Potential Role of Interleukin‐18 in Liver Disease Associated with Insulin Resistance

Objective: Interleukin (IL)‐18 has been associated with obesity and insulin resistance, both risk factors for the development of liver disease, but the role of IL‐18 in liver disease associated with insulin resistance is presently unknown. We hypothesized that circulating IL‐18 would be related to serum concentrations of liver chemistry tests (LCTs) in apparently healthy subjects and wished to study whether this correlation was dependent on insulin sensitivity (S_I). Research Methods and Procedures: One hundred six apparently healthy white men consecutively enrolled in a cross‐sectional, population‐based study dealing with S_I in men were studied, and S_I (minimal model analysis), LCTs (colorimetry), and IL‐18 serum concentrations (immunoassay) were assessed. Results: Compared with subjects in the lowest quartile for serum IL‐18, subjects in the highest quartile exhibited increased serum triglycerides and decreased S_I, in addition to higher serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (all p < 0.05). The direct association between both ALT and AST and IL‐18 was further confirmed by examining the distribution of serum IL‐18 by quartiles of ALT and AST. Subjects in the highest quartile for serum ALT and AST had higher IL‐18 concentrations compared with subjects in the lowest quartile for these LCTs (both p = 0.01). In multiple regression analysis, IL‐18, but not S_I, was an independent predictor of serum concentrations of ALT and AST, explaining 7% and 4% of their variance, respectively. Discussion: In summary, IL‐18 serum concentrations are associated in apparently healthy humans with plasma concentrations of various LCTs. IL‐18 could contribute to the development of liver disease associated with insulin resistance.     

Generative FDG-PET and MRI Model of Aging and Disease Progression in Alzheimer's Disease

The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimer''s Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation.     

甲基乙二醛在阿尔茨海默病中的作用

糖酵解毒性副产物甲基乙二醛（methylglyoxal,MG）以其高反应活性在阿尔茨海默病（Alzheimer''s disease,AD）发生发展过 程中起到了重要的作用。MG 在AD病人脑中累积并促进beta淀粉样蛋白(beta-amyloid peptide,A beta)的产生和寡聚。大量累积的MG 通 过形成晚期糖基化终末产物(advanced glycosylation end products,AGEs)加剧了神经元中tau 蛋白的过度磷酸化。研究还发现MG 和AGEs 均参与了AD 脑中活性氧（reactive oxygen species,ROS）的产生和炎症的发生发展。本文总结了MG 在AD 病理过程中 的作用,并加以综述。     

The Role of IGF-system in Vascular Insulin Resistance

Insulin and IGF-I are closely related peptides, which interact by several mechanisms. In high supraphysiological concentrations (>/=10 (-8) M), they cross-react with each other's receptors with 100- to 1000-fold lower affinity than with their cognate receptors. This can cause confusion, since in many in vitro studies, insulin has been used in high unphysiological concentrations, which activate IGF-I receptors. Due to the differences in affinity, insulin and IGF-I probably do not activate each other's receptors in vivo. IGF-I receptors are several-fold more abundant than insulin receptors in human micro- and macrovascular endothelial cells and in human vascular smooth muscle cells. Both insulin and IGF-I receptor protein can be demonstrated and they are activated by their cognate ligand at physiological concentrations of 10 (-9)-10 (-10) M. In vascular smooth muscle cells, IGF-I but not insulin stimulates metabolism and growth. IGF-I stimulates DNA-synthesis and growth in microvascular endothelial cells, but neither insulin nor IGF-I have any effect on macrovascular endothelial cells. Both insulin and IGF-I have been shown to stimulate nitric oxide production in endothelial cells, but only the effect of IGF-I was obtained at a physiological concentration. In both endothelial and vascular smooth muscle cells, insulin and IGF-I receptors occur as insulin/IGF-I hybrid receptors with high affinity to IGF-I and low for insulin. Due to the low number of insulin receptors and the presence of hybrid receptors the insulin receptor signal is probably too attenuated to elicit biological effects, explaining the insulin resistance of vascular cells in vitro. In vivo both insulin and IGF-I have been reported to increase muscle blood flow in physiological concentrations. Whether this is due to direct effects on endothelial cells or indirectly induced is not clear. The effect of insulin is attenuated by insulin resistance. In conclusion, the in vitro data suggest that endothelial cells and vascular smooth muscle cells are sensitive to IGF-I, but insensitive to insulin, and this is due to a preponderance of IGF-I receptors and the presence of insulin/IGF-I hybrid receptors.     

