Latest ArticlesBased on the structure of inhibitors XL765 and WR23, the quinoxaline scaffold was selected as an attractive structure for drug design. In this protocol, the 2-position of quinoxaline was modified with a substituted phenoxy fragment. Meanwhile, the linking chain at the 3-position was changed to a sulfonyl hydrazine or was removed. A series of substituent groups were added at the 6-position of the quinoxaline scaffold. Twenty-two quinoline derivatives were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR, and ESI-MS. All compounds were screened for anti-tumor activity in vitro in A549, MCF-7, HCT-116 and HepG2 cancer cells. The results showed that P6b was effective, P6e and P6f had better activity against HCT116 (IC50=3.24, 4.78 and 4.50 μmol·L-1), and P6d had strong inhibitory effect on MCF-7 (IC50=0.228 7 μmol·L-1).
Plant polyphenols have a wide range of pharmacological activities and application prospects. Liquid polyphenol preparations have special physical phases and complex chemical compositions, with problems such as poor stability and easy precipitation during production and marketing. Taking the multi-precipitation mechanism of plant polyphenol liquid preparations as an example, we discuss the chemistry and composition of the precipitation, how it forms, whether precipitationcan be controlled, and the interaction law of three precipitation approaches. An unstable mechanism model is proposed where hydrolyzed tannin hydrolysis and catechin non-enzymatic oxidative polymerization repeatedly induces associative colloid aggregation and precipitation. This study explains the complex physicochemical changes in polyphenol solutions and the microcosmic mechanism of instability in the induced system and proposes a steady state reconstruction of liquid polyphenol preparation consistent with the common law of precipitation and control. It has scientific significance for promoting the development and manufacture of high quality liquid polyphenol preparations.
Two new trichilin-type limonoids were isolated from the fruits of Trichilia connaroides along with two known limonoids, 3α-deacetylamoorastatin (3) and mesendanins K (4). Their planar structure and relative configuration were elucidated by comprehensive analyses of HR-ESI-MS, 1H NMR, 13C NMR, HSQC, HMBC and ROESY data. An antitumor activity assay showed that compounds 1, 2 and known compound 4 had weak cytotoxicity against a human cervical cancer cell line (HeLa).
3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the first rate-limiting enzyme of terpenoid biosynthesis in the mevalonic acid pathway (MVA) pathway. It is an important regulatory site in terpenoids metabolism pathway in the cytoplasm. According to the transcriptome database of Cinnamomum camphora, two HMGRs named CcHMGR1 (GenBank:MN163055) and CcHMGR2 (GenBank:MN163056) were cloned by cDNA from C. camphora. The ORF of CcHMGR1 and CcHMGR2 is composed of 1 689 bp and 1 683 bp, respectively, encoding 562 and 560 amino acids. The bioinformatics analysis of CcHMGR1 and CcHMGR2 indicated that the molecular weight of the encoded protein is 59.819 kDa and 59.397 kDa, with a theoretically isoelectric point of 8.20 and 8.61, respectively. There are 2 transmembrane structures without signal peptide existing in the encoded amino acid of CcHMGRs. The analysis of sequence alignment and phylogenetic tree showed that the CcHMGRs belonged to the HMGR family. The camphor is divided into five chemitypes, according to the main chemical compounds in C. camphora. The results of the real time PCR indicated that the expression level of CcHMGRs in Cineol type was higher than that in Linalool type, iso-nerolidol type, Camphor type and Borneol type. CcHMGRs expressed highest in roots and lowest in branches. In this study, the cDNA full length of CcHMGRs were cloned from C. camphora for the first time. Our results revealed that the expression level of CcHMGRs were different among five chemical types and different plant tissues, and the research provides foundation for further study of the terpenoids biosynthetic pathway in C. camphora.
