The aim of this study was to identify the anti-inflammatory markers of Zhachong shisanwei pills (ZC-13) and characterize their mechanisms. UPLC/Q-TOF-MS combined with an NF-κB dual fluorescence reporter gene system and NO content detection were utilized to identify the anti-inflammatory bioactive substances in ZC-13. Network pharmacology and bioinformatics methods were used to predict the main targets and pathways of these anti-inflammatory markers, and to verify the main anti-inflammatory pathways of costunolide. Results showed that in ZC-13, four kinds of markers related to NF-κB inhibition were identified: gallic acid, ellagic acid, liquiritin apioside, glycyrrhizic acid, and four kinds of markers related to NO release inhibition were found: gallic acid, liquiritigenin, costunolide, and dehydrocostus lactone. The above components exert anti-inflammatory activities mainly through the regulation of PDK1 (3-phosphoinositide-dependent protein kinase 1), MAPK14 (mitogen-activated protein kinase), GSK3β (glycogen synthase kinase-3β) and other anti-inflammatory-related targets, and further adjust the PI3K-AKT (phosphoinositide 3-kinase- protein kinase B), MAPK, mTOR (mammalian target of rapamycin) pathways. Among them, costunolide can inhibit AKT phosphorylation and NF-κB nuclear transfer. The above results identified the anti-inflammatory markers and possible mechanisms of ZC-13, and provide a theoretical basis for standardizing the clinical application and quality of ZC-13.

More and more clinical evidence shows that patients with Coronavirus Disease 2019 (COVID-19) died due to severe complications such as acute respiratory distress syndrome and multiple organ failure due to the aggravation of the disease in the later period, and the main cause of the aggravation is "cytokine storm". There is no specific drug for the treatment of severe COVID-19 patients. Although western medicine can improve some symptoms, it leaves a large sequela, while traditional Chinese medicine plays an important role in this outbreak. In this paper, based on the clinical reported cytokines storm-related indicators, the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was used to mine and screen the traditional Chinese medicines acting on these cytokines based on the theory of "damp toxin invading the lung". It was found that 19 cytokines, including interleukin-6 (IL-6), tumor necrosis factor α (TNFα), granulocyte-macrophage colony stimulating factor (GM-CSF) and so on, were closely related to COVID-19, and 22 traditional Chinese medicines such as Ephedrae Herba, Glycyrrhizae Radix Et Rhizoma and Lonicerae Japonicae Flos acted on these cytokines, so as to provide certain reference for the reasonable choice of prescription and addition or modification of drugs for COVID-19 patients in the middle and late stage of Chinese medicine clinical treatment.

This study was performed to determine the metabolic profile of a new illicit drug, PX-2, in human liver microsomes. Q Exactive™ HF Quadrupole-Orbitrap LC-MS (LC-QE-HF-Orbitrap-MS) was employed to determine the metabolic sites and pathways of phase Ⅰ and phase Ⅱ metabolism. PX-2 was added to a microsomal incubation model to simulate human hepatic metabolism. The results showed that a total of 18 phase Ⅰ metabolites and 3 glucuronidated phase Ⅱ metabolites were generated, with the main metabolic pathways of phase Ⅰ metabolism including amide hydrolysis, fluoropentyl oxidative defluorination, benzyl hydroxylation, and carbazole ring hydroxylation. Based on the type and sites of metabolism, phase Ⅰ metabolites M1.1 (amide hydrolysis), M4.1 (carbazole cyclic hydroxylation), and M3.1 (oxidative defluorinative hydroxylation) are proposed to be potential poisoning markers. The results of this study provide a basis for identification of related drugs and establishment of testing methods in biological samples.

Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia among elderly people. The pathogenesis of AD is still unclear, and currently approved drugs only provide symptomatic benefits and do not prevent or delay progressive neurodegeneration. Meanwhile, potential drugs in development are facing great challenges in clinical translation. Therefore, finding effective treatment for the unmet clinical needs of AD is of great economic value and social significance. In this review, we will summarize the current models and pharmacodynamics evaluation methods of anti-AD drug based on the recent studies at home and abroad, and provide reference for drug development in AD at nonclinical stage.

