Atherosclerosis (AS) is a complex metabolic syndrome that seriously harms human health, and its occurrence and development are directly related to the metabolic disturbances of free fatty acids (FFA). In this study, macrophage-derived foam cells were established as the model of early AS. Therefore, the metabolic disturbances of FFA in ox-LDL induced foamy macrophages were analyzed using target metabolomics. Then the effect of hydroxysafflor yellow A (HSYA) on regulating FFA was also explored. The quantitative analysis of 27 fatty acids was obtained within 20 min based on dynamic MRM mode. Thirteen metabolic biomarkers of macrophage-derived foam cells were identified using multivariate statistical analysis. It was found that upregulation of total SFA and downregulation of C12:0, C14:0, C18:1, total MUFA were the typical metabolic features in macrophage-derived foam cells. Furthermore, HSYA displayed obvious repairing effect on C12:0, C14:0 and C18:1, which were involved in de novo fatty acid biosynthesis pathway. Oleoyl-(acyl-carrier-protein) hydrolase (OLAH), as the key enzyme in de novo fatty acid biosynthesis pathway, may be a drug target of HSYA.

2, 3:7, 8-Bis(methylenedioxy)benzo[c]phenanthridine was synthesized in a strategy of converging synthesis with 6-bromo-2, 3-dihydroxybenzaldehyde, 5-nitronaphthalene-2, 3-diol, and dibromomethane, respectively, as starting materials. The reaction process included dioxy-de-dibromo nucleophilic substitution under alkaline condition, reduction reaction, Schiff base-forming reaction, and an arene radical cyclization step under the presence of Bu₃SnH and AIBN as radical initiator, among others. The 2, 3:7, 8-bis(methylenedioxy)benzo[c] phenanthridine as intermediate was reacted with NaBH₄ and different aliphatic acids as alkylation agent to afford 2, 3:7, 8-bis(methylenedioxy)-5, 6-dihydro-N⁵-alkylbenzo[c]phenanthridines. These dihydro-type products were aromatized using DDQ as oxidant under alkaline condition, and then, salinized using HCl as source of equilibrium anion to yield the series of target alkyl-de-sanguinarine-N⁵-methyl derivatives. All the synthesized alkyl-de-sanguinarine-N⁵-methyl derivatives exhibited significantly improved in vitro growth inhibitory activities against cancer cell lines as compared with sanguinarine and the positive control. In pharmacological experiments targeting five cancer cell lines, the target compounds showed activities five-fold active than that of sanguinarine. The findings of this study indicated that the structure modification strategy of substituting n-alkyls for the N⁵-methyl of natural sanguinarine can be used to improve the growth inhibitory activities against cancer cell lines through increasing liposolubility and steric hindrance to protect the active 5, 6-imine structure.

Taking cabozantinib as leading compound, 13 novel small molecular c-Met inhibitors were designed and synthesized based on the obtained structure-activity relationships (SARs) of c-Met inhibitors. The structures of compounds were confirmed by ¹H NMR, ¹³C NMR and HR-MS. In vitro anti-tumor activity was evaluated by MTT method, and the mechanism was preliminarily disclosed by real-time dynamic living cell imaging and flow cytometry analysis. The results indicated that most of compounds showed good inhibition activity against human non-small-cell carcinoma cell A549 and human colorectal cancer cell HT-29 which was superior to cabozantinb. Compounds showed excellent cytotoxity and anti-proliferative activity against HT-29, and promoted cell apoptosis.

A rapid identification of the constituents in Gualoupi injection was developed by HILIC/Orbitrap Fusion Lumos HRMS. ACQUITY XBridge Amide column was used to isolate the constituents with large polarity. ESI with positive ion mode was employed and "Top Speed" DDA was applied in the MS² scan. Compound identification was carried out by using Compound Discoverer software through comparing the precursor and product ions information with those in ChemSpider and mzCloud database. As a result, 48 compounds was identified, including alkaloids, amino acid, nucleosides, nucleobases, etc., among which 25 was unambiguously identified by comparing the retention time and mass spectra information with those of reference standards. In general, the main constituents from Gualoupi injection were explained in this study. Additionally, full-scan mass spectra of 21 batches of the injection were collected by the established method. Subsequently, principal component analysis (PCA) with the peak area as the observation ID was employed to analyze the discrimination of different bathes of samples. The results indicated that the batch-to-batch difference was generally from the crude drug, and the preparation process of this injection was relatively stable. In conclusion, a rapid and effective method for the identification of compounds in Gualoupi injection was established by using UHPLC-Orbitrap Fusion Lumos HRMS and the inter-bath stability was also investigated, which may make a great contribution to the study of the bioactive ingredients in Gualoupi injection and also provide vital evidence for the standard promotion.

