3-磷酸甘油酸脱氢酶促进丝氨酸合成在肿瘤进展中的机制

丝氨酸生物合成途径活性的上调是许多癌症明显的共同特征。该途径的第一种限速酶3-磷酸甘油酸脱氢酶(PHGDH)在黑色素瘤、乳腺癌和肾癌等癌组织中高表达，对肿瘤细胞增殖、转移、侵袭有着重要作用。糖酵解中间产物3-磷酸甘油酸在PHGDH作用下，氧化为磷酸羟基丙酮酸并最终合成丝氨酸。丝氨酸转化为甘氨酸，然后在核苷酸、s-腺苷甲硫氨酸(SAM)和还原型谷胱甘肽(GSH)的合成中起着重要的作用。PHGDH 有望成为肿瘤治疗的新靶点。     

Ocular dysfunctions and toxicities induced by antiepileptic medications: Types,pathogenic mechanisms,and treatment strategies

Introduction: Ocular dysfunctions and toxicities induced by antiepileptic drugs (AEDs) are rarely reviewed and not frequently received attention by treating physicians compared to other adverse effects (e.g. endocrinologic, cognitive and metabolic). However, some are frequent and progressive even in therapeutic concentrations or result in permanent blindness. Although some adverse effects are non-specific, others are related to the specific pharmacodynamics of the drug.

Areas covered: This review was written after detailed search in PubMed, EMBASE, ISI web, SciELO, Scopus, and Cochrane Central Register databases (from 1970 to 2019). It summarized the reported ophthalmologic adverse effects of the currently available AEDs; their risks and possible pathogenic mechanisms. They include ocular motility dysfunctions, retinopathy, maculopathy, glaucoma, myopia, optic neuropathy, and impaired retinal vascular autoregulation. In general, ophthalmo-neuro- or retino-toxic adverse effects of AEDs are classified as type A (dose-dependent), type B (host-dependent or idiosyncratic) or type C which is due to the cumulative effect from long-term use.

Expert opinion: Ocular adverse effects of AEDs are rarely reviewed although some are frequent or may result in permanent blindness. Increasing knowledge of their incidence and improving understanding of their risks and pathogenic mechanisms are crucial for monitoring, prevention, and management of patients’ at risk.     

Antioxidant and anti-inflammatory activities of lycopene against 5-fluorouracil-induced cytotoxicity in Caco2 cells

5-fluorouracil (5FU) is widely used to treat colorectal cancer (CC) and its main mechanisms of anticancer action are through generation of ROS which often result in inflammation. Here, we test the effect of Lycopene against 5FU in Caco2 cell line. Caco2 cells were exposed to 3 µg/ml of 5FU alone or with 60, 90, 120 µg/ml of lycopene. This was followed by assessment of cytotoxicity, oxidative stress, and gene expression of inflammatory genes. Our findings showed that Lycopene and 5FU co-exposure induced dose-dependent cytotoxic effect without compromising the membrane integrity based on the LDH assay. Lycopene also significantly enhanced 5FU-induced SOD activity and GSH level compared to control for all mixture concentrations (p < 0.01). Lycopene alone and combination with 5FU-induced expression of IL-1β, TNF-α, and IL-6. Furthermore, IFN-γ expression was significantly enhanced by only mixture of lycopene (90 µg/ml) and 5FU (p < 0.05). In conclusion, Lycopene supplementation with 5FU therapy resulted in improvement in antioxidant parameters such as catalase and GSH levels giving the cell capacity to cope with 5FU-mediated oxidative stress. Lycopene also enhanced IFN-γ expression in the presence of 5FU, which may activate antitumor effects further enhancing the cancer killing effect of 5FU.     

Glutamate hypothesis in schizophrenia

Schizophrenia is a chronic and severe psychiatric disorder that has profound impact on an individual’s life and on society. Thus, developing more effective therapeutic interventions is essential. Over the past quarter‐century, an abundance of evidence from pharmacologic challenges, post‐mortem studies, brain imaging, and genetic studies supports the role of glutamatergic dysregulation in the pathophysiology of schizophrenia, and the results of recent randomized clinical trials based on this evidence have yielded promising results. In this article, we review the evidence that alterations in glutamatergic neurotransmission, especially focusing on the N‐methyl‐d ‐aspartate receptor (NMDAR) function, may be a critical causative feature of schizophrenia, how this contributes to pathologic circuit function in the brain, and how these insights are revealing whole new avenues for treatment development that could reduce treatment‐resistant symptoms, which account for persistent disability.     

DNA vaccine encoding the moonlighting protein Onchocerca volvulus glyceraldehyde-3-phosphate dehydrogenase (Ov-GAPDH) leads to partial protection in a mouse model of human filariasis

River blindness, caused by the filarial parasite Onchocerca volvulus, is a major socio-economic and public health problem in Sub-Saharan Africa. In January 2015, The Onchocerciasis Vaccine for Africa (TOVA) Initiative has been launched with the aim of providing new tools to complement mass drug administration (MDA) of ivermectin, thereby promoting elimination of onchocerciasis in Africa. In this context we here present Onchocerca volvulus glyceraldehyde-3-phosphate dehydrogenase (Ov-GAPDH) as a possible DNA vaccine candidate. We report that in a laboratory model for filariasis, immunization with Ov-GAPDH led to a significant reduction of adult worm load and microfilaraemia in BALB/c mice after challenge infection with the filarial parasite Litomosoides sigmodontis. Mice were either vaccinated with Ov-GAPDH.DNA plasmid (Ov-pGAPDH.DNA) alone or in combination with recombinantly expressed Ov-GAPDH protein (Ov-rGAPDH). During the following challenge infection of immunized and control mice with L. sigmodontis, those formulations which included the DNA plasmid, led to a significant reduction of adult worm loads (up to 57% median reduction) and microfilaraemia (up to 94% reduction) in immunized animals. In a further experiment, immunization with a mixture of four overlapping, synthetic Ov-GAPDH peptides (Ov-GAPDHpept), with alum as adjuvant, did not significantly reduce worm loads. Our results indicate that DNA vaccination with Ov-GAPDH has protective potential against filarial challenge infection in the mouse model. This suggests a transfer of the approach into the cattle Onchocerca ochengi model, where it is possible to investigate the effects of this vaccination in the context of a natural host–parasite relationship.     