This study investigated the effect of a novel adenosine derivative YZG-331 on the glutamate (Glu) content and its receptor N-methyl-D-aspartate receptor (NMDAR) in mouse frontal cortex. All procedures in this research were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. High performance liquid chromatography (HPLC) was used to detect the Glu contents in the mouse frontal cortex tissue homogenate and extracellular fluid which were collected by brain microdialysis method. Western blot and co-immunoprecipitation methods were used to detect the expressions of NMDAR in cell membranes and endosomes, as well as the expression levels of endocytosis-related proteins and their interaction. The results showed that there was no significant change in Glu content in the dialysates from mouse frontal cortex within 0-0.5 h period and 0.5-1 h period after intragastric administration of YZG-331 (40 mg·kg^-1). Compare to the control group, the Glu content in mouse frontal cortex homogenates has no significant statistical differences after 15 minutes of administration of compound YZG-331. YZG-331 significantly decreased the expressions of NMDAR subunits NR1 and NR2B in the mouse frontal cortex cell membrane, meanwhile significantly increased the expressions of NR1 and NR2B proteins in the frontal cortex endosomes. It also increased the phosphorylation levels of NMDAR subunit NR2B in the frontal cortex. In addition, the result of co-immunoprecipitation which used NR2B as bait protein showed that the expression of postsynaptic density-95 (PSD95) in NR2B and PSD95 immunoprecipitation complexes in mouse frontal cortex tissues was significantly reduced. These results indicate that YZG-331 does not affect the Glu content in mouse frontal cortex, but it weakens the interaction between NR2B and PSD95 by increasing the phosphorylation level of NR2B in the mouse frontal cortex. Therefore, it reduces the membrane stability of NMDAR and promotes NMDAR's endocytosis, which leading to the decrease of excitotary transmission. It may be one of the mechanisms of YZG-331 to exert sedative and hypnotic effects.

To identify major bioactive components and metabolites of Gandou decoction (GDD) in urine of normal and copper-laden rats, an integrative approach that ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS^E) coupled with xenometabolomics analytical platform was established. Mass spectral data information about retention time, accurate m/z and ionic strength of rat urine samples was performed under positive and negative ion modes. Unsupervised principal components analysis (PCA) and supervised orthogonal partial least-squared discriminant analysis (OPLS-DA) were used to reveal the differential ions. As a result, a total of 77 compounds including 45 prototypes and 32 metabolites in urine were detected. Results indicated that anthraquinones, alkaloids and tetracyclic triterpenoids and flavonoids were the main chemical components of GDD in rat urine; the main metabolic pathways of these compounds in rat urine mainly include hydroxyl, methylation, sulfating, glucuronidation, and so on. UPLC-QTOF-MS^E coupled with xenometabolomics analytical platform is fast and efficient so that facilitates authentication of the material basis of Chinese herb compound in vivo, can also be used as an effective tool for ascertaining trace bioactive components in vivo. The animal experiments were approved by the Experimental Animal Ethics Committee of Anhui University of Chinese Medicine (No. 2019025).

Bexarotene is a synthetic analogue of retinoic acid and exerts protective effects on the nervous system. However, low bioavailability and poor solubility of the crystal type I form severely limits the application of bexarotene in the clinic. A co-amorphous sample of bexarotene-PVP-K30 was prepared and the structure was characterized by X-ray diffraction and infrared spectroscopy. To determine the pharmacokinetics and tissue distribution of bexarotene, an LC-MS method was established to profile and quantify bexarotene in plasma and tissues of SD rats. In vitro dissolution indicated that the co-amorphous form improved the dissolution of bexarotene in pure water 4.17-fold. After rats were orally administered bexarotene or bexarotene-PVP-K30 co-amorphous (equivalent to 30 mg·kg^-1 bexarotene) the AUC of bexarotene was 7 034.89 and 10 174.03 μg·L^-1·h respectively, the peak time was advanced from 7.33 h to 0.9 h with the amorphous form, and C_max was enhanced from 627.76 to 3 011.88 μg·L^-1. The co-amorphous form yielded higher concentrations of bexarotene in various tissues, especially brain, liver and kidney. Animal welfare and experimental procedures complied with the rules of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. The results indicate that bexarotene-PVP-K30 co-amorphous improves the pharmacokinetic characteristics of bexarotene and provides preclinical data in support of bexarotene-PVP-K30 for the treatment of brain diseases.

