of inflammatory bowel disease (IBD) and atopic dermatitis (AD), but their use has been limited by adverse side effects, such as a short half-life and toxicity. Natural products, as an important source of anti-inflammatory agents, offer minimal side effects and reduced toxicity. This work aimed to identify novel H4R antagonists from natural products. An H4R target-pathway model deconvoluted downstream G i and MAPK signaling pathways was established utilizing cellular label-free integrative pharmacology (CLIP), on which 148 natural products were screened. Cryptotanshinone was identified as selective H4R antagonist, with an IC 50 value of 11.68 ± 1.30 μM, which was verified with Fluorescence Imaging Plate Reader (FLIPR) and Cellular Thermal Shift (CTS) assays. The kinetic binding profile revealed the noncompetitive antagonistic property of cryptotanshinone. Two allosteric binding sites of H4R were predicted using SiteMap, Fpocket and CavityPlus. Subsequent molecular docking and dynamics simulation indicated that cryptotanshinone interacts with H4R at a pocket formed by the outward interfaces between TM3/4/5, potentially representing a new allosteric binding site for H4R. Overall, this study introduced cryptotanshinone as a novel H4R antagonist, offering promise as a new hit for drug design of H4R antagonist. Additionally, this study provided a novel screening model for the discovery of H4R antagonists. [ABSTRACT FROM AUTHOR]

ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism, and abnormally high expression of ACLY occurs in many diseases, including cancers, dyslipidemia and cardiovascular diseases. ACLY inhibitors are prospective treatments for these diseases. However, the scaffolds of ACLY inhibitors are insufficient with weak activity. The discovery of inhibitors with structural novelty and high activity continues to be a research hotpot. Acanthopanax senticosus (Rupr. & Maxim.) Harms is used for cardiovascular disease treatment, from which no ACLY inhibitors have ever been found. In this work, we discovered three novel ACLY inhibitors, and the most potent one was isochlorogenic acid C (ICC) with an IC 50 value of 0.14 ± 0.04 μM. We found dicaffeoylquinic acids with ortho-dihydroxyphenyl groups were important features for inhibition by studying ten phenolic acids. We further investigated interactions between the highly active compound ICC and ACLY. Thermal shift assay revealed that ICC could directly bind to ACLY and improve its stability in the heating process. Enzymatic kinetic studies indicated ICC was a noncompetitive inhibitor of ACLY. Our work discovered novel ACLY inhibitors, provided valuable structure-activity patterns and deepened knowledge on the interactions between this targe tand its inhibitors. [Display omitted] • Three novel ACLY inhibitors were identified from Acanthopanax senticosus. • SAR analysis revealed that caffeoylquinic acids with ortho-dihydroxyphenyl were needful for high inhibition potency. • Isochlorogenic acid C was highly active and directly acted on ACLY in a noncompetitive pattern. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, for which targeted therapy regimens are lacking. The traditional Chinese medicine Menispermum dauricum DC (M. dauricum) and its compounds have been reported to have antitumor activity against various cancers; however, their anti -TNBC activity is unknown. In this work, dauricine and N -desmethyldauricine from M. dauricum were separated and identified to have anti -TNBC via a multi-component bioactivity and structure-guided method. The cell counting kit 8 assay showed that dauricine and N -desmethyldauricine inhibited the proliferation of four tested TNBC cell lines, with half maximal inhibitory concentration values ranging from 5.01 μM to 13.16 μM. Further research suggested that N -desmethyldauricine induced cell apoptosis, arrested cell cycle progression in the G0/G1 phase, and inhibited cell migration. Western blot analysis revealed that the proapoptotic protein cleaved-poly-ADP-ribose polymerase 1 was upregulated, and the G0/G1 phase-related proteins cyclin-dependent kinase 2 and cyclin D1 and the migration-related protein matrix metallopeptidase 9 were downregulated. Furthermore, N -desmethyldauricine decreased the protein expression of p65, an important subunit of nuclear factor kappa-beta (NF-κB). Moreover, an antiproliferation assay of three-dimensional (3D) tumor spheroids showed that N -desmethyldauricine diminished cell‒cell adhesion and suppressed the growth of TNBC 3D spheroids. Taken together, these findings indicate that N -desmethyldauricine inhibited the proliferation of TNBC cells and decreased the expression of p65 in the NF-κB pathway. • Dauricine and N -desmethyldauricine from traditional Chinese medicine M. dauricum. display good bioactivity on anti -TNBC. • N -desmethyldauricine exhibits anti -TNBC activity both in 2D and 3D models in vitro. • N -desmethyldauricine affects TNBC cell cycle, apoptosis, migration and downregulates the expression of NF-κB. [ABSTRACT FROM AUTHOR]

