Arimoclomol: a potential therapy under development for ALS

Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. Treatment with arimoclomol was reported to improve survival and muscle function in a mouse model of motor neuron disease. Several single- and multiple-dose safety studies have been completed in healthy control subjects. A 3-month Phase IIa study in people with ALS demonstrated safety at dosages up to 300 mg/day and another study is currently recruiting participants with familial ALS caused by mutations in the superoxide dismutase gene. We review the rationale for testing arimoclomol in sporadic and familial ALS in the context of available safety and pharmacokinetic data. Published and unpublished literature relative to the drug in the past two decades is discussed. The current review attempts to bring together our existing understanding of the actions of arimoclomol with the disease profile of ALS. The pharmacological profile of arimoclomol and the available preclinical data make it a promising therapeutic possibility in ALS.     

In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis

Diffusion magnetic resonance imaging (MRI) exhibits contrast that identifies macro‐ and microstructural changes in neurodegenerative diseases. Previous studies have shown that MR diffusion tensor imaging (DTI) can observe changes in spinal cord white matter in animals and humans affected with symptomatic amyotrophic lateral sclerosis (ALS). The goal of this preclinical work was to investigate the sensitivity of DTI for the detection of signs of tissue damage before symptoms appear. High‐field MRI data were acquired using a 9.4‐T animal scanner to examine the spinal cord of an ALS mouse model at pre‐ and post‐symptomatic stages (days 80 and 120, respectively). The MRI results were validated using yellow fluorescent protein (YFP) via optical microscopy of spinal cord tissue slices collected from the YFP,G93A‐SOD1 mouse strain. DTI maps of diffusion‐weighted imaging (DWI) signal intensity, mean diffusivity (MD), fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were computed for axial slices of the lumbar region of the spinal cord. Significant changes were observed in FA (6.7% decrease, p < 0.01), AD (19.5% decrease, p < 0.01) and RD (16.1% increase, p < 0.001) at postnatal day 80 (P80). These differences were correlated with changes in axonal fluorescence intensity and membrane cellular markers. This study demonstrates the value of DTI as a potential tool to detect the underlying pathological progression associated with ALS, and may accelerate the discovery of therapeutic strategies for patients with this disease.     

复方健耳剂对DBA/2J小鼠耳蜗组织超氧化物歧化酶1表达的影响

目的研究复方健耳剂对小鼠耳蜗组织超氧化物歧化酶(SOD)1表达的影响,探讨其预防老年性耳蜗感音神经性损害机制。方法选择断奶DBA/2J小鼠10只,随机分为对照组和中药组各5只,对照组小鼠为常规饲料与日常饮水喂养;中药组小鼠为常规饲料与中药溶液喂养;至4.3月龄时两组同时终止实验,取出耳蜗,利用Real Time PCR技术定量检测两组耳蜗组织SOD1的表达。结果中药组SOD1的表达比对照组高(P<0.05)。结论复方健耳剂通过对SOD1的表达影响可能是其有效对抗老年性耳蜗感音神经性损害的重要机制之一。     

High calcium enhances the expression of double‐stranded RNA sensors and antiviral activity in epidermal keratinocytes

Double‐stranded RNA (dsRNA) sensors including TLR3, MDA5 and RIG‐I are expressed in epidermal keratinocytes and play an important immunological role by enhancing various innate and adaptive immune responses. Although the role of elevated extracellular calcium concentration in keratinocyte differentiation is well understood, the effect of high calcium on dsRNA sensors is not well studied. We investigated alterations in dsRNA sensor expression and antiviral activity induced by a high extracellular concentration of calcium in epidermal keratinocytes. Normal human epidermal keratinocytes (NHEKs) were stimulated with high calcium and/or synthetic dsRNA, poly (I:C). TLR3, IFIH1 (MDA5) and DDX58 (RIG‐I) expression were measured via qPCR, and IFN‐β and human beta‐defensin 2 (HBD2) levels were measured using ELISA. TLR3 localization was evaluated with immunocytofluorescence. Antiviral activity was quantified with virus plaque assays using herpes simplex virus type 1 (HSV‐1). High calcium significantly upregulated mRNA expression of TLR3, IFIH1 and DDX58 in NHEKs. In addition, high calcium significantly enhanced poly (I:C)‐induced anti‐HSV‐1 activity in NHEKs. The antiviral molecule HBD2 but not IFN‐β induction by poly (I:C) was enhanced by high calcium. Our findings indicate that high levels of extracellular calcium enhance the expression of dsRNA sensors and augment antiviral activity in epidermal keratinocytes.     

Superoxide dismutases in chronic gastritis

Human gastric diseases have shown significant changes in the activity and expression of superoxide dismutase (SOD) isoforms. The aim of this study was to detect Mn‐SOD activity and expression in the tissue of gastric mucosa, primarily in chronic gastritis (immunohistochemical Helicobacter pylori‐negative gastritis, without other pathohistological changes) and to evaluate their possible connection with pathohistological diagnosis. We examined 51 consecutive outpatients undergoing endoscopy for upper gastrointestinal symptoms. Patients were classified based on their histopathological examinations and divided into three groups: 51 patients (archive samples between 2004–2009) with chronic immunohistochemical Helicobacter pylori‐negative gastritis (mononuclear cells infiltration were graded as absent, moderate, severe) divided into three groups. Severity of gastritis was graded according to the updated Sydney system. Gastric tissue samples were used to determine the expression of Mn‐SOD with anti‐Mn‐SOD Ab immunohistochemically. The Mn‐SOD expression was more frequently present in specimens with severe and moderate inflammation of gastric mucosa than in those with normal mucosa. In patients with normal histological finding, positive immunoreactivity of Mn‐SOD was not found. Our results determine the changes in Mn‐SOD expression occurring in the normal gastric mucosa that had undergone changes in the intensity of chronic inflammatory infiltrates in the lamina propria.     

