单核苷酸多态性与哮喘个体化治疗

哮喘的异质性既包括遗传、环境因素的多样性,也包括患者对治疗反应的差异性。哮喘患者的药物治疗反应差异可能与基因单核苷酸多态性(single nucleotide polymorphisms,SNP)有关。药物-基因组学旨在研究药物作用及代谢通路上的关键分子,并探索相关基因SNP与药物疗效的关系。哮喘药物-基因组学研究有助于阐述患者遗传特性与药物治疗反应之间的关系、发现新的治疗靶点、生物标志物及评估药物疗效。未来药物-基因组学的研究可能为哮喘的个体化治疗带来帮助。

Molecular mechMolecular mechanism of glucocorticoid resistance in inflammatory bowel disease

Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in moderate to severe active Crohn’s disease and ulcerative colitis. Despite their extensive therapeutic use and the proven effectiveness, considerable clinical evidence of wide inter-individual differences in GC efficacy among patients has been reported, in particular when these agents are used in inflammatory diseases. In recent years, a detailed knowledge of the GC mechanism of action and of the genetic variants affecting GC activity at the molecular level has arisen from several studies. GCs interact with their cytoplasmic receptor, and are able to repress inflammatory gene expression through several distinct mechanisms. The glucocorticoid receptor (GR) is therefore crucial for the effects of these agents: mutations in the GR gene (NR3C1, nuclear receptor subfamily 3, group C, member 1) are the primary cause of a rare, inherited form of GC resistance; in addition, several polymorphisms of this gene have been described and associated with GC response and toxicity.However, the GR is not self-standing in the cell and the receptor-mediated functions are the result of a complex interplay of GR and many other cellular partners. The latter comprise several chaperonins of the large cooperative hetero-oligomeric complex that binds the hormonefree GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodeling, that are critical for the hormonal control of target genes transcription in the nucleus. Furthermore, variants in the principal effectors of GCs (e.g. cytokines and their regulators) have also to be taken into account for a comprehensive evaluation of the variability in GC response. Polymorphisms in genes involved in the transport and/or metabolism of these hormones have also been suggested as other possible candidates of interest that could play a role in the observed inter-individual differences in efficacy and toxicity. The best-characterized example is the drug efflux pump P-glycoprotein, a membrane transporter that extrudes GCs from cells, thereby lowering their intracellular concentration. This protein is encoded by the ABCB1/ MDR1 gene; this gene presents different known polymorphic sites that can influence its expression and function. This editorial reviews the current knowledge on this topic and underlines the role of genetics in predicting GC clinical response. The ambitious goal of pharmacogenomic studies is to adapt therapies to a patient’s specific genetic background, thus improving on efficacy and safety rates.

Correlation analysis of gene polymorphisms and β-lactam allergy

A total of 64 patients with β-lactam allergy and 30 control subjects were enrolled in a case-control study. This study is aimed to analyze the relationship between β-lactam allergy and 10 single nucleotide polymorphisms（SNPs） in interleukin-10（IL-10）, IL-13, IL-4Rα, high-affinity immunoglobulin E-receptor β chain（FcεRIβ）, interferon γ receptor 2（IFNGR2）, and CYP3A4, and within the Han Chinese population of Northwest China. Genotyping for the SNPs was conducted using the Sequenom Mass ARRAY platform. SPSS 17.0 was employed to analyze the statistical data and SHEsis was used to perform the haplotype reconstruction and analyze linkage disequilibrium of SNPs of IL-10 and IL-13. The results showed that the genotype distribution of CYP3A4 rs2242480/CT differed significantly between case and control groups of males（P=0.022; odds ratio（OR）=0.167, 95% confidence interval（CI）： 0.032–0.867）. Further analysis showed that CCA, CCG, and TAA haplotypes of IL-10 had no significant correlation in patients with β-lactam allergy. The correlation between CCT and CAC haplotypes of IL-13 and β-lactam allergy needs to be further studied. The analysis did not reveal any differences in the distribution of others gene polymorphisms between cases and controls.