Dactylicapnos scandens (D. scandens) is an ethnic medicine commonly used for the treatment of analgesia. In this study, an integrated strategy was proposed for the quality evaluation of D. scandens based on "phytochemistry-network pharmacology-effectiveness-specificity" to discover and determine the quality marker (Q-marker) related to analgesia. First, phytochemical analysis was conducted using UPLC-Q-TOF-MS/MS and a self-built compound library, and 19 components were identified in D. scandens extracts. Next, the "compounds-targets" network was constructed to predict the relevant targets and compounds related to analgesia. Then, the analgesic activity of related compounds was verified through dynamic mass redistribution (DMR) assays on D2 and Mu receptors, and 5 components showed D2 antagonistic activity with IC 50 values of 39.2 ± 14.7 µM, 5.46 ± 0.37 µM, 17.5 ± 1.61 µM, 7.89 ± 0.79 µM and 3.29 ± 0.73 µM, respectively. Subsequently, nine ingredients were selected as Q-markers in consideration of specificity, effectiveness and measurability, and their content was measured in 12 batches of D. scandens. Furthermore, the hierarchical cluster analysis and heatmap results indicated that the selected Q-marker could be used to discriminate D. scandens and that the content of Q-marker varied greatly in different batches. Our study shows that this strategy provides a useful method to discover the potential Q-markers of traditional Chinese medicine and offers a practical workflow for exploring the quality consistency of medicinal materials. [Display omitted] • Q-marker associated with analgesia were discovered of Dactylicapnos scanden s. • Complete phytochemical analysis was performed on Dactylicapnos scanden s extracts by UPLC-Q-TOF-MS/MS. • Analgesic targets and Q-marker were predicted by network pharmacology, and the activity was verified by DMR assays. • Nine compounds were selected as Q-markers their content was used to evaluate the quality consistency of D. Scanden s. [ABSTRACT FROM AUTHOR]

• Fifteen new bisbenzylisoquinoline derivatives were isolated from Menispermum dauricum DC. • Absolute configuration of 1 was determined by a comparison between the experimental and calculated ECD data. • Compound 1 exhibited significant and selective antagonistic activity on the M3 receptor, with IC 50 value of 2.2 ± 0.5 μM. • 1 R , 1′ R -espinin (15) exhibited antagonistic activities on both Mu and D1 receptors, with IC 50 values of 1.1 ± 0.6 μM and 8.8 ± 2.9 μM, respectively. Fifteen new bisbenzylisoquinoline alkaloids (1 – 15) were isolated from the rhizome of Menispermum dauricum DC. Compounds 1 – 9 were new N -oxides of dauricine-type alkaloids. Compounds 10 – 14 were rare tail-to-tail quaternary alkaloids. Their structures were characterized by comprehensive analysis of spectroscopic data, and absolute configurations were established from electronic circular dichroism (ECD) data and ECD calculations. Compounds were assayed on analgesic-related G-protein coupled receptors (GPCRs) including dopamine D1 and D2 receptors, opioid Mu receptor and muscarinic M3 receptor. Compound 1 showed high affinity and selective antagonistic activity on the M3 receptor with an IC 50 value of 2.2 ± 0.5 μM; compound 15 exhibited the highest antagonistic affinity among the evaluated compounds on Mu (IC 50 = 1.1 ± 0.6 μM) and it also acted as a D1 receptor antagonist (IC 50 = 8.8 ± 2.9 μM). These findings expanded the existing library of bisbenzylisoquinoline alkaloids and provided new structures for the related future drug design and synthesis. [ABSTRACT FROM AUTHOR]

