Biological and Potential Therapeutic Roles of Sirtuin Deacetylases

Sirtuins comprise a unique class of nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylases that target multiple protein substrates to execute diverse biological functions. These enzymes are key regulators of clinically important cellular and organismal processes, including metabolism, cell division and aging. The desire to understand the important determinants of human health and lifespan has resulted in a firestorm of work on the seven mammalian sirtuins in less than a decade. The implication of sirtuins in medically important areas such as diabetes, cancer, cardiovascular dysfunction and neurodegenerative disease has further catapulted them to a prominent status as potential targets for nutritional and therapeutic development. Here, we present a review of published results on sirtuin biology and its relevance to human disease. Received 25 June 2008; received after revision 20 August 2008; accepted 29 August 2008     

Liver X receptors in cardiovascular and metabolic disease

Liver X receptors (LXRs) α and β are nuclear oxysterol receptors and metabolic sensors initially found to regulate cholesterol metabolism and lipid biosynthesis. Recent studies have elucidated the importance of LXR in the development of cardiovascular diseases and metabolic disorders. LXR agonists prevent development of atherosclerosis by modulation of metabolic as well as inflammatory gene expression in rodent models. Moreover, LXR activation inhibits hepatic gluconeogenesis and lowers serum glucose levels, indicating possible application of LXR activation in the treatment of diabetes mellitus. However, first-generation LXR agonists elevate hepatic and serum trigylceride levels, making subtype-specific agonists and selective LXR modulators rather than unselective LXR agonists a potential pharmacological strategy. This review summarizes the multiple physiological and pathophysiological implications of LXRs and observations that identify LXRs as potential targets for therapeutic interventions in human cardiovascular and metabolic disease. Received 30 August 2005; received after revision 10 October 2005; accepted 4 November 2005     

Phytanic acid: production from phytol, its breakdown and role in human disease

Phytanic acid is a branched-chain fatty acid that accumulates in a variety of metabolic disorders. High levels of phytanic acid found in patients can exceed the millimolar range and lead to severe symptoms. Degradation of phytanic acid takes place by α-oxidation inside the peroxisome. A deficiency of its breakdown, leading to elevated levels, can result from either a general peroxisomal dysfunction or from a defect in one of the enzymes involved in α-oxidation. Research on Refsum disease, belonging to the latter group of disorders and characterized by a deficiency of the first enzyme of α-oxidation, has extended our knowledge of phytanic acid metabolism and pathology of the disease greatly over the past few decades. This review will centre on this research on phytanic acid: its origin, the mechanism by which its α-oxidation takes place, its role in human disease and the way it is produced from phytol. Received 4 October 2005; received after revision 24 February 2006; accepted 26 April 2006     

Sialic acid-specific lectins: occurrence, specificity and function

Sialic acids consist of a family of acidic ninecarbon sugars that are typically located at the terminal positions of a variety of glycoconjugates. Naturally occurring sialic acids show an immense diversity of structure, and this reflects their involvement in a variety of biologically important processes. One such process involves the direct participation of sialic acids in recognition events through specific interactions with lectins, a family of proteins that recognise and bind sugars. This review will present a detailed overview of our current knowledge regarding the occurrence, specificity and function of sialic acid-specific lectins, particularly those that occur in viruses, bacteria and non-vertebrate eukaryotes. Received 13 December 2005; received after revision 9 February 2006; accepted 15 February 2006     

Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review, we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt, Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD. Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006     

鳖鳃腺炎的组织病理学研究

用光镜和电镜技术研究鳖鳃腺炎的组织病理变化．观察表明：病变脏器普遍充血、淤血或出血,血细胞变性;肠上皮崩解脱落,微绒毛及胞器减少,AKP活性下降;肝细胞及肾近曲小管上皮细胞肿胀、颗粒变性或透明变性,局部细胞溶解,出现坏死病灶;肝糖原减少甚至消失;肾小球膨大,远曲小管和集合小管腔内充满嗜酸性物质;脾红髓扩大,多数细胞及核异形,严重者细胞破裂、解体;骨骼肌细胞肿胀、核固缩;多数病变细胞内的内质网和线粒体扩张变性．还讨论了该病的病变特征及性质等问题．     