On base of traditional physiological studies, building a comprehensive evaluation system for the efficacy of Liuwei Dihuang Wan (LW) for regulating the growth and development of rats by indicators that the overall metabolic profile and biomarkers of urinary metabonomics. Sixty-seven day-old Sprague-Dawley rats were randomly divided into four groups that are the control group and low-dose, medium-dose, and high-dose groups of LW. At the age of 28 days, different doses of LW extracts were continuously administered for 16 days. On the basis of behavior, body weight, organ index and femur length, a UPLC-HDMS technique was used to establish urine metabolomics method to characterize the profile of urine metabolism before and after intervention of LW, analysis and identificate related to drug effects of differential metabolism markers, and study the effect of LW on the growth and development of rats. LW could improve the overall behavioral ability of rats, promote weight gain and the growth of organs and bones, and 36 differential metabolites and 13 target metabolic pathways of urine under the intervention of LW were identified, and 8 metabolic markers were regarded as a key marker that LW effect the growth and development of rats. LW has a significant regulatory effect on the urine metabolic network during the growth and development of rats. This study interpreted the scientific implications of the effect of "Nourishing Kidney Yin" on the growth and development of rats.

In this study, the change of intestinal microflora in rat fecal samples after amoxicillin administration was observed. In vitro incubation experiments combined with LC-MS/MS assay were used to test the role of intestinal flora in the metabolism of nifedipine. The effect of changes of intestinal flora was determined after amoxicillin administration on the metabolism of nifedipine. We found that the number and types of intestinal flora decreased after taking amoxicillin. After incubation for 12 h, the results showed that the remaining amounts of nifedipine in the N1 group (nifedipine) and N2 group (amoxicillin + nifedipine) were 0.057 6 and 0.064 8 μmol·L^-1, respectively, while the remaining amounts of nifedipine after 24 h of incubation were 0.039 6 and 0.050 4 μmol·L^-1, respectively. These results show that the intestinal flora is involved in the metabolism of nifedipine. After administration of amoxicillin, the metabolism of nifedipine was slowed down, the AUC_0-t was increased by 39.10%, t_max was advanced by 0.45 h, and the CL was reduced 34.71%. The data suggest that the combination may enhance the therapeutic effect of nifedipine. Therefore, drug-drug interactions mediated by gut microbiota cannot be ignored when combined with antibiotics and nifedipine, one of the important factors affecting drug efficacy.

Oral formulations of nanoemulsions (NE) were systematically designed, and then their effects on oral absorption of raloxifene (RAL), including their absorption mechanisms were investigated. RAL solubility in water and various excipients of NE and oil-water partition coefficient[P_(O/W)] of RAL were examined. Next the optimal compatibility between emulsifiers and oils in NE were ascertained by emulsification ability. Proportions of each component and optimal RAL-NE were fully confirmed by a pseudo-ternary phase diagram and drug loading, respectively. RAL-NE quality was evaluated by particle size, zeta potential, morphology, entrapment efficiency and stability in simulated gastrointestinal fluid. A MDCK cell model was used to study the in vitro transport mechanism of RAL-NE. Oral bioavailability of RAL-NE was eventually performed in SD rats. RAL can be classified as BCSⅡ based on the solubility and P_(O/W). The best formulation of RAL-NE was composed of linoleic acid (LOA):isopropyl palmitate (IPP):cremophor RH40 (RH40):alcohol as 1.67:3.33:3:2. Drug loading in pre-nanoemulsion was 15 mg·g^-1 andentrapment efficiency of RAL in NE was (79.4 ±0.4)%. The particle size, zeta potential and drug content of RAL-NE were maintained in the simulated gastrointestinal fluid. The in vitro transport mechanism of RAL-NE in MDCK cells was mainly clathrin-mediated endocytosis. The oral bioavailability of RAL in RAL-NE relative to RAL-suspension was 171.9%. The best formulation of RAL-NE studied systematically was confirmed to significantly improve the RAL absorption by in vitro and in vivo evaluations (P < 0.05). This paper provides references for oral NE research and development.