Orexin A decreases lipid peroxidation and apoptosis in a novel hypothalamic cell model

Current data support the idea that hypothalamic neuropeptide orexin A (OxA; hypocretin 1) mediates resistance to high fat diet-induced obesity. We previously demonstrated that OxA elevates spontaneous physical activity (SPA), that rodents with high SPA have higher endogenous orexin sensitivity, and that OxA-induced SPA contributes to obesity resistance in rodents. Recent reports show that OxA can confer neuroprotection against ischemic damage, and may decrease lipid peroxidation. This is noteworthy as independent lines of evidence indicate that diets high in saturated fats can decrease SPA, increase hypothalamic apoptosis, and lead to obesity. Together data suggest OxA may protect against obesity both by inducing SPA and by modulation of anti-apoptotic mechanisms. While OxA effects on SPA are well characterized, little is known about the short- and long-term effects of hypothalamic OxA signaling on intracellular neuronal metabolic status, or the physiological relevance of such signaling to SPA. To address this issue, we evaluated the neuroprotective effects of OxA in a novel immortalized primary embryonic rat hypothalamic cell line. We demonstrate for the first time that OxA increases cell viability during hydrogen peroxide challenge, decreases hydrogen peroxide-induced lipid peroxidative stress, and decreases caspase 3/7 induced apoptosis in an in vitro hypothalamic model. Our data support the hypothesis that OxA may promote obesity resistance both by increasing SPA, and by influencing survival of OxA-responsive hypothalamic neurons. Further identification of the individual mediators of the anti-apoptotic and peroxidative effects of OxA on target neurons could lead to therapies designed to maintain elevated SPA and increase obesity resistance.     

子宫颈上皮内瘤变患者CD4＋、CD8＋T细胞表达与高危型HPV感染的关系

目的探讨不同级别宫颈上皮内瘤变（CIN）组织中CD4＋、CD8＋T细胞表达及与高危型人乳头瘤病毒（HR-HPV）的关系。方法对2005年1月至2008年8月在珠海市人民医院阴道镜下宫颈活检诊断为CIN并行宫颈锥切治疗的72例患者的资料进行分析,采用杂交捕获第二代方法（HC-Ⅱ）检测高危型HPVDNA含量;采用免疫组化检测30例CIN1、43例CIN2/3及10例正常宫颈组织中CD4＋、CD8＋T细胞的表达。结果 CIN2/3组的HR-HPV感染率显著高于CIN1组（P〈0.05）,CIN组HR-HPV感染率高于慢性宫颈炎组（P〈0.01）。慢性宫颈炎组、CIN1组和CIN2/3组CD4＋T细胞表达率分别为60.0%、43.3%和33.3%,CD8＋T细胞的表达率分别为70.0%、46.7%和31.0%;CD4＋、CD8＋T细胞在CIN1组及CIN2/3组的表达显著低于慢性宫颈炎组（P〈0.05）。结论 CD4＋、CD8＋T细胞表达下调可能促进宫颈HR-HPV感染的发生,并对宫颈癌前病变的发生、发展起一定的作用。     

银杏叶提取物EGb761对铜与高胆固醇共处理家兔主动脉病变的影响

目的 观察银杏叶提取物EGb761对铜和高胆固醇诱导的家兔主动脉病变的保护作用.方法 采用Sparks的方法复制铜和高胆固醇家兔模型,EGb761以50 mg·kg-1·d-1的剂量灌胃3 w后,苏丹Ⅲ和HE染色观察主动脉的大体和镜下形态改变,图像分析测量动脉粥样硬化面积占主动脉面积的百分比,酶法检测血清总胆同醇(TC)、甘油三酯( TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)水平,硫代巴比妥酸( TBA)法测定血清丙二醛(MDA)水平,实时定量RT-PCR法检测肝组织LDLR和LR PI mRNA表达.结果 模型组主动脉可见明显的动脉粥样硬化改变,EGb761组动脉粥样硬化病变较模型组减轻,图像分析结果显示,EGb761组斑块面积百分比显著降低,与模型组相比差别具有统计学意义(P＜0.05).模型组血清TC、TG、HDL-C、LDL-C和MDA水平均显著升高,与正常组相比差别具有统计学意义(P＜0.05);EGb761组血清LDL-C和MDA水平均显著降低,与模型组相比差别具有统计学意义(P＜0.05).EGb761组肝组织LRPI mRNA表达显著升高,与模型组相比差别具有统计学意义(P＜0.05).结论 EGb761具有改善动脉粥样硬化病变的作用,其作用机制与调节血脂水平和抗过氧化损伤有关.