A pre-column derivatization and ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS) method was developed for qualitative and quantitative determination of medium-and short-chain fatty acids in mice feces, and was further applied to evaluate variations in the feces of mice before and after antibiotic treatment. This animal experiment had been approved by Animal Experimental Ethics Committee of Jiangsu Province Academy of Traditional Chinese Medicine. By optimizing the derivatization conditions and UHPLC-QTOF-MS/MS parameters a new UHPLC-QTOF-MS/MS method with 3-nitrophenylhydrazine as the derivatization reagent was developed for simultaneous determination of 16 medium-and short-chain fatty acids. Validation studies showed that the linearity of the calibration curves was good (R2 > 0.99), the RSD of intra-day and inter-day precision was less than 10%, the repeatability RSD was less than 6%, the recovery rate was between 80%-120% at three spiked levels, and the stability RSD was less than 7% within 36 h. The types and amounts of the detected medium-and short-chain fatty acids in feces significantly changed after the mice were treated with antibiotics. The content of formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and lactic acid decreased, whereas that of heptanoic acid and succinic acid increased significantly. All these results suggest that the newly established method is accurate and reliable, and can be used for determination of medium-and short-chain fatty acids in feces.
1H NMR-based metabonomic analysis was used to elucidate the hypoglycemic mechanism of Astragalus Radix and Dioscoreae Rhizomacomes. Thirty-seven SD rats were divided into four groups:model group (M group), control group (C group), Astragalus Radix and Dioscoreae Rhizomacomes group (HS group), metformin group (Y group). A T2DM model was induced with a high fat diet and streptozotocin (STZ). Drug was continuously administered for 8 weeks, after which blood and the kidneys were collected to determine the biochemical index and the kidney coefficients of each group. Using 1H NMR metabolomics technology, we measured the metabolites in the urine of rats in each group to identify appropriate biomarkers. The results showed that total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (L-DLC), blood urea nitrogen (BUN), hemoglobin A1c (HbA1c) and the kidney coefficients were significantly increased with high density lipoprotein (H-DLC) significantly decreased in the diabetic group, but these changes were largely reversed with treatment with Astragalus Radix and Dioscoreae Rhizomacomes. A total of 20 biomarkers were found in rat urine in the diabetic group and Astragalus Radix and Dioscoreae could reverse the changes of 16 of these metabolites to varying degrees, similar to that of metformin (200 mg·kg-1). The changes in metabolomics mainly involved butanoate metabolism, the tricarboxylic acid (TCA) cycle, taurine and hypotaurine metabolism, synthesis and degradation of ketone bodies, and pyruvate metabolism. Dioscoreae Rhizomacomes and Astragalus Radix may have a therapeutic role in the treatment of diabetes through the above five metabolic pathways, revealing the possible therapeutic mechanisms for Dioscoreae Rhizomacomes and Astragalus Radix.
To prepare the mimetic exosomes and co-delivery proteins and nucleic acids, and achieve efficient and safe co-delivery of multi-component drugs, an optimized formulation was designed by modifying a polylactic acid-glycolic acid copolymer (PLGA) matrix with a cationic lipid excipient dioleyl trimethylammonium propane (DOTAP), and a PLGA/DOTAP nanoparticles packaged protein and nucleic acid was prepared by double emulsion method, and the outermost membrane structure prepared by reverse phase evaporation method and consists of 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol and membrane proteins. The structure of the mimetic exosomes is formed by ultrasonic dispersion and extrusion, and analyzed its characteristics and nature of the transfer effect. The size of mimetic exosomes was about 156.13 nm, with negative charge (-18.23 ±0.57 mV), and it could efficiently co-transfer protein and siRNA, and siRNA could effectively inhibit the expression of target gene Trim28. The mimetic exosomes simulate the structure of exosomes and achieve safe and efficient co-delivery of multi-component drugs.