As the common pathway of chronic renal diseases leading to end-stage renal failure, renal tubulointerstitial fibrosis is characterized by the deposition of extracellular matrix and scar hardening. Our study aimed to construct an in vitro cell culture platform to explore the impact of matrix stiffness on cell morphology and function of renal tubular epithelial cells. Photopolymerized polyacrylamide gels (PAA gel) with varying stiffnesses as model substrates was selected to simulate the matrix stiffness of normal and fibrotic renal tissues with elastic moduli ranging from 1 to 40 kPa. The human renal tubular epithelial cells (HK-2) were seeded on the surface of PAA gels. The impact of matrix stiffness on the morphology of HK-2 were investigated via immunofluorescence staining and confocal microscopy. The expression levels of glucose transporter 1 (GLUT1), glucose transporter 2 (GLUT2), glucose transporter 5 (GLUT5) were semi-quantitatively analyzed. With increasing matrix stiffness, both the levels of GLUT1 and GLUT5 in HK-2 cells were significantly decreased, whereas the expression level and the distribution pattern of GLUT2 in HK-2 remained unchanged with stiffness variation.

S-adenosylmethionine synthetase, a key enzyme in plant metabolism, plays an essential role in the plant defence system. In present study, a full length cDNA sequence of AsSAMS1 gene was cloned by RACE and reverse transcription PCR from Aquilaria sinensis calli. Meanwhile, the bioinformatics, prokaryotic expression, tissue-specific expression analysis, and expression analysis under different abiotic stresses and hormone treatments were performed. The open reading frame (ORF) of AsSAMS1 gene was 1 183 bp, encoding a protein of 393 amino acids with a calculated molecular mass (MW) of 43.13 kDa. Bioinformatic analysis indicated that AsSAMS1 contained 3 SAMS characteristic sequences. The phylogenetic analysis indicated that AsSAMS1 protein had the highest level of homology with SAMS protein from Glycine soja. The recombinant AsSAMS1 protein was successfully expressed in Escherichia coli BL21 (DE3) cells using the prokaryotic expression vector pET28a-AsSAMS1 and the recombinant AsSAMS1 was purified by Ni²⁺ affinity chromatography. Expression analysis results in different tissues indicated that AsSAMS1 was primarily observed in stems, and then stem tips and leaves, following by roots. The transcript level of AsSAMS1 and the content of S-adenosylmethionine (SAM) were induced by various abiotic stresses including salt, drought, cold, and heavy metal stress. Furthermore, AsSAMS1 expression level was enhanced upon methyl jasmonate (MeJA), salicylic acid (SA), gibberellin (GA3), and abscisic acid (ABA) treatment. These results provided valuable insights for further study on the role of SAMS in the mechanism of agarwood formation and plant resistance.

Wu-tou decoction (WTD) and Baihu-Guizhi decoction (BHGZD) as described in the Synopsis of the Golden Chamber have been used extensively for the treatment of rheumatoid arthritis (RA) with apparent therapeutic efficacy. However, characteristics of pharmacological effects and their underlying molecular mechanisms have not been fully elucidated due to a lack of appropriate scientific methodology. In the current study, we performed an integrative approach applying gene expression profiling and network analysis to examine the therapeutic effects and molecular mechanisms of WTD and BHGZD based on adjuvant-induced arthritis (AIA) animal model. Results demonstrated that both WTD and BHGZD could relieve the severity of arthritis in AIA rats, while the significant differences were observed in the changes of the withdrawal response scores and latency time of AIA rats treated with WTD and BHGZD. Mechanistically, our network pharmacology-based investigation demonstrated that the major candidate targets of WTD and BHGZD were significantly associated with several inflammation-immune regulatory pathways, such as Toll-like receptor signaling pathway, T cell receptor signaling pathway, cytokine-cytokine receptor interaction, chemokine signaling pathway, B cell receptor signaling pathway, antigen processing and presentation, Fc epsilon RI signaling pathway, natural killer cell mediated cytotoxicity, as well as leukocyte transendothelial migration. In particular, the major candidate targets of WTD were also involved in the regulation of hormone and energy metabolism, which might be imbalanced during RA progression. In conclusion, the current study revealed differences and similarities regarding the effects and network regulatory mechanisms of WTD and BHGZD. These findings may present a scientific basis for elucidation of mechanisms by which WTD and BHGZD alleviates RA.