Insomnia is a common and refractory disease. Since more than 2000 years ago, people have been using Ziziphi Spinosae Semen (ZSS). However, there are lack of molecular mechanisms of sleep promotion effects of ZSS. The purpose of this study is to clarify the active ingredients in ZSS that are used to treat insomnia. Using a method called cellular label-free integrative pharmacology (CLIP), we established five insomnia-related target models, including serotonin (5HT 2A and 5HT 1A), melatonin (MT 1), dopamine (D 2) and epinephrine (β 2) receptors. The one-dimensional (1D) fractions of ZSS extract were prepared on a RZC18 column and assayed on five models. Subsequently, the active fraction was further analyzed, fractionated and quantified using a two-dimensional (2D) liquid phase method coupled with a charged aerosol detector (CAD), This CAD-coupled 2D-LC method requires micro-fractions from the 1D separation and thus it greatly saves sample amounts and corresponding preparation time, and quickly conduct activity screening. The composition of the active 2D fractions was then determined using three-dimensional (3D) HPLC-MS, and molecular docking was separately carried out for the described compounds on the targets for activity prediction. Seven compounds were predicted to be active on 5HT 2A , and two compounds on D 2. We experimentally verified the prediction and found that vitexin exhibited D 2 agonistic activity, and nuciferine exhibited 5HT 2A antagonistic activity. This study revealed the effective components and their targets of ZSS in the treatment of insomnia, also highlighted the potential of the CLIP technique and bioactivity guided multi-dimensional HPLC-MS in molecular mechanism elucidation for traditional Chinese medicines. [Display omitted] [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease characterized by symptoms of shortness of breath and chronic inflammation. Curcuma zedoaria (Christm.) Roscoe is a well-documented traditional medical herb that is frequently used in the treatment of COPD. Previously, we identified a diarylheptanoid compound (1-(4-hydroxy-5-methoxyphenyl)-7-(4,5-dihydroxyphenyl)-3,5-dihydroxyheptane; abbreviated as HMDD) from this herb that exhibited potent agonistic activity on β2-adrenergic receptors (β2 adrenoreceptor) that are present on airway smooth muscle cells. In this work, we used chemically synthesized HMDD compound, and confirmed its bioactivity on β2 adrenoreceptors. Then by a proteomics study and anti-inflammatory evaluation detections, we found that HMDD downregulated the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) signaling pathway and suppressed the NLRP3 receptor expression in RAW264.7 macrophages and in a COPD model in A549 lung carcinoma cells. HMDD also decreased nitric oxide production levels, and impacted other interleukins and the phosphorylation of NF-κB and ERK pathways. We performed molecular docking of HMDD on β2 adrenoreceptor and NLRP3 protein models. This work reports the anti-inflammatory effects of HMDD and suggests a dual-targeting mechanism of β2-adrenoreceptor agonism and NLRP3 inhibition. Such a mechanism scientifically supports the clinical uses of Curcuma zedoaria (Christm.) Roscoe in treating COPD, as it can simultaneously relieve persistent breathlessness and inflammation. HMDD can be considered as a potential non-steroidal anti-inflammatory drug in novel therapy design for the treatment of COPD and other inflammatory diseases. [Display omitted] • HMDD from C. zedoaria showed β2-adrenoreceptor agonism and NLRP3 inhibition. • HMDD showed anti-inflammatory effects in cell models related to COPD. • The dual-targeting mechanism of HMDD can be considered in new COPD therapy. [ABSTRACT FROM AUTHOR]

A new optimization strategy for purification of alkaloids from Rhizoma Corydalis using preparative liquid chromatography was developed, featuring a selective separation of different types of alkaloids into different parts by a reversed-phase/weak cation-exchange mixed-mode column (named C18WCX) at first. The total alkaloids of Rhizoma Corydalis were divided into four fractions with fraction III and IV corresponding to the tertiary type medium bases and the quaternary type strong bases, respectively. For fraction III, a conventional C18 column was used to isolate tertiary alkaloids using acetonitrile and 0.1% phosphoric acid (adjusted with triethylamine to pH 6.0) as mobile phases. High selectivity and symmetrical peak shapes of tertiary alkaloids were obtained, resulting in six main tertiary alkaloids isolated in a single run. As strong bases, quaternary alkaloids often suffer from serious peak tailing problem on conventional C18 columns. Therefore, a silica-based strong cation-exchange (SCX) column was used for purification of fraction IV. On the SCX column, good peak shapes in high sample loading were achieved. Five main quaternary alkaloids were isolated and identified from the fraction in one-step. The procedures presented effective for the preparative isolation and purification of alkaloids from Rhizoma Corydalis. • A new optimization strategy for purification of alkaloids from Rhizoma Corydalis. • Tertiary and quaternary alkaloids were successfully classified on a C18WCX column. • Tertiary and quaternary alkaloids were purified by C18 and SCX columns respectively. • Six tertiary alkaloids and Five quaternary alkaloids were obtained in one-step. [ABSTRACT FROM AUTHOR]

