丙戊酸盐治疗双相情感障碍的研究进展

作为心境稳定剂,丙戊酸盐治疗各型双相情感障碍均有一定的疗效。近年来对各型双相情感障碍患者进行的临床研究证实：丙戊酸盐能改善躁狂症状;联合镇静药物治疗可有效改善抑郁症状;联合抗抑郁药物预防抑郁发作的疗效优于锂盐。丙戊酸盐与其他心境稳定剂联合治疗快速循环型双相情感障碍患者时可能更有益,也更适用于非快速循环型双相情感障碍患者的长程治疗。     

丙戊酸盐在精神科的临床应用分析

丙戊酸盐类药物是治疗各类癫痫的廉价药物,近年来在精神科应用较为广阔,可能成为较有潜力的一种精神药品。我科应用丙戊酸盐治疗精神性糖尿病患者462例,现将其在精神科临床应用的机制和不良反应报道如下。1资料与方法选择2011年1月-2012年3月我院收治应用丙戊酸盐的精神性糖尿病患者462例,对其进行病例分析及不定期的回访调查。     

不同丙戊酸盐和丙戊酸剂型对丙戊酸血药浓度的影响

目的：研究不同丙戊酸盐和丙戊酸剂型对丙戊酸血药浓度的影响。方法：回顾性分析某院270例丙戊酸血药浓度监测报告,记录患者姓名、年龄、体质量、丙戊酸的用法与用量、联合用药情况（合用药品及其用法与用量）和血药浓度监测结果。分析不同丙戊酸盐和丙戊酸剂型对丙戊酸标准血药浓度的影响。结果：二元Logistic回归分析结果表明丙戊酸盐类型和剂型对标准血药浓度有显著影响（P<0.05）;丙戊酸镁的标准血药浓度[（9.18±3.54）μg·kg·mL^-1·mg^-1]大于丙戊酸钠盐的标准血药浓度[（6.76±2.54）μg·kg·mL^-1·mg^-1];丙戊酸缓释片的标准血药浓度[（8.38±3.49）μg·kg·mL^-1·mg^-1]大于丙戊酸普通片的标准血药浓度[（6.88±2.54）μg·kg·mL^-1·mg^-1],差异均具有显著性（P<0.05）。结论：不同丙戊酸盐和丙戊酸剂型对丙戊酸血药浓度存在明显影响,如何选择丙戊酸盐和丙戊酸剂型对丙戊酸的合理运用具有重要意义。     

基于倾向值匹配的丙戊酸盐对奥氮平血药浓度的影响

目的：探讨在自然条件下丙戊酸盐对奥氮平稳态血药浓度的影响。方法：在医院HIS系统中调取2017年6-10月住院期间测定了奥氮平血药浓度的精神分裂症患者病例，并通过医院病例系统收集相关信息；采用倾向值匹配的方法，对奥氮平合并使用丙戊酸盐组（处理组）和奥氮平组（控制组）进行1∶1匹配后分析。结果：对2组间进行倾向值匹配后，所有混杂因素均在2组间达到平衡。匹配后处理组比控制组奥氮平血药浓度降低了14.37%（P=0.003）。结论：丙戊酸盐会降低奥氮平的稳态血药浓度。     

癫痫和双相情感障碍女性患者服用丙戊酸盐期间生殖系统的超声改变

目的 观察癫痫和双相情感障碍女性患者服用丙戊酸盐(VPA)期间生殖系统的超声改变。方法 选取单独服用VPA治疗癫痫和双相情感障碍的女性患者100例作为治疗组，分别于入组时和服用VPA 1个月、3个月和6个月时行妇科彩色多普勒超声检查。另选取同期体检健康女性67例作为对照组，分别于入组时和6个月时行妇科彩色多普勒超声检查。观察治疗组服用VPA后生殖系统的超声改变，记录卵巢体积和子宫内膜厚度。对比两组观察期内卵巢多囊改变及子宫内膜病变发生率。结果 治疗组服用VPA 3个月及6个月时彩色多普勒超声检查可见双侧卵巢均匀性增大，包膜增厚，回声增强，皮质可见多个无回声区，子宫内膜可见回声均匀或不均匀增厚。治疗组服用VPA 6个月时卵巢多囊改变和子宫内膜病变的发生率均高于对照组(P<0.05)。治疗组服用VPA 3个月和6个月时的卵巢体积和子宫内膜厚度大于入组时和服药1个月时(P<0.05)。结论 VPA可致卵巢多囊改变以及子宫内膜病变，且随着用药时间的延长，改变越显著。临床应谨慎使用VPA,需控制好用药时间，同时定期进行妇科彩色多普勒超声检查，监测卵巢及子宫状况。     

