Mechanisms of transthyretin cardiomyocyte toxicity inhibition by resveratrol analogs

The transthyretin amyloidoses are a subset of protein misfolding diseases characterized by the extracellular deposition of aggregates derived from the plasma homotetrameric protein transthyretin (TTR) in peripheral nerves and the heart. We have established a robust disease-relevant human cardiac tissue culture system to explore the cytotoxic effects of amyloidogenic TTR variants. We have employed this cardiac amyloidosis tissue culture model to screen 23 resveratrol analogs as inhibitors of amyloidogenic TTR-induced cytotoxicity and to investigate their mechanisms of protection. Resveratrol and its analogs kinetically stabilize the native tetramer preventing the formation of cytotoxic species. In addition, we demonstrate that resveratrol can accelerate the formation of soluble non-toxic aggregates and that the resveratrol analogs tested can bring together monomeric TTR subunits to form non-toxic native tetrameric TTR.     

临床路径在老年性白内障手术患者中的应用评价

目的 探讨临床路径在老年性白内障手术患者中的应用及实施效果。方法 选取2009年6月—2012年6月期间在某三甲医院住院手术治疗的3 758 例老年性白内障病人为研究对象,采用对照研究,经患者同意,将其分为对照组（1 995例）和观察组（1 764例）,比较两组平均住院日、平均住院费用、西药费用、辅助诊断费、患者满意度、健康知识知晓程度。结果 观察组的平均住院日、平均住院费用、西药费用、辅助诊断费、并发症发生率均低于对照组（P <0.000 1）, 患者满意度及健康知识掌握情况均高于对照组（P<0.05）,差别具有统计学意义。结论 临床路径应用于白内障手术,可以缩短住院天数,降低医疗费用及辅助诊断费,提高患者的满意度,提高患者对健康知识的掌握率,减少术后并发症的发生。     

Variable Deposition of Amyloid β-Protein (Aβ) with the Carboxy-Terminus that Ends at Residue Valine40 (Aβ40) in the Cerebral Cortex of Patients with Alzheimer's Disease: A Double-Labeling Immunohistochemical Study with Antibodies Specific for Aβ40 and the Aβ that Ends at Residues Alanine42/Threonine43 (Aβ42)

Amyloid -protein (A) deposits in the cerebral cortices of patients with Alzheimer's disease (AD) were investigated immunohistochemically to determine their carboxy terminal sequences. Antibodies specific for A terminating at residue valine₄₀ (A40) and at residues alanine₄₂/threonine₄₃ (A42) were used. Virtually all parenchymal A deposits were positive for A42. Many of these deposits were also partially or completely labeled for A40. The degree of A40 labeling varied from area to area within a given brain and from AD case to AD case. In contrast to parenchymal deposits, A40 labeled essentially all the vascular deposits which constitute amyloid angiopathy (AA), with A42 occurring variably in some of these deposits. Occasional AA was found, however, in which A42 predominated or was exclusively deposited. Such a diversity of A species, both in brain parenchyma and in AA, suggests that multiple C-terminal processing mechanisms occur in the cell types responsible for these deposits.     

Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model

Alzheimer's disease (AD) is characterized by senile plaques and neurodegeneration although the neurotoxic mechanisms have not been completely elucidated. It is clear that both oxidative stress and inflammation play an important role in the illness. The compound curcumin, with a broad spectrum of anti-oxidant, anti-inflammatory, and anti-fibrilogenic activities may represent a promising approach for preventing or treating AD. Curcumin is a small fluorescent compound that binds to amyloid deposits. In the present work we used in vivo multiphoton microscopy (MPM) to demonstrate that curcumin crosses the blood-brain barrier and labels senile plaques and cerebrovascular amyloid angiopathy (CAA) in APPswe/PS1dE9 mice. Moreover, systemic treatment of mice with curcumin for 7 days clears and reduces existing plaques, as monitored with longitudinal imaging, suggesting a potent disaggregation effect. Curcumin also led to a limited, but significant reversal of structural changes in dystrophic dendrites, including abnormal curvature and dystrophy size. Together, these data suggest that curcumin reverses existing amyloid pathology and associated neurotoxicity in a mouse model of AD. This approach could lead to more effective clinical therapies for the prevention of oxidative stress, inflammation and neurotoxicity associated with AD.     