Abstract Titanium dioxide (TiO 2)/fluorine-doped tin dioxide (FTO) bilayer films were deposited on glass substrates by spray pyrolysis. The effects of hydrogen plasma exposure on structure, morphology and optical properties of the films were studied. The distribution of elements in the double layer film was investigated by glow discharge spectrometer. The results indicate that the TiO 2 film provides effective protection of the underlying FTO film from the bombardment with hydrogen ions and radicals. Without the TiO 2 protective layer, SnO 2 will be reduced to sub-oxidized SnO and metallic Sn by hydrogen ions and radicals with increasing the exposure time. In addition, the TiO 2 /FTO film presents a nano-flower shaped appearance due to the small particles (TiO 2) agglomerated on the surface of large particles (SnO 2), the novel textured morphology is preferred for improving light scattering and haze of the film. A high haze value of 36.7% was obtained when the approximate thickness of the prepared TiO 2 layer is 213 nm. This work may provide an alternative for improving performance of a-Si based solar cells. Highlights • Titanium dioxide/fluorine-doped tin dioxide bilayer films were successfully deposited. • The double-layer film exhibits a nano-flower shaped appearance. • A high haze value of 36.7% was obtained. • Adequate thickness of titanium dioxide effectively protects the FTO film from the bombardment with hydrogen ions. [ABSTRACT FROM AUTHOR]

The TiO 2 nanotube (TONT) based heterojunction photocatalyst was developed via the coupling of reduced graphene oxide (rGO) and SnO 2 :F film (FTO). Based on the characterization of Raman analysis, XRD, SEM, TEM, XPS and ESR, the crystal phase, morphology, heterojunction interfacial interaction and the photoinduced electron chemical environment of the samples are studied. In the photodegradation of methylene blue (MB) solution under UV irradiation, the rGO-TONT/FTO heterojunction photocatalyst exhibits the improved photocatalytic reaction rate, 3 times greater than that of pure TONT. The enhanced photocatalytic mechanism was discussed by PL. The effectively separate charge in heterojunction structure of rGO-TONT/FTO is responsible for the enhanced photocatalytic activity. Wherein, the abundant oxygen vacancies at TiO 2 surface and the chemically bonded interface in rGO-TONT heterojunction also contributes to the interfacial electron transfer. Besides, the introduction of rGO enhanced its optical absorption capacity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ten new indole alkaloids were isolated from Uncaria rhynchophylla. • Their structures were elucidated by the analysis of spectroscopic data and quantum chemical calculations. • Eight of the ten new compounds exhibited at least one antagonistic effect on the dopamine D2 and Mu opioid receptors. • Compounds 1 and 21 processed dual-target activities on the two receptors. Ten new indole alkaloids (1 – 10) as well as eleven known analogs (11 – 21) were isolated from the stems and hooks of Uncaria rhynchophylla. Their structure elucidation was based on extensive NMR studies, MS and ECD data, with the essential aid of DFT prediction of ECD spectra. Compound 1 was determined as a 17,19 - seco - cadambine - type alkaloid, and compound 3 was confirmed to be a 3,4 - seco - tricyclic monoterpene indole alkaloid, which are the first seco - alkaloids possessing such cleavage positions from U. rhynchophylla. All the isolated compounds were evaluated for their bioactivities on dopamine D2 and Mu opioid receptors for discovering natural therapeutic drugs targeting central nervous system (CNS) diseases. Compounds 1 , 2 , 4 , 5 , 20 and 21 showed antagonistic bioactivities on the D2 receptor (IC 50 0.678–15.200 μM), and compounds 1 , 3 , 6 , 9 , 10 , 13 , 18 , 19 and 21 exhibited antagonistic effects on the Mu receptor (IC 50 2.243–32.200 μM). Among them, compounds 1 and 21 displayed dual - target activities. Compound 1 showed conspicuous antagonistic activity on D2 and Mu receptors with the IC 50 values of 0.678 ± 0.182 μM and 13.520 ± 2.480 μM, respectively. Compound 21 displayed moderate antagonistic activity on the two receptors with the IC 50 values at 15.200 ± 1.764 μM and 32.200 ± 5.695 μM, respectively. [ABSTRACT FROM AUTHOR]