红景天苷的神经保护作用及作用机制研究进展

动物实验结果显示红景天苷对多种原因引起的神经细胞和脑组织损伤均有保护作用,有望用于周围神经损伤以及脑缺血性和神经变性疾病（如脑梗死、老年痴呆、帕金森病、癫痫、抑郁、抽动秽语综合征、肌萎缩性侧索硬化症和糖尿病脑病等）的防治。其神经保护作用机制主要包括3个方面：（1）通过抗氧化作用,抑制NOX2/ROS/MAPKs和REDD1/mTOR/p70S6K信号通路,激活AMPK/SIRT1、RhoA-MAPK和PI3K/Akt信号通路,对抗各种损伤因子引起的氧化应激,抑制炎性细胞因子表达,防止细胞内Ca²⁺超载和半胱天冬酶-3活化,保护神经细胞和干细胞免遭凋亡性损伤;（2）抑制淀粉样前体蛋白β位裂解酶-1的表达和β-分泌酶活性,阻滞内源性伤害因子β-淀粉样肽生成;（3）通过阻滞Notch信号通路,促进BMP信号通路,上调多种神经营养因子表达,诱导间充质干细胞和神经干细胞定向分化成神经元,提高许旺细胞增殖和功能,从而加速神经修复、再生和功能恢复。     

锂盐神经保护作用机制的研究进展

锂盐作为治疗躁狂抑郁症的主要药物，在近年来的研究中发现它在体内外均具有很好的神经保护作用，可用于治疗阿尔茨海默病、亨廷顿舞蹈病和脑缺血等脑血管疾病。其神经保护作用机制涉及多个方面，包括糖原合酶激酶，3、NMDA离子通道、bcl-2蛋白家族、脑源性神经营养因子信号传导通路、丝裂原激活的蛋白激酶信号传导通路、c-fos及c-jun，目前尚未完全阐明。综述锂盐的神经保护作用及其机制的研究进展。     

美国警告丙戊酸盐致神经管缺陷的风险

美国食品药品监督管理局（FDA）提醒医疗专业人员，怀孕期间胎儿暴露于丙戊酸盐相关产品（丙戊酸、双丙戊酸钠／divalproex sodium）可导致神经管缺陷和其他严重出生缺陷的风险升高，如颅面缺损、心血管畸形。FDA和生产企业将对产品说明书进行修订。     

转录因子Nrf2的神经保护作用及其机制

NF-E2相关因子2(Nrf2),感受体内反应活性氧(Reactive oxygen species,ROS)变化后,与体内的锚定蛋白Keap1解聚,发生核转位并调控下游多种抗氧化应激蛋白,解毒酶及转运体基因的表达,参与抗氧化应激生理及病理过程.目前,许多研究发现,Nrf2转录调控的下游靶基因可以对抗由脑中风氧化应激引起的神经系统病变,阿尔茨海默病(Alzheimer's disease),帕金森病(Parkinson's disease),侧索硬化(Amyotrophic lateral sclerosis,ALS).本文对近年来Nrf2在神经保护方面的作用及其机制,以及Nrf2作为药物治疗靶点治疗神经退行性病变的最新研究成果进行总结.     

丙戊酸盐:增加神经元结节缺损及其他新生儿畸形

美国FDA告诫职业医务工作者及广大病人,母亲妊娠期间胎儿暴露于丙戊酸盐(valproate)及相关药物(丙戊酸与丙戊酰钠),可增加新生儿神经元结节及其他重要畸形,如颜面缺损及心血管畸形。根据FDA的资料,美国一般人群中,新生儿神经元结节缺损发生率为1/1500,而母亲妊娠前3个月服用该药,婴儿出生后神经元结节缺损发生率为1/20,     

Neuropharmacological Mechanisms Underlying the Neuroprotective Effects of Methylphenidate

