Delineation of biomarkers and molecular pathways of residual effects of fluoxetine treatment in juvenile rhesus monkeys by proteomic profiling

Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective serotonin reuptake inhibitor,the possible long-term effects of fluoxetine on brain development in children are poorly understood.In the current study,we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques(Macaca mulatta)one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling.We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex(DLPFC)and cingulate cortex(CC)that correlated with impulsivity in animals,suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment.Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.

Role of ZAC1 in transient neonatal diabetes mellitus and glucose metabolism

Transient neonatal diabetes mellitus 1(TNDM1) is a rare genetic disorder representing with severe neonatal hyperglycaemia followed by remission within one and a half year and adolescent relapse with type 2 diabetes in half of the patients. Genetic defects in TNDM1 comprise uniparental isodisomy of chromosome 6, duplication of the minimal TNDM1 locus at 6q24, or relaxation of genomically imprinted ZAC1 /HYMAI. Whereas the function of HYMAI, a non-coding m RNA, is still unidentified, biochemical and molecular studies show that zinc finger protein 1 regulating apoptosis and cell cycle arrest(ZAC1) behaves as a factor with versatile transcriptional functions dependent on binding to specific GC-rich DNA motives and interconnected regulation of recruited coactivator activities. Genome-wide expression profiling enabled the isolation of a number of Zac1 target genes known to regulate different aspects of β-cell function and peripheral insulin sensitivity. Among these, upregulation of Pparγ and Tcf4 impairs insulinsecretion and β-cell proliferation. Similarly, Zac1-mediated upregulation of Socs3 may attenuate β-cell proliferation and survival by inhibition of growth factor signalling. Additionally, Zac1 directly represses Pac1 and Rasgrf1 with roles in insulin secretion and β-cell proliferation. Collectively, concerted dysregulation of these target genes could contribute to the onset and course of TNDM1. Interestingly, Zac1 overexpression in β-cells spares the effects of stimulatory G-protein signaling on insulin secretion and raises the prospect for tailored treatments in relapsed TNDM1 patients. Overall, these results suggest that progress on the molecular and cellular foundations of monogenetic forms of diabetes can advance personalized therapy in addition to deepening the understanding of insulin and glucose metabolism in general.

AGNP精神科治疗药物监测共识指南：2011

治疗药物监测(Therapeutic drug monitoring,TDM),如通过定量测定血清或血浆药物浓度指导用药剂量优化,已经成为对患者进行精神药物治疗的很有价值的工具。在患者用药依从性难以判断、药物耐受性不佳、治疗剂量下无效以及可能存在药代动力学药物-药物相互作用等情况下,测定药物浓度是很有用的。在精神科,有可能明显获益于TDM的主要患者群体包括儿童、孕妇、老年患者、智力障碍患者、涉及司法的患者、已知或怀疑携带药代动力学相关基因变异的患者,以及合并躯体疾病影响药代动力学的患者。然而,只有将TDM充分整合到临床治疗过程中去,才能发挥其优化药物治疗的潜在优势。为了促进TDM的合理应用,神经精神药理学与药物精神病学协会(Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie,AGNP)的TDM专家组在2004年发表了精神药物治疗药物监测指南。之后,随着知识不断更新,又有许多可能需要进行TDM的新药上市。因此,本次更新将神经精神药物的种类扩展到了128种,并将其TDM必要性划分为从"强烈推荐"到"可能有用"的四个等级。经过大量细致且全面的文献检索与分门别类的汇总整理,将基于循证医学理念的"治疗参考浓度范围"和"剂量相关参考浓度范围"呈现给大家。本共识指南引入了"实验室警戒浓度"的新概念,即实验室需要马上告知治疗医生的药物浓度上限。本共识指南还给出了诸如药物作为细胞色素P450酶的底物和抑制剂的性质,代谢物与母药浓度比值的常见范围,以及与结果解释相关的内容,还提供了何时将TDM与遗传药理学检测相结合的建议。遵循本指南,有助于改善许多患者精神药物治疗的效果,特别是那些存在药代动力学异常的患者。TDM是一门交叉学科,有时针对看起来不一致的数据,需要多学科坦诚地讨论,只有这样,患者才能从这种合作中获益。

神经精神药理学治疗药物监测共识指南:2017版

治疗药物监测(Therapeutic Drug Monitoring,TDM)通过定量测定和解释血药浓度以优化药物治疗。TDM着眼于药代动力学的个体差异,使个体化药物治疗成为可能。在精神病学和神经病学领域中,有可能明显获益于TDM的主要患者群体包括少年儿童、孕妇、老年患者、智障患者、药物滥用者、涉法精神病患者、已知或怀疑药代动力学异常的患者以及合并躯体疾病影响药代动力学的患者。常规剂量下治疗无效,用药依从性难以判断,药物耐受性不佳,以及可能存在药代动力学方面的药物-药物相互作用等情况都是治疗药物监测的典型指征。然而,只有将TDM充分整合到临床治疗过程中,才能发挥其优化药物治疗的潜在优势。为了向临床医生和实验室提供有效的TDM信息,神经精神药理学与药物精神病学协会(Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie,AGNP)的TDM专家组在2004年发表了第一版《精神科治疗药物监测指南》。2011年进行了更新之后,现在再次更新。遵循新版指南,可能会改善神经精神药物治疗的效果,加快很多患者的康复,并降低医疗费用。