Fast CT-PRESS-based spiral chemical shift imaging at 3 Tesla.

A new sequence is presented that combines constant-time point-resolved spectroscopy (CT-PRESS) with fast spiral chemical shift imaging. It allows the acquisition of multivoxel spectra without line splitting with a minimum total measurement time of less than 5 min for a field of view of 24 cm and a nominal 1.5x1.5-cm2 in-plane resolution. Measurements were performed with 17 CS encoding steps in t1 (Deltat1=12.8 ms) and an average echo time of 151 ms, which was determined by simulating the CT-PRESS experiment for the spin systems of glutamate (Glu) and myo-inositol (mI). Signals from N-acetyl-aspartate, total creatine, choline-containing compounds (Cho), Glu, and mI were detected in a healthy volunteer with no or only minor baseline distortions within 14 min on a 3 T MR scanner.     

吗啡依赖和戒断对大鼠杏仁核神经甾体和氨基酸递质水平的影响

目的研究吗啡依赖和戒断时大鼠杏仁核中神经甾体和氨基酸递质水平的变化。方法连续7天给予大鼠盐酸吗啡建立吗啡依赖模型。使用纳洛酮(2mg/kg)催促戒断,观察戒断症状并进行评分。将大鼠断头处死后,剥离大脑并分离出杏仁核,用液-液萃取和固相萃取法提取游离型和结合型神经甾体。神经甾体(包括脱氢表雄酮、孕烯醇酮、别孕烯醇酮、脱氢表雄酮硫酸酯和孕烯醇酮硫酸酯)的含量使用高效液相色谱-质谱法测定。甘氨酸、谷氨酸和γ-氨基丁酸的含量采用柱前OPA衍生-电化学检测-高效液相色谱法测定。结果与盐水对照组相比,吗啡依赖大鼠杏仁核中的脱氢表雄酮水平降低33 %(P<0·01)。与戒断对照组比较,吗啡戒断大鼠杏仁核中的孕烯醇酮和别孕烯醇酮水平分别升高45 %和42 %(P<0·05) ,γ-氨基丁酸水平降低18 %(P<0·01)。与吗啡依赖组比较,吗啡戒断组大鼠杏仁核中的孕烯醇酮和孕烯醇酮硫酸酯水平分别升高60 %和40 %(P<0·05) ,甘氨酸水平降低14 %(P<0·05)。结论吗啡依赖大鼠杏仁核中的脱氢表雄酮可能参与吗啡依赖的形成而与吗啡戒断症状的表达无关。其他神经甾体(包括孕烯醇酮、别孕烯醇酮和孕烯醇酮硫酸酯)则可能参与吗啡的戒断而与依赖的形成无关。纳洛酮催促戒断时,大鼠杏仁核中抑制性氨基酸递质的合成和释放受到抑制。表明大鼠杏仁核中的各种神经甾体和氨基酸递质在吗啡依赖和戒断时发生了不同的变化。     

强迫谱系障碍与第Ⅱ组代谢型谷氨酸受体相关候选基因位点的连锁分析

目的 了解代谢型谷氨酸受体mGlu2受体（mGluR2）基因、mGlu3受体（mGluR3）基因等与强迫谱系障碍（OCSDs）的连锁关系。方法 选取一个连续三代发病的强迫谱系障碍家系，采集到该家系中12个正常个体，8个受累个体的血样，选取mGluR2、mGluR3基因附近7对微卫星标记引物，采用两点和多点非参数分析的方法对该家系进行连锁分析。结果 7对微卫星标记位点的两点和多点非参数分析LOD值（NPL值），位于mGluR3基因附近的标记D7S644两点非参数分析NPL值为1．719（P=0．078），多点非参数分析NPL值为1．712（P=0．078），达到验证性连锁的阈值（NPL=1．2），但未达到提示性连锁的阕值（NPL=2．2），D7S2481两点非参数分析NPL值为0．628（P=0．179），多点非参数分析NPL值为0．852（P=0．141），接近验证性连锁的阈值，其余5对微卫星标记位点非参数分析NPL值均未达到验证性连锁的阈值。结论 提示mGluR3基因与OCSDs可能存在连锁关系，不能排除mGluR2基因与OCSDs的相关性。     

Correction of frequency and phase variations induced by eddy currents in localized spectroscopy with multiple echo times.

As a consequence of the time-varying magnetic field induced by eddy currents, frequency drifting occurs when the sampling window of localized spectroscopy continuously shifts. The frequency drifting and the concomitant phase variations can severely affect spectroscopy results when data are acquired with multiple echo times (TEs), such as in the measurement of glutamate (Glu) concentration using the TE-averaged method. Specifically, the averaged spectra are further broadened and distorted in the presence of residual eddy currents, and editing of the coupled spins of Glu C4 protons is affected, resulting in errors in the measured relative intensity ratio. Postacquisition correction using unsuppressed water as reference can effectively minimize this detrimental effect, as manifested by the significantly enhanced signal intensity. Also, it is demonstrated that the methyl signals of creatine (Cr) at 3.0 ppm and choline (Cho) at 3.2 ppm can be used as internal references in finding frequency and phase disparities between different TEs.