Prevention of pathological change and cognitive degeneration of Tg2576 mice by inoculating Aβ1–15 vaccine

This study aims to discuss the effect of preventing pathological changes and cognitive degeneration of Tg2576 mice by inoculating the subunit fragment of Aβ vaccine. Thirty-two Tg2576 mice were randomly divided into four groups, each having eight mice: Group I, the control group, inoculated with adjuvants; Group II, the Aβ42 group, inoculated with Aβ^₄₂ vaccine; Group III, the Aβ_1―15 group, inoculated with Aβ_1―15 vaccine; and Group IV, the Aβ_36―42 group, inoculated with Aβ_36―42 vaccine. The titer of the serum anti-body against Aβ₄₂ (Group II) was significantly higher than that of the control group (Group I), and a low level of antibodies could be detected in the brain homogenate in the three vaccine-inoculated groups. Morris water maze test showed that the Aβ42 group, Aβ_1―15 group and Aβ_36―42 group were obviously im-proved compared with the control group. The cultured splenocytes sampled from each group were induced by Con A or their respective antigens, and the cell proliferation of the three vaccine-inoculated groups was significantly higher than that of the control group. In the Aβ₄₂ group, IL2 and IFN-γ were relatively low and IL4 and IL10 were relatively high. By contrast, IL4 and IL10 were much higher in the Aβ_1―15 group and IL2 and IFN-γ were much higher in the Aβ_36―42 group. The immunohistochemical test showed a large number of senile plaques in the brain cortex and hippocampus of the mice in the con-trol group, no senile plaque in the brain of the Aβ_1―15 group and Aβ₄₂ group mice, and a small number of senile plaques in the brain of the Aβ_36―42 group mice. The results suggest that the subunit fragment of Aβ_1―15 vaccine could prevent not only cognitive and behavioral degeneration but also Aβ deposition and formation of senile plaques in Tg2576 mice.     

Mechanisms of amyloid beta protein-induced modification in ion transport systems: implications for neurodegenerative diseases

1. Alzheimer's disease (AD) is a neurodegenerative disorder that affects the cognitive function of the brain. Pathological changes in AD are characterized by the formation of amyloid plaques and neurofibrillary tangles as well as extensive neuronal loss. Abnormal proteolytic processing of amyloid precursor protein (APP) is the central step that leads to formation of amyloid plaque, neurofibrillary tangles, and neuronal loss.2. The plaques, which accumulate extracellularly in the brain, are composed of aggregates and cause direct neurotoxic effects and/or increase neuronal vulnerability to excitotoxic insults. The aggregates consist of soluble pathologic amyloid beta peptides AP[1–42] and AP[1–43] and soluble nonpathologic AP[1–40]. Both APP and AP interact with ion transport systems. AP induces a wide range of effects as the result of activating a cascade of mechanisms.3. The major mechanisms proposed for AP-induced cytotoxicity involve the loss of Ca²⁺ homeostasis and the generation of reactive oxygen species (ROS). The changes in Ca²⁺ homeostasis could be the result of (1) changes in endogenous ion transport systems, e.g. Ca²⁺ and K⁺ channels and Na⁺/K⁺-ATPase, and membrane receptor proteins, such as ligand-driven ion channels and G-protein-driven releases of second messengers, and (2) formation of heterogeneous ion channels.4. The consequences of changes in Ca²⁺-homeostasis-induced generation of ROS are (a) direct modification of intrinsic ion transport systems and their regulatory mechanisms, and (b) indirect effects on ion transport systems via peroxidation of phospholipids in the membrane, inhibition of phosphorylation, and reduction of ATP levels and cytoplasmic pH.5. We propose that in AD, AP with its different conformations alters cell regulation by modifying several ion transport systems and also by forming heterogeneous ion channels. The changes in membrane transport systems are proposed as early steps in impairing neuronal function preceding plaque formation. We conclude that these changes damage the membrane by compromising its integrity and increasing its ion permeability. This mechanism of membrane damage is not only central for AD but also may explain other malfunctioned protein-processing–related pathologies.     