Traditional Chinese Medicine (TCM) is an ancient medical practice which has been used to prevent and cure diseases for thousands of years. TCMs are frequently multi-component systems with mainly unidentified constituents. The study of the chemical compositions of TCMs remains a hotspot of research. Different strategies have been developed to manage the significant complexity of TCMs, in an attempt to determine their constituents. Reversed-phase liquid chromatography (RPLC) is still the method of choice for the separation of TCMs, but has many problems related to limited selectivity. Recently, enormous efforts have been concentrated on the development of efficient liquid chromatography (LC) methods for TCMs, based on selective stationary phases. This can improve the resolution and peak capacity considerably. In addition, high-efficiency stationary phases have been applied in the analysis of TCMs since the invention of ultra high-performance liquid chromatography (UHPLC). This review describes the advances in LC methods in TCM research from 2010 to date, and focuses on novel stationary phases. Their potential in the separation of TCMs using relevant applications is also demonstrated. [ABSTRACT FROM AUTHOR]

ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism with therapeutic prospect for treating hyperlipidemia and various cancers. Much effort has been put into discovering ACLY inhibitors. However, current screening approaches have limitations in sensitivity, portability and high-throughput. To develop a general screening assay, we investigated series of conditions affecting the enzymatic reaction based on the ADP-Glo luminescence assay. Bovine serum albumin (0.001%) added triggered strong and stable fluorescence signal. The optimized assay was validated and applied to screen our natural product library. Two novel inhibitors were identified with IC 50 values of 3.86 ± 0.62 μM (2) and 15.48 ± 2.51 μM (4). Their aggregations and target specificities were also examined. 2 was characterized as a noncompetitive inhibitor of ACLY, while 4 was a competitive inhibitor of CoA, which was also elucidated by docking studies. In anticancer activity evaluation, 2 with higher inhibition potency did not exhibit anticancer effect, probably owing to its insufficient cell-permeability. 4 showed moderate inhibition in the proliferation of A549 and PC3 cells. This study not only developed a general approach for ACLY inhibitor discovery, but also identified a new scaffold ACLY inhibitor, which could be served as a hit compound in drug design. • We established a general method for ACLY inhibitors study. • Compound 4 is a competitive inhibitor of CoA with a novel scaffold. • Compound 4 exhibits moderate anticancer effect in vitro experiment. [ABSTRACT FROM AUTHOR]

Bufadienolides possess various bioactivities especially antitumor. Due to the high structural diversity, the separation of bufadienolides often suffers from coelution problem on conventional RP columns. In this work, an off-line two-dimensional normal-phase liquid chromatography × reversed-phase liquid chromatography (2D-NPLC × RPLC) method was developed to separate and characterize bufadienolides in toad skin. Several RP and NP columns were evaluated with five reference bufadienlides. The XUnion C18 and XAmide columns exhibited superior chromatographic performances for bufadienlide separation, and were selected in RPLC and NPLC, respectively. RPLC was used in the second-dimension for the good compatibility with MS, while NPLC was adopted in the first-dimension. The orthogonality of the 2D-NPLC × RPLC system was investigated by the geometric approach using fifteen bufadienolide mixtures. The result was 49.6%, demonstrating reasonable orthogonality of this 2D-LC system. By combining the 2D-LC system with MS, 64 bufadienlides including 33 minor ones and 11 pairs of isomers in toad skin were identified. This off-line 2D-NPLC × RPLC allowed to solve the coelution problem of bufadienlides in one-dimension RPLC, and thus facilitated the identification significantly. [ABSTRACT FROM AUTHOR]

