Latest ArticlesPrecision medicine (PM) involves the application of "omics" analysis and system biology to analyze the cause of disease at the molecular level for targeted treatments of individual patient. Based on the targeted treatment PM is closely related to pharmaceuticals, which, as a therapeutic means and supply front, mainly embody the two aspects:drug discovery/development, and clinical administration. Innovation of new molecular entities with safety and specific efficacy is the prerequisite and guarantee for the PM practice; on the other hand, the outcome and clues in clinical PM feedback to new drug research. PM and drug research/application are interdependent and promote each other. Aimed at precision medicine, drug discovery and development involve well-known contents:the discovery and validation of targets, the association between target functions and indications (proof of concept), lead discovery and optimization, the association between preclinical investigations and clinical trials, the lean of industrialization and pharmacoeconomics. At the molecular level the therapeutic efficacy originates from the interactive binding between specific atoms or groups of the drug molecule and the complementary atoms or groups of the macromolecular target in three-dimensional space. The strict arrangement of such critical atoms, groups, or fragments reflect specific features for a precise binding to the corresponding target. An alteration of amino acid residues in mutational targets leads to the change in conformation of the target protein, and an accurate structure of drug is necessary for binding to the mutant species and avoiding off-targeting effect. For the tailoring of clinical treatment to the individual patient design and development of various new molecular entities are critical for treatment choice according to the molecular features of biological markers of patients. This article provides some examples and methods of drug design and development in the new period.
This study was designed to investigate effects of pargyline on histone methylation in the promoter and enhancer regions and transcription of cytochrome P450 3A4/3A7 (CYP3A4/3A7) gene. Human primary fetal liver cells were isolated, cultured and randomly divided into several groups including control, solvent, pargyline low, middle, high dose (treated with 0.6, 1.2, 2.4 mmol·L-1). HepG2 cells were cultured and treated with 0.03, 0.3, 3 mmol·L-1 pargyline. After 48 hours, total RNAs were prepared from the cells to determine the expression of CYP3A mRNA in primary fetal cells and HepG2 cells with real-time quantative PCR (qPCR). HepG2 cells were cultured and then treated with 3 mmol·L-1 pargyline for 48 hours. The chromatin immunoprecipitation (ChIP) assay was performed with dimethylation of histone H3 at lysine 4 (H3K4me2), and IgG antibodies respectively. The precipitated DNA was resuspended and used for qPCR. Primers were used to detect different regions of CYP3A4/3A7 promoter and enhancer. Occupancy of H3K4me2 was shown as percent of input DNA relative to control cells. The results suggested that pargyline has an effect on primary fetal liver cells and HepG2 cells proliferation. The level of CYP3A7 was markedly enhanced in human primary fetal liver cells by treatment with 1.2, 2.4 mmol·L-1 of pargyline (P＜0.05, P ＜0.01) and the levels of CYP3A4/3A7 were remarkably enhanced by treatment with 3 mmol·L-1 of pargyline in HepG2 cells (P＜0.001) compared with solvent control. Occupancy of H3K4me2 on human CYP3A4 promoter (-362 to +53) and enhancer segment (-7 836 to -6 093) harbored the overlapping hepatocyte nuclear factors 4A (HNF4A) binding site compared with a negative control. Occupancy of H3K4me2 on human CYP3A7 promoter (-163 to +103) and enhancer segment (-4 054 to -3 421, -6 265 to -6 247) overlapped with glucocorticoid receptor (GR) binding site. In conclusion, the enriched H3K4me2 in the promoter and enhancer regions was induced by pargyline with HNF4A or GR binding site in CYP3A4/3A7 gene to activate the corresponding genes.
The study was designed to explore the effects of HS060098 on activation of peroxisome proliferator-activated receptors (PPARα, γ and δ) and in the down-regulation of hyperlipidemia in golden hamster. Luciferase gene reporters of PPARα, PPARγ and PPARδ were constructed in HepG2 cells and the green fluorescent protein (GFP) was used as an internal reference. Transfected cells were then cultured with various concentrations of HS060098 for 24 h. The peroxisome proliferator-response element luciferase activity was determined by the dual-luciferase reporter gene assay system. To investigate the lipid-lowering effect of HS060098, hyperlipidemic golden hamsters fed by high-diet were administered orally with HS060098 through prophylactic and therapeutic approaches respectively. The levels of blood lipids such as total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and fat index in hamsters were evaluated. The results showed that HS060098 was a potent activator of PPAR δ with a good selectivity and the median effective concentration (EC 50) is 0.01 μmol·L-1, while no obvious PPARα and PPARγ activation was observed. In the golden hamster, oral administration of HS060098 (5, 10, 20 mg·kg-1·d-1) for 2 weeks, led to a significant decrease the concentrations of plasma TC, TG, LDL-C and fat index (P＜0.05 or P＜0.01), whereas the contents of plasma HDL-C were increased significantly (P＜0.05 or P＜0.01). The data suggest that HS060098 is a novel PPAR δ agonist with a significant activity in the prevention and therapy of hyperlipemia in golden hamster.
This study is prepared to provide the basis of rheological parameters for the additional quality standard of ophthalmic gels, the rheological properties of the ophthalmic gels and the other three types of ophthalmic preparations. The medicines were compared through the study of the rheological properties for four types of ophthalmic preparations. The cone-plate rheometer was used to determine the dynamic and steady rheological parameters of four types of ophthalmic preparations. The similarities and differences of the measured results were analyzed to summarize the rheological indexes and parameters which are applied to distinguish the ophthalmic gels and the other types of ophthalmic preparations. ① The elastic modulus should be greater than the viscous modulus for the ophthalmic gels in the range of the linear viscoelastic region. ② The ophthalmic gels should be shear thinning non-Newtonian fluid with a certain yield stress and thixotropy. ③ The dynamic viscosity of the ophthalmic gels should be greater than 0.5 Pa·S at the temperature of 25℃ with the 50 s-1 shear rate. The typical rheological indexes and parameters of the ophthalmic gels were proposed in this article. The determination methods are simple and feasible. The rheological indexes and parameters have an important significance in the prescription design, production technology and quality control of the ophthalmic gels.
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