关于金钗石斛抗氧化损伤作用的微综述

金钗石斛（Dendrobium nobile Lindl.）为兰科（Orchidaceae）石斛属（Dendrobium SW.）植物,具有益胃生津、滋阴清热等功效。药理学研究发现金钗石斛在防治肿瘤、肝硬化、老年痴呆及抗氧化应激损伤等方面具有良好的应用前景。金钗石斛可作为天然抗氧化剂的候选药材,金钗石斛总多酚、总多糖、总黄酮、总生物碱均有不同程度的自由基清除能力。研究发现这些化合物在降低活性氧水平,增强抗氧化酶活性,激活相关抗氧化通路,以及保护蛋白质、DNA、脂质免受氧化损伤等方面具有重要作用。对近年来发表的有关金钗石斛主要活性化合物抗氧化损伤作用的文献进行了综述,旨在为后续金钗石斛的开发应用提供参考。     

Somatostatin in Alzheimer's disease: A new Role for an Old Player

The amyloid beta (Aβ) peptide is central to the pathogenesis of Alzheimer's disease (AD). Insights into Aβ-interacting proteins are critical for understanding the molecular mechanisms underlying Aβ-mediated toxicity. We recently undertook an in-depth in vitro interrogation of the Aβ1–42 interactome using human frontal lobes as the biological source material and taking advantage of advances in mass spectrometry performance characteristics. These analyses uncovered the small cyclic neuropeptide somatostatin (SST) to be the most selectively enriched binder to oligomeric Aβ1–42. Subsequent validation experiments revealed that SST interferes with Aβ fibrillization and promotes the formation of Aβ assemblies characterized by a 50–60 kDa SDS-resistant core. The distributions of SST and Aβ overlap in the brain and SST has been linked to AD by several additional observations. This perspective summarizes this body of literature and draws attention to the fact that SST is one of several neuropeptide hormones that acquire amyloid properties before their synaptic release. The latter places the interaction between SST and Aβ among an increasing number of observations that attest to the ability of amyloidogenic proteins to influence each other. A model is presented which attempts to reconcile existing data on the involvement of SST in the AD etiology.     

Protective effects of carnosine on dehydroascorbate-induced structural alteration and opacity of lens crystallins: important implications of carnosine pleiotropic functions to combat cataractogenesis

The high level of dehydroascorbic acid (DHA) in the lenticular tissue is an important risk factor for the development of age-related cataracts. In this study, the effects of DHA on structure and function of lens crystallins were studied in the presence of carnosine using gel mobility shift assay, different spectroscopic techniques, and lens culture analysis. The DHA-induced unfolding and aggregation of lens proteins were largely prevented by this endogenous dipeptide. The ability of carnosine to preserve native protein structure upon exposure to DHA suggests the essential role of this dipeptide in prevention of the senile cataract development. Although the DHA-modified α-crystallin was characterized by altered chaperone activity, functionality of this protein was significantly restored in the presence of carnosine. The increased proteolytic instability of DHA-modified lens proteins was also attenuated in the presence of carnosine. Furthermore, the assessment of lens culture suggested that DHA can induce significant lens opacity which can be prevented by carnosine. These observations can be explained by the pleiotropic functions of this endogenous and pharmaceutical compound, notably by its anti-glycation and anti-aggregation properties. In summary, our study suggests that carnosine may have therapeutic potential in preventing senile cataracts linked with the increased lenticular DHA generation, particularly under pathological conditions associated with the oxidative stress.