Ursodeoxycholic acid (UDCA) is a safe bile acid effective in reducing hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). However, the mechanism of action linked to this effect is poorly defined. In the present study, we identified that UDCA acted as a free fatty acid receptor 4 (FFA4) agonist with EC 50 of 10.4 ± 0.7 μM, and its activity was determined by dynamic mass redistribution, fluorometric imaging plate reader, inositol monophosphate and bioluminescence resonance energy transfer assays. Moreover, UDCA showed FFA4 selectivity over eleven other G protein-coupled receptors. Real-Time PCR and immunocytochemistry analyses showed that FFA4 was abundantly expressed in human hepatocytes HuH-7 cells. In an in vitro model of NAFLD induced by oleic acid (OA), UDCA downregulated lipid accumulation in HuH-7 cells and suppressed sterol-regulatory element binding protein-1c (SREBP-1c) mRNA expression. This suppression of SREBP-1c was restored when FFA4 expression was knocked down in siRNA assay. In a mouse model of hepatic steatosis, db/db mice were exposed to a high-fat diet (HFD), and treatment of UDCA or docosahexaenoic acid (DHA, an endogenous FFA4 agonist) effectively prevented body weight gain and hepatic fat deposition and reduced triglyceride (TG) levels in serum and liver. This study not only identified a new skeleton of FFA4 agonists, but also demonstrated that FFA4 signal was accounting for the protective effects of UDCA in the NAFLD treatment. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine (TCM) has a long history in the prevention and treatment of pandemics. The TCM formula Lung Cleansing and Detoxifying Decoction (LCDD), also known as Qing Fei Pai Du Decoction, has been demonstrated effective against Coronavirus Disease 2019 (COVID-19). This work aimed to elucidate the active ingredients, targets and pathway mechanism of LCDD related to suppression of inflammatory, immunity regulation and relaxation of airway smooth muscle for the treatment of COVID-19. Mining chemical ingredients reported in LCDD, 144 compounds covering all herbs were selected and screened against inflammatory-, immunity- and respiratory-related GPCRs including GPR35, H1, CB2, B2, M3 and β2-adrenoceptor receptor using a label-free integrative pharmacology method. Further, all active compounds were detected using liquid chromatography-tandem mass spectrometry, and an herb-compound-target network based on potency and content of compounds was constructed to elucidate the multi-target and synergistic effect. Thirteen compounds were identified as GPR35 agonists, including licochalcone B, isoliquiritigenin, etc. Licochalcone B, isoliquiritigenin and alisol A exhibited bradykinin receptor B2 antagonism activities. Atractyline and shogaol showed as a cannabinoid receptor CB2 agonist and a histamine receptor H1 antagonist, respectively. Tectorigenin and aristofone acted as muscarinic receptor M3 antagonists, while synephrine, ephedrine and pseudoephedrine were β2-adrenoceptor agonists. Pathway deconvolution assays suggested activation of GPR35 triggered PI3K, MEK, JNK pathways and EGFR transactivation, and the activation of β2-adrenoceptor mediated MEK and Ca2+. The herb-compound-target network analysis found that some compounds such as licochalcone B acted on multiple targets, and multiple components interacted with the same target such as GPR35, reflecting the synergistic mechanism of Chinese medicine. At the same time, some low-abundance compounds displayed high target activity, meaning its important role in LCDD for anti-COVID-19. This study elucidates the active ingredients, targets and pathways of LCDD. This is useful for elucidating multitarget synergistic action for its clinical therapeutic efficacy. [Display omitted] [ABSTRACT FROM AUTHOR]

Dopamine receptors are long-standing primary targets in the treatment of mental diseases and there is growing evidence that suggests relationships between obesity and the dopamine system, especially dopamine D1 and D2 receptors. Leaves of Nelumbo nucifera Gaertn. (lotus leaves) have been medically used for helping long-term maintenance of weight loss. Whether and how components of lotus leaves function through the dopamine receptors remains unclear. This work aimed to discover dopamine receptor-active alkaloids isolated from the lotus leaves, to evaluate their potencies and to analyze their structure activity relationship. Dried lotus leaves were prepared and total extract was divided into alkaloids and flavones. Eight alkaloids were separated and characterized by a combination of high-performance liquid chromatography, quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance, and assayed by a fluorometric imaging plate reader platform. Human embryonic kidney 239 cell lines expressing dopamine D1, D2 and serotonin 2A (5-HT2A) receptors, respectively, were cultured and used in the assay. Alkaloids in the lotus leaves were the bioactive phytochemicals and inhibited dopamine from accessing the D1 and D2 receptors. All eight compounds functioned as D1-receptor antagonists and except N-nornuciferine, seven alkaloids functioned as D2-receptor antagonists. (S)-coclaurine and (R)-coclaurine are optical isomers and antagonized both D1 and D2 with equivalent potencies, suggesting that the optical rotation of the methylene linker in the monobenzyl isoquinoline backbone did not influence their activity. Among the eight alkaloids, O-nornuciferine was the potent antagonist to both receptors (the lowest IC 50 values, D1: 2.09 ± 0.65 μM and D2: 1.14 ± 0.10 μM) while N-nornuciferine was found to be the least potent as it moderately antagonized D1 and was inactive on D2. O-nornuciferine was also a 5-HT2A antagonist (IC 50 ~20 μM) while N-nornuciferine had no activity. These hinted the importance of a methyl group attached to the nitrogen atom in the aporphine backbone. Armepavine showed a nearly 10-fold selectivity to D2. In this work, eight alkaloids were isolated from the leaves of Nelumbo nucifera Gaertn. and assayed on the D1 and D2 receptors. They were D1/D2 antagonists with IC 50 values in the mid- to low-micromolar range and O-nornuciferine was the most potent alkaloid among the eight. This family of alkaloids was biochemically evaluated on the dopamine receptors by the same platform for the first time. [Display omitted] • Leaves of Nelumbo nucifera Gaertn. (lotus) are a traditional herbal medicine for anti-obesity. • Alkaloids in the lotus leaf extract were the bioactive components to D1 and D2 receptors. • Eight alkaloids were determined to be D1 and/or D2 receptor antagonists. • O-nornuciferine exhibited the highest potency (IC 50 ~2 μM) at both subtypes. [ABSTRACT FROM AUTHOR]

