GW bodies: from RNA biology to clinical implications in autoimmunity

Evaluation of: Lian S, Fritzler M, Katz J et al. Small interfering RNA-mediated silencing induces target-dependent assembly of GW/P bodies. Mol. Biol. Cell 18, 3375–3387 (2007).

GW bodies (GWBs) are also known as mammalian processing bodies and are involved in 5´–3´ mRNA degradation. Conversely, siRNA is a powerful tool for silencing genes. Recently, components of RNAi have been associated with GWBs, but as more components of this complex pathway become known, such relationships remain to be clarified. This paper evaluates the induction of GWBs by siRNA transfection. The main results of these studies indicate that siRNA increased the GWBs, such an increase is also dependent on the endogenous expression of the target mRNA; siRNA increases require GW182 or Ago-2 proteins, but not rck/p54 or LSm1. Results of the present studies propose a regulatory function of RNAi in GWB assembly; therefore, cell biology implications of GWBs may open a new area in pathogenic mechanisms of autoimmunity.     

GW117: A novel serotonin (5-HT2C) receptor antagonist and melatonin (MT1/MT2) receptor agonist with potential antidepressant-like activity in rodents

AimsTo evaluate the antidepressant‐like effect of compound GW117 in rodents using in vitro binding and uptake assays as well in vivo behavioral tests.MethodsWe investigated the target profile of GW117 using [³⁵S]‐GTPγS and [³H]PIP binding. Using the forced swimming test and chronic unpredictable stress in rats, tail suspension test in mice and rats, and learned helplessness model in mice, we further revealed the antidepressant‐like and anxiolytic‐like effects of GW117.ResultsThe current study suggests that GW117 displays serotonin 2C (5‐HT_2C) receptor antagonist and melatonin type 1 and 2 (MT₁/MT₂) receptor agonist properties, as well as evident antidepressant and anxiolytic effects.ConclusionThese data suggest that GW117 is probably a potent antidepressant.     

阿托伐他汀缓解百草枯中毒大鼠肺纤维化机制的研究

目的：观察阿托伐他汀对百草枯中毒所致肺纤维化疗效,并探讨其可能的作用机制。方法取健康成年 SD 大鼠120只,随机分为生理盐水组和百草枯组,每组10只,百草枯+阿托伐他汀10、20、40 mg 组(实验1、2、3组),百草枯+阿托伐他汀40 mg +吡格列酮组(PLZ 组)和百枯草+阿托伐他汀40 mg + GW9662组(GW9662组),每组20只。百草枯肺间质纤维化模型以百草枯溶液3.5 mg/ kg 的剂量腹腔注射制备,生理盐水组则以等体积的生理盐水腹腔注射,其余各药物干预组均在建立百草枯模型的基础上给予相应的药物,连续给药14 d 后处死大鼠,比较各组大鼠肺泡灌洗液中炎性细胞数目、肺组织中羟脯氨酸、血清中转化生长因子(TGF)-β1的含量。结果肺泡灌洗液中炎性细胞数目、肺组织中羟脯氨酸、血清中 TGF-β1的含量百草枯组均高于生理盐水组,实验2、3组均低于百草枯组(P <0．05,P <0．01)。 GW9662组肺泡灌洗液中炎性细胞数目和肺组织中羟脯氨酸低于实验3组,PLZ 组高于实验3组(P <0．05,P <0．01)。 GW9662组和 PLZ 组血清中 TGF-β1的含量均高于实验3组,但 PLZ 组升高更明显(P <0．05,P <0．01)。结论阿托伐他汀可缓解百草枯中毒所致的肺纤维化,且呈剂量依赖的方式,其作用机制可能是通过 PPARγ途径而实现。     

Evaluation of peroxisome proliferator‐activated receptor agonists on interleukin‐5‐induced eosinophil differentiation

Peroxisome proliferator‐activated receptor (PPAR) agonists have been suggested as novel therapeutics for the treatment of inflammatory lung disease, such as allergic asthma. Treatment with PPAR agonists has been shown to inhibit airway eosinophilia in murine models of allergic asthma, which can occur through several mechanisms including attenuated generation of chemoattractants (e.g. eotaxin) and decreased eosinophil migrational responses. In addition, studies report that PPAR agonists can inhibit the differentiation of several cell types. To date, no studies have examined the effects of PPAR agonists on interleukin‐5 (IL‐5) ‐induced eosinophil differentiation from haemopoietic progenitor cells. Non‐adherent mononuclear cells or CD34⁺ cells isolated from the peripheral blood of allergic subjects were grown for 2 weeks in Methocult^® cultures with IL‐5 (10 ng/ml) and IL‐3 (25 ng/ml) in the presence of 1–1000 nm PPARα agonist (GW9578), PPARβ/δ agonist (GW501516), PPARγ agonist (rosiglitazone) or diluent. The number of eosinophil/basophil colony‐forming units (Eo/B CFU) was quantified by light microscopy. The signalling mechanism involved was assessed by phosphoflow. Blood‐extracted CD34⁺ cells cultured with IL‐5 or IL‐5 + IL‐3 formed Eo/B CFU, which were significantly inhibited by rosiglitazone (100 nm , P < 0·01) but not GW9578 or GW501516. In addition, rosglitazone significantly inhibited IL‐5‐induced phosphorylation of extracellular signal‐regulated kinase 1/2. We observed an inhibitory effect of rosiglitazone on eosinophil differentiation in vitro, mediated by attenuation of the extracellular signal‐regulated kinase 1/2 signalling pathway. These findings indicate that the PPARγ agonist can attenuate tissue eosinophilia by interfering with local differentiative responses.     