In order to explore MYB transcription factors related to developmental processes and secondary metabolism in Morinda officinalis, we analyzed MoMYB expression based on transcriptome data from three tissues (root, stem and leaf). We used this analysis to provide a theoretical foundation for regulating the metabolism of M. officinalis. RNA-seq data along with the five databases including PFAM and plantTFDB and others were used to screen and classify MoMYB, including GO functional annotation and classification, subcellular localization, signal peptide prediction, conserved motif discovery, and comparative phylogenetic analysis. RT-qPCR was carried out to detect tissue-specific expression differences of MoMYB genes. According to transcriptome data, 109 MoMYB sequences were identified and divided into four classes, containing 51 sequences related to R2R3-MYB. Subcellular localization analysis indicated that a majority of sequences were located in nucleus. Blast2GO analysis showed that 109 MoMYB sequences were classified into three major functional ontologies including molecular function (112), biological processes (76) and cellular components (239). The R2-MYB conserved motif of 51 R2R3-MYB sequences possessed three significantly conserved tryptophan residues, whereas a phenylalanine replaced the first tryptophan in R3-MYB. The results of multiple sequence alignment and phylogenetic analysis revealed that the R2R3-MYB was distributed in all subgroups, apart from the S10, S19 and S21 subgroups. RT-qPCR indicated that several R2R3-MYB genes were differentially expressed among the three tissues, and this finding was consistent with transcriptome data. The 109 MoMYB sequences were annotated and divided into different classes, which lays the foundation for further study on MYB transcriptional factors in M. officinalis.
A QuEChERS-ultra high performance liquid chromatography-tandem mass spectrometry method was developed for qualitative screening of 169 veterinary drug residues in bear bile powder, including β-agonists and inhibitors, antibiotics (penicillins, β-lactams, sulfomamides, quinolones, chloramphenicals, tetracyclines, nitroimidazoles, macrolides, polyethers, etc.), antiviral drugs, anthelminitics, steroid hormones, nonsteroidal antiinflammatory drugs (NSAIDs) and sedatives. The samples were extracted by Na2EDTA-McIlvaine buffer solution and 5% fomic acid-acetonitrile solution, then purified by dispersive solid phase extraction. Detection of veterinary drug residues by ultra high performance liquid chromatography-triple quadrupole mass spectrometry was conducted and qualitative confirmed by ion ratios. The limits of detection of 169 veterinary drugs were 1-1 000 μg·kg-1. The method is simple and fast, which had been used for the analysis of actual samples, and can be extended to the detection of similar matrix.
We compared the pharmacokinetic and pharmacodynamic profiles of desmopressin acetate after intraocular, intravenous and intragastric administration in rabbits to better understand the systemic delivery of peptide drugs through intraocular administration. Fifteen rabbits were randomly divided into three groups (intraocular administration, 7 μg·kg-1; intravenous administration, 0.7 μg·kg-1; and intragastric administration, 7 μg·kg-1). Blood samples were taken from the heart at predetermined time points after dosing and the plasma desmopressin concentration was analyzed by enzyme-linked immunosorbent assay (ELISA). Another 21 rabbits were randomly divided into three groups (intraocular administration, 7 μg·kg-1; intravenous administration, 0.7 μg·kg-1; intragastric administration, 7 μg·kg-1) for a pharmacodynamics study. Urine was collected at predetermined intervals after dosing. The pharmacokinetic parameters after intravenous administration were as follows:Cmax was 143.0 pg·mL-1; the area under the plasma concentration-time curve for desmopressin (AUC0-t) was 999.9 pg·h·mL-1. The pharmacokinetic parameters after intraocular administration were as follows:tmax was 5 min, Cmax was 125.6 pg·mL-1, AUC0-t was 873.1 pg·h·mL-1, and absolute bioavailability (F) was 8.7%. The pharmacokinetic parameters after intragastric administration were as follows:tmax was 10 min, Cmax was 104.1 pg·mL-1, AUC0-t was 451.8 pg·h·mL-1, and absolute bioavailability was 4.5%. Intraocular administration and intravenous administration of one tenth of the dosage showed a similar effect, and the urine volume remained decreased for 12 h, but urine volume increased significantly in the second collection period after intragastric administration, and there was no decrease in volume 12 h after dosing. This study demonstrates that peptide drugs such as desmopressin can be absorbed more rapidly after intraocular administration than after intragastric administration and can exert systemic therapeutic effects. In this study, the program of animal testing had been approved by the Laboratory Animal Care and Use Committee at Anhui University of Chinese Medicine.
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