Mu opioid receptor (MOR) is mainly a drug target for analgesia. Opioid-like agonists such as morphine have been clinically used for analgesia but have potential adverse effects. MOR antagonists have been demonstrated to alleviate these side effects. Plants (Carthamus tinctorius L, Cynanchum otophyllum C. K. Schneid., Coffea arabica L., Prinsepia utilis Royle and Lepidium meyenii Walp.) and Ganoderma fungi (Ganoderma hainanense J. D. Zhao , Ganoderma capense (Lloyd) Teng , Ganoderma cochlear (Blume et Nees) Bres. , Ganoderma resinaceum Boud and Ganoderma applanatum (Pers.) Pat.) are traditional medicines with beneficial effects on immunoregulation, analgesia and the nervous system, but whether MORs are engaged in their effects remains unknown. This work aimed to identify MOR ligands among compounds isolated from the above-mentioned 10 species, and to investigate selectivity against four opioid receptor subtypes. By analyzing the structure-activity relationship and off-target effects, we could provide a new direction for the future development of MOR drugs. Four opioid receptor subtype models, including MOR, delta (DOR), kappa (KOR) and nop (NOR), were established with a label-free phenotypic dynamic mass redistribution assay to systematically profile the pharmacological properties of known ligands. Then, 82 natural compounds derived from the 10 species were screened against MOR to identify new ligands. The selectivity of the new ligands was characterized against the four subtypes, and off-target effects were also investigated on eight G protein-coupled receptors (GPCRs). The pharmacological properties of known ligands on transfected HEK293T-MOR, HEK293-DOR, HEK293-KOR and HEK293-NOR cell lines were characterized. Seven compounds purified from Ganoderma cochlear (Blume et Nees) Bres. and Carthamus tinctorius L were MOR antagonists with micromolar potency. Among them, compound 35 showed the strongest antagonistic activity on MOR with an IC 50 value of 10.0 ± 3.0 μM. To a certain extent, these seven new antagonists, exhibited antagonistic activity on the other opioid receptor subtypes, and they had almost no effect on other GPCRs, including CB1, CB2, M2 and beta2AR. Additionally, a compound from Lepidium meyenii Walp. displayed MOR agonistic activity. The established screening models opened new avenues for the discovery and evaluation of opioid receptor ligand selectivity. Together, the novel MOR antagonists and agonists will enrich the inventory of MOR ligands and benefit related therapies. Image 1 [ABSTRACT FROM AUTHOR]

FFA4 is a novel therapeutic target for the treatment of metabolic diseases, such as type II diabetes. However, there are still few ligands with structural diversity, selectivity and high potency, and the signaling pathway downstream of FFA4 remains to be poorly characterized. In this study, a high performance liquid chromatography-corona charged aerosol detector (HPLC-CAD) combined with label-free dynamic mass redistribution (DMR) method was introduced to guide the discovery of FFA4 agonists from Arnebia euchroma (Royle) Johnst. Ten compounds were identified as FFA4 agonists and structure-activity relationship was obtained. Among them, shikonin displayed the most potent activity with pEC 50 value of 6.02 ± 0.19. The activity of shikonin was confirmed by FLIPR (fluorometric imaging plate reader) assay. Signaling pathways of FFA4 were explored in HT-29 cells endogenously expressing FFA4 using shikonin and known FFA4 agonists α-linolenic acid (ALA) and TUG891. Multiple pathways included Gq/11-PLC-Ca2+-PKC, RohA, JNK, p38 MAPK, Gi/o and PI3K signaling but may not involve Gs signaling triggered by shikonin, ALA and TUG891. Besides, shikonin, TUG891 and ALA could induce ERK1/2 and AKT phosphorylation in HT-29 cells. Moreover, anti-diabetes effects of shikonin were evaluated on the glucose intolerance in diabetic db/db mice. Shikonin reduced plasma glucose level, suggesting that it had the potential in treatment of type II diabetes. The agonists identified in this study provided structure guidance for FFA4 drug design. This study was also useful for understanding FFA4 pharmacology and its biological function. [ABSTRACT FROM AUTHOR]