Methylphenidate is a psychostimulant that inhibits the neuronal dopamine transporter. In addition, methylphenidate has the intriguing ability to provide neuroprotection from the neurotoxic effects of methamphetamine and perhaps also Parkinson’s disease; both of which may likely involve the abnormal accumulation of cytoplasmic dopamine inside dopaminergic neurons and the resulting formation of dopamine-associated reactive oxygen species. As delineated in this review, the neuroprotective effects of methylphenidate are due, at least in part, to its ability to attenuate or prevent this abnormal cytoplasmic dopamine accumulation through several possible neuropharmacological mechanisms. These may include 1) direct interactions between methylphenidate and the neuronal dopamine transporter which may attenuate or prevent the entry of methamphetamine into dopaminergic neurons and may also decrease the synthesis of cytoplasmic dopamine through a D2 receptor-mediated signal cascade process, and 2) indirect effects upon the functioning of the vesicular monoamine transporter-2 which may increase vesicular dopamine sequestration through both vesicle trafficking and the kinetic upregulation of the vesicular monoamine transporter-2 protein. Understanding these neuropharmacological mechanisms of methylphenidate neuroprotection may provide important insights into the physiologic regulation of dopaminergic systems as well as the pathophysiology of a variety of disorders involving abnormal dopamine disposition ranging from substance abuse to neurodegenerative diseases such as Parkinson’s disease.     

Mechanisms Underlying the Comorbidity of Schizophrenia and Type 2 Diabetes Mellitus

The mortality rate of patients with schizophrenia is high, and life expectancy is shorter by 10 to 20 years. Metabolic abnormalities including type 2 diabetes mellitus (T2DM) are among the main reasons. The prevalence of T2DM in patients with schizophrenia may be epidemiologically frequent because antipsychotics induce weight gain as a side effect and the cognitive dysfunction of patients with schizophrenia relates to a disordered lifestyle, poor diet, and low socioeconomic status. Apart from these common risk factors and risk factors unique to schizophrenia, accumulating evidence suggests the existence of common susceptibility genes between schizophrenia and T2DM. Functional proteins translated from common genetic susceptibility genes are known to regulate neuronal development in the brain and insulin in the pancreas through several common cascades. In this review, we discuss common susceptibility genes, functional cascades, and the relationship between schizophrenia and T2DM. Many genetic and epidemiological studies have reliably associated the comorbidity of schizophrenia and T2DM, and it is probably safe to think that common cascades and mechanisms suspected from common genes’ functions are related to the onset of both schizophrenia and T2DM. On the other hand, even when genetic analyses are performed on a relatively large number of comorbid patients, the results are sometimes inconsistent, and susceptibility genes may carry only a low or moderate risk. We anticipate future directions in this field.     

土槿乙酸衍生物PBA-D1诱导Hela细胞凋亡及其机制

目的研究土槿乙酸衍生物PBAD1体外能否诱导宫颈癌细胞株(Hela细胞)发生凋亡及其发生机制。方法采用MTT、SRB、细胞生长曲线、细胞集落、荧光显微镜检测凋亡细胞、DNAladder、流式细胞仪等方法进行凋亡检测,用Westernblot方法检测凋亡过程中相关基因表达的变化。结果土槿乙酸衍生物PBAD1在体外试验中对Hela细胞的杀伤力强,荧光显微镜观察到了凋亡小体;DNAladder法检测到凋亡时DNA降解形成的梯带,流式细胞仪检测到了细胞凋亡峰,同时观察到细胞周期的变化。在凋亡过程中,凋亡相关基因p53基因表达明显增高,而bcl2表达下调。结论PBAD1体外能诱导Hela细胞发生凋亡,其机制可能与p53基因表达上调及bcl2基因表达下调有关。     

Possible Mechanisms Underlying Statin-Induced Skeletal Muscle Toxicity in L6 Fibroblasts and in Rats

3-Hydroxy-3-methylglutaryl CoA reductase inhibitors (statins) are safe and well-tolerated therapeutic drugs. However, they occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Here, we investigated the mechanism of statin-induced myotoxicity in L6 fibroblasts and in rats in vivo. L6 fibroblasts were differentiated and then treated with pravastatin, simvastatin, or fluvastatin for 72 h. Hydrophobic simvastatin and fluvastatin decreased cell viability in a dose-dependent manner via apoptosis characterized by typical nuclear fragmentation and condensation and caspase-3 activation. Both hydrophobic statins transferred RhoA localization from the cell membrane to the cytosol. These changes induced by both hydrophobic statins were completely abolished by the co-application of geranylgeranylpyrophosphate (GGPP). Y27632, a Rho-kinase inhibitor, mimicked the hydrophobic statin-induced apoptosis. Hydrophilic pravastatin did not affect the viability of the cells. Fluvastatin was continuously infused (2.08 mg/kg at an infusion rate of 0.5 mL/h) into the right internal jugular vein of the rats in vivo for 72 h. Fluvastatin infusion significantly elevated the plasma CPK level and transferred RhoA localization in the skeletal muscle from the cell membrane to the cytosol. In conclusion, RhoA dysfunction due to loss of lipid modification with GGPP is involved in the mechanisms of statin-induced skeletal muscle toxicity.     

