Latest ArticlesNitric oxide (NO) is widely present in peripheral and central nervous system and regulates many physiological functions. Sleep-arousal is an advanced physiological activity. Studies have shown that NO is involved in the regulation of sleep and arousal. Nitric oxide synthases (NOSs) are a family of enzymes that catalyze the production of NO from L-arginine. Through guanylate cyclase or S-nitrosation of protein, NO can affect the activity of the ascending reticular activating system to regulate the sleep-arousal process. This paper summarizes the production of NO, its effect on sleep-arousal and its mechanism in the ascending reticular activating system, and provides new ideas and directions for the study of sleep and arousal.
Most peptides have high binding affinity and good selectivity for endogenous receptors and are good lead compounds to develop into drugs. Many approved drugs are derived from the structural optimization of peptide molecules, such as the antihypertensive drug captopril and the anti-hepatitis C drug telaprevir. At present, the main problems in the development of peptide drugs include poor stability, short half-life, and high plasma clearance rate; lack of oral availability and poor patient compliance, a complex production process, and high production cost. Therefore, rational modification of peptides can not only reduce the production cost, but also improve the druggability of the peptides. Here we review structural modification strategies for peptides from the perspective of improving their physicochemical properties. These modification strategies are divided into two parts:one is modification of the peptide backbone, including unnatural amino acid modification, pseudopeptide strategy, inverse-peptide strategy, cyclization strategy, and terminal structure modification. Another is modification of the side chains of peptides, including fatty acid conjugation, polyethylene glycol conjugation, protein fusion strategy, and cholesterol conjugation.
The protein proteolysis-targeting chimeras (PROTAC) are a kind of bifunctional compound that can recruit target proteins and degrade the enzyme of target proteins. The mechanism of PROTAC is using the ubiquitin-proteasome pathway to degrade target protein specifically. Because of its potential to target non-proprietary proteins and to play roles in drug resistance, PROTAC has attracted wide attention. This review summarizes the application of small molecule PROTAC in previous studies of different targets, such as nuclear proteins, membrane proteins and cytoplasmic proteins.
Liquid chromatography-tandem mass spectrometry (LC-MS) is a promising alternative or complementary method for traditional ligand-binding assays (LBA) in antibody drug bioanalysis. However, issues related to method development, sample preparation, sensitivity and quantitative accuracy need to be addressed. This paper reviews progress in bioanalysis of antibody drugs by LC-MS methods, introduces the principle of the LC-MS method for the analysis of antibody drugs, and describes the challenges faced in quantitative antibody analysis by the LC-MS method. New strategies that can be used to deal with these challenges include:selection of surrogate peptides, purification and enrichment of samples, improvement in enzymatic digest efficiency, enrichment of peptides, and use of low rate LC. We review the application of LC-MS technology in the biological analysis of antibody drugs and discuss the prospect of using the LC-MS method for the analysis of antibody drugs.
"Kidney essence" is a profound concept in the theory of traditional Chinese medicine. But its biological basis is unknown until now, resulting in the therapeutic effects of traditional Chinese drugs on reinforcing kidney for supplementing essence hard to be evaluated. This study aimed, to explore the potential biological basis and mechanism of traditional Chinese drugs of reinforcing kidney for supplementing essence on diseases related to deficiency of kidney essence through network pharmacology analysis on the intersection of targets of drugs and diseases. The targets for ingredients in Rehmanniae radix praeparata (RRP), Polygoni multiflori radix praeparata (PMRP) and Polygonati rhizome (PR) were gathered from TCMSP and TCMID database. Osteoporosis, Alzheimer's disease, anemia, infertility and oligospermia targets were collected from OMIM and DisGeNET database. Drug-compound-target-disease (DCTD) network was established with Cytoscape 3.6.1 software, then Clue GO and DAVID database was used to acquire the annotation about GO terms and signaling pathways. Natural aging mice, an acknowledged syndrome model of deficiency of kidney essence, and RRP were used to verify the predictive targets by Western blot analysis. All animal experiments were conducted in accordance with the international guidelines and regulations for the care and use of animals. DCTD network showed that the intersection of drugs and diseases included 175 common targets. After topology analysis, 71 key were screened out targets which were associated with GO annotation exhibited that biological processes (including transcription regulation, RNA metabolism regulation, and DNA-dependent transcription regulation), cell composition (including nuclear lumen, organelle lumen, and membrane closure lumen), molecular function (including transcription regulation, transcription factor activity, and enzyme binding), and signaling pathway (including peroxisome proliferator-activated receptor alpha (PPARα), mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1 (HIF-1), erythropoietin (EPO) and other signaling pathways. In natural aging mice, the expressions of HIF-1α, growth factor receptor-bound protein 2 (GRB2), MAPK3, signal transducer and activator of transcription 5A (STAT5A), transcription factor AP-1 (JUN) and proto-oncogene c-Fos (FOS) in EPO pathway were significantly decreased. RRP significantly reversed the decrease of the above targets. Above all, these results indicated that the therapeutic effects of traditional Chinese drugs of reinforcing kidney for supplementing essence on deficiency of kidney essence may be related to the regulation of nuclear transcriptional activity and EPO signaling pathway.