Recent advance in SNP identifying methods and individualized medication

Polymorphisms associated with genes coding for a variety of drug-metabolizing enzymes （DMEs） and associated transport proteins can influence the drug metabolism rate of individuals, potentially affecting the efficacy of drug and the occurrence of adverse reactions. Single nucleotide polymorphisms （SNPs） are prevalent in all types of genetic variations. Reliable SNP genotyping provides excellent markers for detecting genetic polymolphisms, genetic disorders, and resistance of pathogen to drug, which are needed for the genetic diagnosis of disease and subtle genetic factors. With a large number of SNP genotyping studies being conducted, a lot of novel SNP identifying methods have been developed. Several SNP genotyping methods and techniques have been introduced for clinical test. These include TaqMan drug metabolism genotyping assays, pH-sensing semiconductor system, high-resolution melting curve analysis （HRM） of polymerase chain reaction （PCR） amplicons, novel multiplexed electrochemical biosensor with non-fouling surface, DNA hybridization detection using less than 10-nm gap silicon nanogap structure, tetra-primer ARMS-PCR method, acoustic detection of DNA conformation in genetic assays combined with PCR, microbeads-mass spectrometry （MEMS）-based approach, and liquid chromatography-electrospray ionization mass spectrometry. Personalized medicine has changed the conventional ways of using drugs according to experiences. It focuses on making the individualized pattern for each individual based on their own characteristics. Lots of researchers are using the analysis of clinical samples to explain the relationship between the drug adverse reactions and genetic polymorphisms. But it takes a long time from collecting the blood samples for DNA extraction and genotyping to getting results on the side effect of drug through clinical study. Therefore, it is desirable to develop improved in vitro methods to study the drug metabolizing-enzymes and transport protein genetic polymorphisms.

Recent advances in biosynthesis of bioactive compounds in traditional Chinese medicinal plants

Plants synthesize and accumulate large amount of specialized （or secondary） metabolites also known as natural products, which provide a rich source for modem pharmacy. In China, plants have been used in traditional medicine for thousands of years. Recent development of molecular biology, genomics and functional genomics as well as high-throughput analytical chemical technologies has greatly promoted the research on medicinal plants. In this article, we review recent advances in the elucidation of biosynthesis of specialized metabolites in medicinal plants, including phenylpropanoids, terpenoids and alkaloids. Th- ese natural products may share a common upstream path- way to form a limited numbers of common precursors, but are characteristic in distinct modifications leading to highly variable structures. Although this review is focused on traditional Chinese medicine, other plants with a great medicinal interest or potential are also discussed. Under- standing of their biosynthesis processes is critical for producing these highly value molecules at large scale and low cost in microbes and will benefit to not only human health but also plant resource conservation.

Plant pharmacophylogeny:past,present and future

The concept of“pharmacophylogeny”was proposed by Peigen Xiao in the 1980s based on long-term studies of Chinese researchers since ancient times and especially the 1950s.The complicated relationships and connectivity between kinship of medicinal plants,their chemical profiles and therapeutic utilities are consistent goals of pharmacophylogeny studies,which benefit innovative drug R&D.In the present work,we reviewed the origin and a brief history of research in this field,as well as the status quo and recent progress of pharmacophylogeny.The concept“pharmacophylogenomics”is put forward to represent the expanding utility of pharmacophylogeny in botanical drug R&D.Pharmacophylogeny and pharmacophylogenomics are the synthesis of multiple disciplines,such as chemotaxonomy,plant morphology,plant biochemistry/molecular biology and omics,etc.Medicinal plants within the same phylogenetic groups may have the same or similar therapeutic compounds/effects,thus forming the core of pharmacophylogeny,which is the scientific law summed up from practice and applied to practice after refining and sublimation.In the past,pharmacophylogeny plays a big role in looking for alternative resources of imported drugs in China.At present,it continues to play an active role in expanding medicinal plant resources,quality control/identification of herbal medicines,as well as predicting the chemical constituents or active ingredients of herbal medicine and the identification and determination of chemical constituents.In the ongoing future,it will play a bigger role in the search for new drugs,sorting out,summarizing,and improving herbal medicine experiences,thus boosting the sustainable conservation and utilization of traditional/natural medicinal resources.