药物表型组学:药理毒理学和个体化医学的新模式(英文)

近年来,药物基因组学(pharmacogenomics)研究收集了大量有关遗传多态性对药物反应(疗效和毒性反应)的普遍影响的信息,并突出显示了基因组指导下的个体化药物治疗的必要性。然而,由于疾病和药物治疗临床效果和毒性反应的内在复杂性,并且往往涉及数十个或数百个基因和环境因素的动态变化的影响,将药物基因组学的知识转化为个体化医学的临床实践面临着重大的挑战和障碍。为了克服这些障碍,些包括药物蛋白质组学(pharmacoproteomics)和药物代谢组学(pharmacometabolomics)等在内的新学科应运而生。同时,这些"组学"研究也揭示了在越来越详细的基因组/蛋白质组学/代谢组学的变异性与目前定义的各种临床疾病和药物治疗表型的复杂性之间存在着种非平行关系。因而要种新的研究模式来重新定义这种表型与基因组/蛋白质组/代谢组之间的非平行关系。此文将介绍个跨领域的新学科,它能为从只注重于单纯的表型-基因型关系的研究模式转化到系统性的表型组-基因组关系的研究方法提供整套新的技术平台,从而在系统生物学水平重新定义具有整合性的药物治疗靶点群,改进药物研究的模式,使其更适合于临床个体化医学与药物治疗。这个新学科就是"药物表型组学(pharmacophenomics)"。表型组(phenome)是在特定环境影响下有机体基因组/蛋白质组/代谢组表达的整体表型特征的总和。表型组学(phenomics)则是对表型组与基因组/转录组(transcritome)/蛋白质组/代谢组/相互作用组(interactome)和环境因素变化之间的复杂关系的定量研究。药物表型组学将系统性地确定对应于定义明确的疾病表型组的综合性药物靶标群。因此,药物表型组学将与药物基因组学、药物蛋白质组学组学和药物代谢组学等学科互补,为药物作用和毒性的研究提供个革命性的新模式。

Chloride channels in vascular function and disease

Vascular smooth muscle cells（VSMCs） are the major component of vascular wall which are often stretched and compressed by pounding intravascular pressure.These mechanical signals are usually transformed to electrical signals by the opening or closing of ion channels in VSNCs and endothelial cells.Intravascular pressure causes a graded membrane potential depolarization of the VSMCs and leads to vasoconstriction（i.e.,myogenic response）,independent of the vascular endothelium. Although the important role of cation channels including L-type Ca2+ channels,K+ channels,and TRP channels in the regulation of vascular tone has been well established the functional roles played by Cl- channels in the regulation of the membrane potential and vascular tone remain essentially obscure. Recent emerging evidence implicates very important roles of Cl- channels in vascular function ranging from the control of membrane potential equilibrium, vascular contraction and relaxation to the regulation of intracellular pH,cell volume homeostasis,cell proliferation,migration,and apoptosis.

S1B-1 CLC-3 Chloride Channels in the Nervous System:Missed Targets in Cerebrovascular and Brain Diseases?

CLC-3 chloride(Cl-)channel,a member of an extended family of voltagegated CLC chloride channels and transporters,are ubiquitously expressed throughout the nervous system,including in the cerebrovascular smooth muscle cells(CVSMC)and neurons in the brain.CLC-3 chloride channels play critical roles in the regulation of vascular tone and cell volume regulation,migration,proliferation,and apoptosis.Remodeling of CLC-3 Cl-channels in CVSMC contributes significantly to the development of vascular pathology and remodeling and may be novel mechanisms for hypertension and stroke.Targeting Cl-channels may be a novel therapeutic strategy for the treatment of hypertension and stroke.CLC-3 Cl-channels are also involved in neuronal apoptosis and are important regulators of cell volume and hippocampal neuronal apoptosis.Expression of CLC-3 in the presynaptic vesicles determines quantal size of inhibitory transmission in the hippocampus through impact on GABAergic synaptic transmission.A distinct presynaptic CLC-3 dependent regulatory mechanism may represent a novel target for the regulation of synaptic vesicle acidification and filling.It extends the role of Cl-in inhibitory transmission from that of a postsynaptic permeant species to a presynaptic regulatory element.The CLC-3 Cl-channels are important targets for glioma and cancer therapy.CLC-3 channels(Cl.vol)/transporters may play important roles in the regulation of many cellular functions and integrate their physiological and pathological roles with multi-chloride channels,including TMEM16A(Cl.ca),CFTR at the phenomic level in the cerebrovascular and nervous system.Deep understandings of CLC-3 Cl-channels expression and function in the nervous system may provide novel molecular insights into the cerebrovascular disease and brain disease including brain cancers.

Astragaloside IV derivative HHQ16 ameliorates infarctioninduced hypertrophy and heart failure through degradation of lncRNA4012/9456

Reversing ventricular remodeling represents a promising treatment for the post-myocardial infarction(MI)heart failure(HF).Here,we report a novel small molecule HHQ16,an optimized derivative of astragaloside IV,which effectively reversed infarction-induced myocardial remodeling and improved cardiac function by directly acting on the cardiomyocyte to reverse hypertrophy.The effect of HHQ16 was associated with a strong inhibition of a newly discovered Egr2-affliated transcript Inc9456 in the heart.While minimally expressed in normal mouse heart,Inc9456 was dramatically upregulated in the heart subjected to left anterior descending coronary artery ligation(LADL)and in cardiomyocytes subjected to hypertrophic stimulation.The critical role of Inc9456 in cardiomyocyte hypertrophy was confirmed by specific overexpression and knockout in vitro.A physical interaction between Inc9456 and G3BP2 increased NF-kB nuclear translocation,triggering hypertrophy-related cascades.HHQ16 physically bound to Inc9456 with a high-affinity and induced its degradation.Cardiomyocyte-specific Inc9456 overexpression induced,but knockout prevented LADL-induced,cardiac hypertrophy and dysfunction.HHQ16 reversed the effect of Inc9456 overexpression while lost its protective role when Inc9456 was deleted,further confirming Inc9456 as the bona fide target of HHQ16.We further identified the human ortholog of Inc9456,also an Egr2-affliated transcript,Inc4012.Similarly,Inc4012 was significantly upregulated in hypertrophied failing hearts of patients with dilated cardiomyopathy.HHQ16 also specifically bound to Inc4012 and caused its degradation and antagonized its hypertrophic effects.Targeted degradation of pathological increased Inc4012/lnc9456 by small molecules might serve as a novel promising strategy to regress infarction-induced cardiac hypertrophy and HF.

Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation

The clinical application of doxorubicin(DOX) in cancer chemotherapy is limited by its lifethreatening cardiotoxic effects. Chrysophanol(CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes.However, the effects of CHR’s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9 C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide(3 AB)and ABT888. Ectopic expression of PARP1 effectively blocked this CHR’s cardioprotection against DOX-induced cardiomyocyte injury in H9 C2 cells. Furthermore, pre-administration with both CHR and 3 AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague–Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.