Recently, hepatic sinusoidal obstruction syndrome (HSOS) induced by misuse of Gynura japonica has increased and gained global attention. Large amounts of pyrrolizidine alkaloids (PAs) are present in G. japonica; these PAs are metabolically activated to generate pyrrole-protein adducts (PPAs). In this study, male SD rats were treated orally with a single dose of G. japonica extract (GJE) at 0.062 5, 0.25, 0.5, 1, and 2 g·kg-1. Blood was collected from the orbital venous plexus at 2, 12, 24 and 48 h, and at 48 h after treatment the rats were anesthetized with isoflurane and livers were collected for hematoxylin & eosin staining. The kinetics of PPAs at different doses were studied at 10, 20, 30 min, 1, 2, 4, 6, 12, 24 h, and 48 h, after a single gavage of GJE. The experimental scheme was approved by the ethics committee of animal experiments of Shanghai University of Traditional Chinese Medicine (PZSHUTCM190912019). The concentration of PPAs in serum was determined by liquid chromatography-mass spectrometry (LC-MS). Kinetic data were processed by using the non-compartmental pharmacokinetics data analysis software program PK solutions 2TM. The results demonstrate that the concentration of PPAs increased with the dose of GJE and positively correlated with the severity of liver injury. The elimination rate of PPAs in rats was significantly prolonged at higher doses. The level of PPAs and their clearance rate may serve as useful references for the detoxification of PAs-induced injuries.
Butylphthalide and ferulic acid exhibit excellent therapeutic effects in ischemic stroke. In this research, twelve 3-n-butylphthalide derivatives were designed by molecular hybridization strategy. The target compounds were obtained by nucleophilic substitution, reduction reaction, esterification reaction and elimination reaction, and the structure was confirmed by 1H NMR, 13C NMR and ESI-MS. All compounds were evaluated for neuroprotective activity against OGD/R-induced neurotoxicity in rat cortical neurons by MTT assay. The compounds with the best neuroprotective activity were biologically evaluated for their ability to inhibit platelet aggregation induced by arachidonic acid (AA) and adenosine diphosphate (ADP) via the Bron method.The results indicate that 7b exhibited potent neurocyte protective activity as well as prominent anti-platelet aggregation activity. Compound 7b has potential to be developed as a drug for ischemic stroke.
The chemical constituents of Zingiber officinale peel were isolated and purified by various chromatographic separation techniques such as Diaion HP-20, MCI Gel CHP-20, Sephadex LH-20, ODS, silica gel and semi-preparative HPLC. Seven terpenoids were identified by physicochemical properties and spectral data:(4R, 6S)-1-(hydroxymethyl)-5, 5-dimethylbicyclo[3.1.1]hept-2-en-4-ol (1), 4-(hydroxymethyl)-1-isopropylcyclohex-2-ene-3, 4-diol (2), 3, 5, 6-trihydroxy-7-megastigmen-9-one (3), 3-(3-hydroxybutyl)-2, 4, 4-trimethyl-2, 5-cyclohexadien-1-one (4), angelicoidenol (5), grasshopper ketone (6), and dihydrophaseic acid (7), in which compounds 1, 2 are new compounds, named:(4R, 6S)-1-(hydroxymethyl)-5, 5-dimethylbicyclo[3.1.1]hept-2-en-4-ol and 4-(hydroxymethyl)-1-isopropylcyclohex-2-ene-3, 4-diol, and compounds 3-7 were obtained from this plant for the first time.
The ethyl acetate fraction of 80% ethanol extract from Bidens parviflora Willd.was isolated and purified by silica, polyamide, Sephadex LH-20 and HPLC. A total of eleven compounds were isolated and identified by physicochemical properties and spectral data as (2S)-11E-tetradecene-3, 5, 7, 9-tetrayne-1, 2, 13-triol (1), pyridine-4-formyl-O-β-D-glucopyranoside (2), maritimein (3), trichocarpine (4), okanin-4-methyl ether-3'-O-β-D-glucopyranoside (5), okanin-4-methyl ether-4'-O-β-D-(6″-acetyl)-glucopyranoside (6), (Z)-6-O-(4″-acetyl-6″-O-p-coumaroyl-β-D-glucopyranosyl)-6, 7, 3', 4'-tetrahydroxyaurone (7), quercetin-3-O-α-L-arabinoside (8), hyperoside (9), (3S)-(6E, 12E)-tetradecadiene-8, 10-diyne-1, 14-diol-3-O-β-D-glucopyranoside (10), bipinnata polyacetyloside B (11). Compounds 1 and 2 are new compounds, compounds 4 and 8 were isolated from the genus Bidens for the first time, compounds 5-7, 10 and 11 were isolated from this plant for the first time.
Atherosclerosis is one of the causes of many cardiovascular diseases. Lipid metabolism disorder is an important risk factor for atherosclerosis. Lipase-targeted screening may help discovery of hypolipidemic and anti-atherosclerotic drugs. Traditional methods for enzyme-based screening exhibit drawbacks of tedious operation steps, reduced enzyme activity, slow mass transfer, as well as high false positive rate. In this paper, an integrated perfusion enzyme affinity selection system based on hollow fiber was constructed to screen hypolipidemic and anti-atherosclerotic compounds from traditional Chinese medicines, and the total saponins of Kudingcha were taken as a case. First, we built a hollow fiber based perfusion system and optimized the methodology for enzyme affinity selection. Then, two active compounds of kudinosides A and C were identified as potential lipase inhibitors from the total saponins of Kudingcha by the proposed system. Last, the activity of kudinosides A and C was verified by lipase inhibitory assay and formation of foam cell model induced by low density lipoprotein aggregates, exhibiting the reliability of the system. This platform shows the advantages of integration, fast mass transfer, simple operation, low cost, as well as improved throughput and efficiency, which is especially suitable for rapid screening active components from traditional Chinese medicine.
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