Free fatty acid receptor 4 (FFA4) has been recognized as an attractive target in metabolic diseases. To find potent and selective FFA4 agonist, 28 compounds of 3-(4-(phenoxymethyl)phenyl)propanoic acid and N -phenylbenzenesulfonamide derivatives were designed and synthesized, featuring O C and SO2-N linkage. For the O C linkage compounds, 1g showed the most potent FFA4 agonistic activity with a pEC 50 of 5.81 ± 0.04 and exhibited at least 64-fold selectivity against FFA1. For SO2-N linkage agonists, 2m had a pEC 50 of 5.66 ± 0.04 and displayed>46-fold selectivity against FFA1. Among these two series of compounds, 1g was the most potent agonist at FFA4 and the best selectivity against FFA1, demonstrated by docking simulation. Moreover, 1g showed receptor selectivity on other seven GPCRs. In anti-diabetic evaluation, 1g dose-dependently reduced blood glucose, which was better than a clinical phase III drug TAK875. This study provides guidance for FFA4 ligand design and drug optimization. [ABSTRACT FROM AUTHOR]

• Integrated method accelerated alkaloid drug discovery. • XCharge C18 column provided good peak shape for alkaloids. • Charged aerosol detector (CAD) ensured accurate screening of trace samples. • Molecular network predicted active compounds. Natural products, including alkaloids, are important resources for new drugs. However, in today's high throughput screening (HTS) environment, natural product drug discovery programs are challenged for their low efficiency. In order to adapt to current HTS models, we here developed a rapid, sample-saving and miniaturized paradigm that seamlessly integrated alkaloid micro-fractionation, quantitative analysis, qualitative analysis and phenotypic screening. In the work, alkaloid samples were analyzed and fractionated on an analytical charged C18 column (150 × 4.6 mm, i.d.), and fraction qualities were determined by a charged aerosol detector (CAD). Fraction activities on dopamine D2 receptor were screened by cellular dynamic mass redistribution (DMR) assay and active fractions were further characterized by high-resolution mass spectrometry (MS). The whole workflow was first validated by mixed standard for accuracy, and then by 300 μg of Corydalis yanhusuo extract for its feasibility in complex samples. Finally, the method was applied for sample prioritization in four papaveraceae family plants and 21 compounds were predicted to be active, and Corydalis yanhusuo and Corydalis decumbens were determined as promising species for activity tracking. Overall, these results highlighted the feasibility of this miniatured and integrated model in rapid alkaloid screening. Advantages of this workflow were: first, the highly efficient separation method accelerated alkaloid fractionation; second, the analytical and biological test were conducted on the same scale; third, the quantification method ensured accurate screening on microscale; last, the combination of MS analysis and data mining strategy accelerated the decision-making process in the primary screening. [ABSTRACT FROM AUTHOR]

• Chemical profiling of spermidines in goji berry was conducted by UPLC-DAD-Q-TOF/MS. • Fragmentation rules of four different groups of spermidines were summarized. • An effective SCX-SPE method was developed for selective enrichment of spermindines. • A total of 41 out of 58 spermidines were tentatively characterized from goji berry. Lycium barbarum fruit (Goji berry) have been used as a traditional Chinese medicine (TCM) with its outstanding biological and pharmacological activities. Spermidine alkaloids are a major class of bioactive constituents in goji berry, nevertheless, detailed information related to its identification remains scarce. In this study, chemical profiling of spermidines in goji berry was carried out by ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Four structure types of standards were used to study the comprehensive fragmentation rules of spermidines. Different types of spermidines were identified by distinctive MS/MS fragment ions. Noticeably, it was first proposed that the co-existence of fragment ions at m / z 220 and 222 was the key characteristic for distinguishing spermidine isomers. According to the structural feature of spermidines, a quick, convenient, highly selective strong cation exchange solid-phase extraction (SCX-SPE) combined with RP-LC procedure was developed for selective enrichment and the MS detection compatibility. A total of 41 out of 58 spermidines were tentatively characterized using the established method, of which 26 were reported for the first time from goji berry. This study provides guidelines and references for the identification of spermidines in natural products. [ABSTRACT FROM AUTHOR]