过氧化物酶体增殖物激活受体γ及配体在脑缺氧缺血性疾病中的作用

过氧化物酶体增殖物激活受体γ(PPARγ)是配体活化的核转录因子,属核受体超家族成员。目前研究发现其在脑缺氧缺血性疾病中有对抗炎症介质、抗脂质过氧化反应、对抗神经元的兴奋性毒性等作用。因此,对其及配体在脑缺血缺氧性疾病中进行作用机制的研究,可能有助于对脑缺血缺氧性疾病预防或治疗中起作用的新药物靶位点的发现。     

Growth trajectories of the human fetal brain tissues estimated from 3D reconstructed in utero MRI

In the latter half of gestation (20-40 gestational weeks), human brain growth accelerates in conjunction with cortical folding and the deceleration of ventricular zone progenitor cell proliferation. These processes are reflected in changes in the volume of respective fetal tissue zones. Thus far, growth trajectories of the fetal tissue zones have been extracted primarily from 2D measurements on histological sections and magnetic resonance imaging (MRI). In this study, the volumes of major fetal zones—cortical plate (CP), subplate and intermediate zone (SP + IZ), germinal matrix (GMAT), deep gray nuclei (DG), and ventricles (VENT)—are calculated from automatic segmentation of motion-corrected, 3D reconstructed MRI. We analyzed 48 T2-weighted MRI scans from 39 normally developing fetuses in utero between 20.57 and 31.14 gestational weeks (GW). The supratentorial volume (STV) increased linearly at a rate of 15.22% per week. The SP + IZ (14.75% per week) and DG (15.56% per week) volumes increased at similar rates. The CP increased at a greater relative rate (18.00% per week), while the VENT (9.18% per week) changed more slowly. Therefore, CP increased as a fraction of STV and the VENT fraction declined. The total GMAT volume slightly increased then decreased after 25 GW. We did not detect volumetric sexual dimorphisms or total hemispheric volume asymmetries, which may emerge later in gestation. Further application of the automated fetal brain segmentation to later gestational ages will bridge the gap between volumetric studies of premature brain development and normal brain development in utero.     

CD133和GW112在胃癌中的表达及其与预后的关系

目的 研究胃癌组织CD133 mRNA和GW112 mRNA的表达水平及其与患者临床病理参数、无瘤生存率和生存率的关系.方法 采用实时定量PCR技术检测25例手术切除的胃癌及相应癌外正常胃黏膜组织中CD133mRNA和GW112mRNA的表达,随访患者进行生存分析.结果 (1)胃癌组织CD133 mRNA和GW112 mRNA表达量[0.07(0.01～0.13),0.12(0.04～0.36)]均显著高于正常胃黏膜组织[0.01(0.00～0.07),0.02(0.01～0.05)](P＜0.05).(2)GW112 mRNA表达量随患者年龄增高(＞60岁),合并淋巴结转移,TNM分期Ⅲ期或Ⅳ期而升高,差异均有统计学意义(P＜0.05).CD133 mRNA则和临床病理参数无显著关系.(3)随访所有病例,5年生存率为(28.0+9.0)%,无瘤生存率为(24.6±9.5)%.分别按照癌组织CD133和GW112表达水平分为高、低表达组.CD133高、低表达组5年生存率(7.7%比50.0%)和无瘤生存率(0%比50.5%)差异均有统计学意义(P＜0.05);GW112高、低表达组5年生存率(11.1%比71.4%)和无瘤生存率(20%比29%)差异也均有统计学意义(P＜0.05).Cox多因素分析表明癌组织CD133和GW112的表达水平是患者无瘤生存期的独立影响因子(相对危险度分别为3.792和5.155);GW112同时也是患者生存期的独立影响因子(RR=4.978).(4)ROC曲线分析发现,联合检测CD133和CEA对患者预后有一定的预测价值.结论 胃癌组织CD133 mRNA和GW112 mRNA 表达水平与胃癌恶性潜能有关,可预测胃癌患者的预后.