神经精神药理学治疗药物监测共识指南:2017版

2.2剂量相关参考浓度范围对于TDM结果的解释,除了治疗参考浓度范围外还有另一个浓度范围,即所谓的剂量相关参考浓度范围。治疗参考浓度范围的应用是药效动力学问题,而剂量相关参考浓度范围的运用是药代动力学问题。后者比较的是测得的药物浓度与理论预期药物浓度范围。参照药代动力学研究,优先考虑没有合并用药或药物基因组异常的患者群(“正常”患者),在日维持剂量(Daily maintenance dose,D m)、给药间隔(Dosing interval,d i)、总清除率(Total clearance,CL)和生物利用度(Bioavailability,F)已知情况下,某种药物在某个“正常”患者体内的预期平均稳态浓度(Average steady-state concentration,C av)可通过下面的公式计算。

Imprinted Zac1 in neural stem cells

Neural stem cells(NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with animportant role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging.

Lipid metabolism is associated with temperament,corticosteroid,and hematological measures in infant rhesus monkeys(Macaca mulatta)

DEAR EDITOR,Individuals can differ in how their behavioral and physiological systems are organized.The fact that these individual differences persist across life suggests they are supported by physical structures that may co-vary.Here,we explored three datasets associated with health and behavioral outcomes,which were obtained from infant rhesus monkeys during standardized assessment of biobehavioral organization.Variation in biobehavioral measures was related to variation in molecular pathways,as assessed by metabolomics.

静脉注射IgG的中和作用对Lambert-Eaton肌无力综合征患者的突触前效应

Intravenous immunoglobulin (IVIg) treatment improves mus- cle strength in Lambert-Eaton myasthenic syndrome (LEMS), butits specific mod e of action is unknown. We have delineated its mode of action on neuromuscular b locking properties of LEMS IgG. The effect of sera and purified IgG from six pat ients with LEMS on evoked quantal release was investigated after direct applicat ion to the motor nerve terminal by the perfused macro-patch-clamp electrode in mouse hemidiaphragms. The effect of LEMS IgG was analyzed alone and after coinc ubation with different concentrations of IVIg or its Fab fragments. All LEMS ser a and purified LEMS IgG fractions taken before IVIg treatment inhibited evoked q uantal release in a dose-dependent manner. When LEMS IgG was coincubated with a therapeutic IVIg preparation, presynaptic inhibitory activity of LEMS IgG was d iminished in a dose-dependent fashion. Monovalent Fab fragments were as effecti ve in neutralizing the activity of LEMS IgG as whole IVIg. These direct neutrali zing effects of IVIg may explain its therapeutic efficacy.

Peripheral immune cell-derived matrix metalloprotease 8(MMP8):brain trafficking promotes depression-like behavior

In a study recently published in Nature,Cathomas et al.1 report that social stress in mice increases the levels of matrix metalloprotease(MMP)8 in circulating immune cells,thereby altering extracellular space(ECS)and neuronal activity,and ultimately social behavior in susceptible animals.Behavioral deficits resembled those from major depressive disorder(MDD)raising the prospect of MMP8 as a new druggable target in tailored treatments.

Nucleoside reverse transcriptase inhibitors and Kamuvudines inhibit amyloid-βinduced retinal pigmented epithelium degeneration

Nonfibrillar amyloid-βoligomers(AβOs)are a major component of drusen,the sub-retinal pigmented epithelium(RPE)extracellular deposits characteristic of age-related macular degeneration(AMD),a common cause of global blindness.We report that AβOs induce RPE degeneration,a clinical hallmark of geographic atrophy(GA),a vision-threatening late stage of AMD that is currently untreatable.We demonstrate that AβOs induce activation of the NLRP3 inflammasome in the mouse RPE in vivo and that RPE expression of the purinergic ATP receptor P2RX7,an upstream mediator of NLRP3 inflammasome activation,is required for AβO-induced RPE degeneration.Two classes of small molecule inflammasome inhibitors—nucleoside reverse transcriptase inhibitors(NRTIs)and their antiretrovirally inert modified analog Kamuvudines—both inhibit AβOs-induced RPE degeneration.These findings crystallize the importance of P2RX7 and NLRP3 in a disease-relevant model of AMD and identify inflammasome inhibitors as potential treatments for GA.

An Artemisinin Derivative ART1 Induces Ferroptosis by Targeting the HSD17B4 Protein Essential for Lipid Metabolism and Directly Inducing Lipid Peroxidation

Artemisinin and its derivatives,commonly known as antimalarial drugs,have gradually come to be regarded as potential antitumor agents,although their cytotoxic efficacy and mechanisms of action remain to be settled.Herein,we report that an artemisinin analog,ART1,can potently induce ferroptosis in a subset of cancer cell lines.Structure–activity relationship(SAR)analysis reveals that both the endoperoxide moiety and the artemisinin skeleton are required for the antitumor activity of ART1.Aided with ART1-based small-molecule tools,chemical proteomic analysis identified the HSD17B4 protein as a direct target of ART1.HSD17B4 resides in peroxisomes and is an essential enzyme in the catabolism of very-long-chain fatty acids.Our results demonstrate that ART1 initiates ferroptosis through selective oxidation of the fatty acids in peroxisomes by hijacking the HSD17B4 protein without disturbing its enzymatic function,providing a promising mechanism to develop therapeutics for cancer treatment.