Estrogenic Endocrine-Disrupting Chemicals: Molecular Mechanisms of Actions on Putative Human Diseases

Endocrine-disrupting chemicals (EDC), including phthalates, bisphenol A (BPA), phytoestrogens such as genistein and daidzein, dichlorodiphenyltrichloroethane (DDT), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are associated with a variety of adverse health effects in organisms or progeny by altering the endocrine system. Environmental estrogens, including BPA, phthalates, and phytoestrogens, are the most extensively studied and are considered to mimic the actions of endogenous estrogen, 17β-estradiol (E2). Diverse modes of action of estrogen and estrogen receptors (ERα and ERβ) have been described, but the mode of action of estrogenic EDC is postulated to be more complex and needs to be more clearly elucidated. This review examines the adverse effects of estrogenic EDC on male or female reproductive systems and molecular mechanisms underlying EDC effects that modulate ER-mediated signaling. Mechanisms of action for estrogenic EDC may involve both ER-dependent and ER-independent pathways. Recent findings from systems toxicology of examining estrogenic EDC are also discussed.     

Butea superba–Induced Amelioration of Cognitive and Emotional Deficits in Olfactory Bulbectomized Mice and Putative Mechanisms Underlying Its Actions

This study investigated the effects of alcoholic extract of Butea superba (BS) on cognitive deficits and depression-related behavior using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its actions. OBX mice were treated daily with BS (100 and 300 mg/kg, p.o.) or reference drugs, tacrine (2.5 mg/kg, i.p.) and imipramine (10 mg/kg, i.p.) from day 3 after OBX. OBX impaired non-spatial and spatial cognitive performances, which were elucidated by the novel object recognition test and modified Y maze test, respectively. These deficits were attenuated by tacrine and BS but not imipramine. OBX animals exhibited depression-like behavior in the tail suspension test in a manner reversible by imipramine and BS but not tacrine. OBX down-regulated phosphorylation of synaptic plasticity–related signaling proteins: NMDA receptor, AMPA receptor, calmodulin-dependent kinase II, and cyclic AMP-responsive element-binding protein. OBX also reduced choline acetyltransferase in the hippocampus. BS and tacrine reversed these neurochemical alterations. Moreover, BS inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BS ameliorates not only cognition dysfunction via normalizing synaptic plasticity–related signaling and facilitating central cholinergic systems but also depression-like behavior via a mechanism differing from that implicated in BS amelioration of cognitive function in OBX animals.     

Anti-Inflammatory Effects of Scopoletin and Underlying Mechanisms

The present study determined the anti-inflammatory activity and related mechanisms of scopoletin. It was found that scopoletin significantly inhibited croton oil-induced mouse ear edema. Scopoletin could also decrease the vascular dye leakage induced by topical application of croton oil, consistent with the reduced myeloperoxidase (MPO) activity and polymorphonuclear (PMN) infiltration. The inhibitor of nitric oxide (NO) synthase l-N^ω -nitro-arginine (l-NN, 10 mg/kg) attenuated croton oil-induced ear edema by 56.5%. However, pretreatment of l-NN did not affect the inhibitory effects of scopoletin (100 mg/kg) on mouse ear edema, which suggested that scopoletin exerted anti-inflammatory activities in an endothelial NO-independent manner. Further research revealed that scopoletin reduced the overproduction of PGE₂ and TNF-α in croton oil-treated mouse ears. Scopoletin was also shown to attenuate the hind paw edema induced by carrageenan in mice, and lower the MPO activity and malondialdehyde (MDA) level in paw tissues. These findings imply that the anti-inflammatory activities of scopoletin involve inhibition of eicosanoid biosynthesis, cell influx, and peroxidation.     

Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis

Panax ginseng has been shown to have a protective effect for irradiated animals or cells. Ginsenosides are the most active components isolated from ginseng, and ginsenoside Rd has been identified as one of the effective compounds responsible for the pharmaceutical actions of ginseng. In the present study, we studied the molecular mechanisms for the radio-protective action of ginsenoside Rd in rat intestinal epithelial IEC-6 cells. Cells were irradiated with gamma-ray, and apoptosis was examined using Hoechst staining and Western blot analysis. Treatment with ginsenoside Rd before gamma-irradiation inhibited irradiation-induced apoptosis in IEC-6 cells. Administration of Rd after irradiation also inhibited apoptosis in these cells. Irradiation of IEC-6 cells resulted in inactivation of Akt phosphorylation that was abrogated by Rd. On the other hand, irradiation activated phosphorylation of ERK1/2 but did not affect that of p38 MAPK. Inhibition of Akt phosphorylation prevented the reduction of apoptosis by Rd following irradiation. Pretreatment with an inhibitor of the MEK pathway further decreased the number of apoptotic cells. Rd decreased the ratios of Bax/Bcl-2 and Bax/Bcl-xL, the levels of cytochrome c, and the cleaved form of caspase-3 in irradiated IEC-6 cells. Our results suggest that ginsenoside Rd protects and rescues rat intestinal epithelial cells from irradiation-induced apoptosis through a pathway requiring activation of PI3K/Akt, inactivation of MEK, and also inhibition of a mitochondria/caspase pathway.     

大黄素诱导白血病U937细胞凋亡及机制初探

目的研究中药大黄素(Emodin)对人髓系白血病细胞株U937细胞增殖及凋亡的影响,探讨bcl-2/bax比值变化和procaspase-3(CPP32)的激活在其中的作用。方法MTT法绘制细胞生长曲线;克隆形成试验观察大黄素对U937细胞增殖的影响;线粒体膜电位检测、DNA倍体分析及DNA凝胶电泳分析细胞凋亡;PCR及检测大黄素作用前后bcl-2/bax基因及蛋白表达的变化;流式细胞术测定大黄素作用前后caspase-3活性变化及检测CPP32的蛋白表达的变化。结果大黄素能抑制U937细胞增殖,作用72h的半数抑制浓度(IC50)约为30μmol·L-1;线粒体膜电位、亚G1峰(凋亡峰)及DNA片段化的检出证实大黄素能诱导U937细胞凋亡,并呈量效关系。大黄素作用后G0/G1期细胞比例较对照组增高,S期比例下降,且与药物浓度呈正相关。大黄素作用后U937细胞bcl-2/bax基因及蛋白的表达水平比值下降,被激活的caspase-3阳性细胞增多,CPP32蛋白表达水平下降,并呈时效关系。结论大黄素能通过诱导凋亡来抑制U937细胞增殖,bcl-2/bax比值的降低及CPP32的活化可能参与了大黄素抑制U937细胞增殖和诱导凋亡的过程。     

Pharmacological inhibition of the MAPK/ERK pathway increases sensitivity to 2-chloro-2'-deoxyadenosine (CdA) in the B-cell leukemia cell line EHEB

EHEB leukemic cells, which are derived from a patient suffering B-cell chronic lymphocytic leukemia (B-CLL), display intermediate sensitivity to the purine analogue 2-chloro-2'-deoxyadenosine (CdA). Because the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway can rescue cancer cells from apoptotic signals, we investigated MAPK/ERK signaling in EHEB cells in response to CdA. We observed that CdA, at concentrations around its IC50, dose- and time-dependently increased the phosphorylation state of ERK 1/2 (p-ERK), indicating an activation of the MAPK/ERK pathway. This activation required CdA metabolism and de novo protein synthesis, and was independent on caspase activation. Interruption of ERK signaling, using the specific MEK inhibitors U-0126 and PD-98059, significantly enhanced CdA cytotoxicity, evaluated by the MTT assay. Drug interaction analysis showed synergism in the majority of combinations between CdA and MEK inhibitors tested. MEK inhibitors also dramatically increased apoptosis induced by CdA alone, evaluated by caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage. Collectively, these observations show that ERK 1/2 activation elicited by CdA serves as a cytoprotective function and suggest that inhibitors of this pathway could be combined with CdA in the treatment of selected hematological malignancies.