LOD score exclusion analyses for candidate disease susceptibility genes using case-parents design

The focus of almost all the association studies of candidate genes is to test for their importance. We recently developed a LOD score approach that can be used to test against the importance of candidate genes for complex diseases and quantitative traits in random samples. As a complementary method to regular association analyses, our LOD score approach is powerful but still affected by the population admixture, though it is more conservative. To control the confounding effect of population heterogeneity, we develop here a LOD score exclusion analysis using case?parents design, the basic design of the transmission disequilibrium test (TDT) approach that is immune to population admixture. In the analysis, specific genetic effects and inheritance models at candidate genes can be analyzed and if a LOD score is ≤-2.0, the locus can be excluded from having an effect larger than that specified. Simulations show that this approach has reasonable power to exclude a candidate gene having small genetic effects if it is not a disease susceptibility locus (DSL) with sample size often employed in TDT studies. Similar to association analyses with the TDT in nuclear families, our exclusion analyses are generally not affected by population admixture. The exclusion analyses may be implemented to rule out candidate genes with no or minor genetic effects as supplemental analyses for the TDT. The utility of the approach is illustrated with an application to test the importance of vitamin D receptor (VDR) gene underlying the differential risk to osteoporosis.     

对一类带时滞的SIRS型媒介传染病的稳定性分析

讨论了一类带时滞的SIRS型媒介传染病模型,通过分析系统平衡点处的特征方程研究时滞的引入对平衡点稳定性的影响,同时表明了时滞能破坏系统的稳定性引发Hopf分支产生周期解.     

肾上腺少见疾病诊治19例报告

目的探讨临床上少见肾上腺疾病的诊断和治疗的关键问题。方法对19例病人的诊疗过程进行回顾性分析。结果12例术前确诊,7例术后确诊,其中17例施行手术,16例成功行根治性切除,1例因肿瘤广泛生长粘连无法切除只行活检,2例穿刺活检明确诊断。肿块大小从微小结节状到20cm×25cm×30cm,重约20～5000g。恶性肿瘤者术后行放疗或化疗,随访1年以上生活质量好。结论全面的术前准备最重要,治疗上首选手术探查,争取根治性切除肿瘤。     

载脂蛋白E定量测定的实验评价及临床应用

目的 :评价定量测定载脂蛋白E免疫比浊法 (液体双试剂 )的实验性能 ,讨论载脂蛋白E在心脑血管疾病及老年性痴呆症发病中的作用。方法 :对测定血清载脂蛋白E免疫比浊法的线性、精密度、回收、对比、重复性试验进行测定。正常对照组 12 0例 ,分 4组 ,每 15周岁为一组 ,每组进行载脂蛋白E的测定 ;心肌梗死、脑梗塞各 2 4例 ,高血压 67例 ,老年性痴呆症 2 0例和正常对照组 12 0例 ,分别检测血清脂蛋白 (a) (Lp(a) )、总胆固醇 (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)、载脂蛋白A1(apoA1)、载脂蛋白B(apoB)、载脂蛋白E(apoE) ,对检测结果做统计学分析。结果 :免疫比浊法线性范围为 0～ 10mg/dL ,Y =0 .93 87X + 0 .3 4,r =0 .9972 ;三种不同浓度的血清精密度试验批内CV值分别是2 .85 %、2 .0 6%、2 .47% ;批间CV值分别为 4.0 1%、3 .89%、3 .67% ;内加入法平均回收率为 10 0 .14% ,两种试剂对比试验 ,Y =0 .93 4X - 0 .0 75 ,r=0 .988;重复性试验其批内批间CV值分别为 3 .12 %、3 .98%。正常对照组 4组间进行比较 ,P >0 .0 5 ,各组分别与文献报道结果比较 ,P >0 .0 5 ,无显著性差异 ;心梗与脑梗血清中apoE、Lp(a)、TG、apoB均升高 ,与正常对照组间差异显著 ,P <0 .0 5