The aim of this study was to analyze the anti-cancer effect and mechanism of action of the flavonoids of Astragalus membranaceus (TFA) when combined with cisplatin on Lewis lung carcinoma-bearing mice. This animal experiment was approved by the Committee of the Ethics of Animal Experiment of Shanxi University (SXULL2018012). Pharmacological indices such as tumor weight, tumor volume growth curves, inhibition rate and organ indices showed that the TFA could reduce toxicity and enhance the efficacy of cisplatin. The target of TFA was predicted by network pharmacology analysis and the result showed that calycosin-7-O-β-D-glucoside might be the main active compound responsible for the anticancer effect of TFA. TRP53 (cellular tumor antigen p53), RAC1 (Ras-related C3 botulinum toxin substrate 1), ERBB2 (receptor tyrosine-protein kinase erbB-2), VEGFA (vascular endothelial growth factor A) and STAT3 (signal transducer and activator of transcription 3) may be associated with TFA in enhancing efficacy and reducing the toxicity of cisplatin. The IL-6 content in serum and expression levels of STAT3 and p53 in tumor tissues suggested that TFA may inhibit tumor growth through the IL-6/STAT3 pathway; UPLC-MS-based serum metabolomic analysis suggested that the metabolic pathways related to lung cancer include sphingolipid metabolism, retinol metabolism, glycerophospholipid metabolism, primary bile acid biosynthesis, and the TFA-regulated corresponding pathway of bile acid biosynthesis. In this study, the anti-cancer effect and mechanism of action of TFA combined with cisplatin on Lewis lung carcinoma-bearing mice was analyzed by the combination of various techniques, which lay a foundation for further development of anticancer drugs.

Metabolic reprogramming is an important feature of tumor cell metabolism. Glutamine, as a conditionally essential amino acid, provides material and energy for cell growth and maintains the redox homeostasis of tumor cells. This article reviews the role of glutamine in tumorigenesis, development and metastasis, discusses the relationship between glutamine and key biomacromolecules, and provides ideas for finding new targets in cancer therapy.

This study analyzed the effect of the Radix Bupleuri-Radix Paeoniae Alba herb pair on endogenous metabolites in rats with chronic unpredictable mild stress (CUMS)-induced depression by using LC-MS liver metabolomics. Rats were randomly divided into 5 groups:a normal control group, a CUMS model group, a venlafaxine-positive group, and a high-low dose group for the Radix Bupleuri-Radix Paeoniae Alba herb pair, with continuous modeling and administration over 28 days. The efficacy of Radix Bupleuri-Radix Paeoniae Alba herb pair was evaluated by measuring traditional pharmacodynamic indicators of depression (body weight, open field test, sucrose preference test and forced swimming test). Animal experimentation was approved by the Committee on the Ethics of Animal Experiments of Shanxi University (SXULL2016036). Liver metabolic profiles were obtained by the UHPLC-Q Exactive Orbitrap-MS metabolomics technique. The results show that the Radix Bupleuri-Radix Paeoniae Alba herb pair can significantly decrease depression-like behavior of rats in the CUMS model group. Increases in 25 depression-related metabolites were identified by LC-MS metabonomics, and the Radix Bupleuri-Radix Paeoniae Alba herb pair could significantly decrease 16 of them. Metabolic pathway analysis showed that D-glutamine and D-glutamate metabolism, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and glutathione metabolism were the main metabolic pathways altered by this herb pair in CUMS model rats.