Tau蛋白在阿尔茨海默病中的作用

阿尔茨海默病(AD)是非常普遍的神经变性性疾病并且是老年人痴呆的主要原因。AD患者的症状特点包括进行性的认知障碍、记忆丧失和行为障碍,与大脑中的病理变化密切相关。AD现成为全球最严重的健康和社会经济问题。在AD患者脑中神经纤维网或神经营养障碍的过程中存在tau蛋白的异常。tau蛋白丧失其促微管组装的生物学功能,导致细胞骨架的破坏、丝状物形成和神经缠结,轴突运输损害,进而导致突触蛋白失去功能和神经退行性病变。其数量和结构的改变将会影响其功能而且会出现异常聚集。调节Tau蛋白的异常聚集的分子机制主要是一些翻译后修饰使其结构及构象发生变化。因此,异常磷酸化和截断的tau蛋白作为tau蛋白病理过程的关键机制而引起学者关注。本文描述了tau蛋白的结构和功能及其在AD中的主要病理变化,同时在本文中还涉及到磷酸化的tau蛋白是神经元对氧化应激的代偿反应这一观点。对tau蛋白进行更加全面的解读。     

Beta-Amyloid Monomer and Insulin/IGF-1 Signaling in Alzheimer's Disease

Alzheimer's disease is the most common form of dementia among older people and is still untreatable. While ??-amyloid protein is recognized as the disease determinant with a pivotal role in inducing neuronal loss and dementia, an impaired brain insulin signaling seems to account in part for the cognitive deficit associated with the disease. The origin of this defective signaling is uncertain. Accumulating toxic species of ??-amyloid, the so-called oligomers, has been proposed to be responsible for downregulation of neuronal insulin receptors. We have found that the nontoxic form of ??-amyloid, the monomer, is able to activate insulin/insulin-like growth factor-1 (IGF-1) receptor signaling and thus behaves as a neuroprotectant agent. Our suggestion is that depletion of ??-amyloid monomers, occurring in the preclinical phase of Alzheimer's disease, might be the cause of early insulin/IGF-1 signaling disturbances that anticipate cognitive decline.     

水杨酸在植物抗病中的作用

水杨酸是一种重要的能激活植物抗病防卫反应的内源信号分子,本文首先介绍了水杨酸的基本性质及水杨酸在植物抗病中的作用,然后从水杨酸与水杨酸结合蛋白的相互作用以及水杨酸介导的信号传导途径与非水杨酸介导的信号途径等方面初步探讨了水杨酸诱导植物抗病性的作用机制,最后总结了研究水杨酸作用机制对植物抗性生理和抗性分子生物学发展的意义。     

水杨酸在植物抗病中的作用

水杨酸是一种重要的能激活植物抗病防卫反应的内源信号分子。本文首先介绍了水杨酸的基本性质及水杨酸在植物抗病中的作用,然后从水杨酸与水杨酸结合蛋白的相互作用以及水杨酸介导的信号传导途径与非水杨酸介导的信号途径等方面初步探讨了水杨酸诱导植物抗病性的作用机制,最后总结了研究水杨酸作用机制对植物抗性生理和抗性分子生物学发展的意义。     

胰岛素抵抗与脂肪肝关系的研究

胰岛素抵抗(IR)是许多疾病的独立危险因素。胰岛素抵抗与脂肪代谢紊乱非常密切,研究发现它在脂肪肝的发生、发展过程中起了很大的作用。近年来,越来越多的人已经意识到脂肪肝与胰岛素抵抗之间的密切关系。在胰岛素抵抗与脂肪肝的研究中关于瘦素及瘦素抵抗在胰岛素抵抗及脂肪肝的关系中的作用是研究比较多的,本文主要介绍了胰岛素抵抗、脂肪肝的发生机制及瘦素、瘦素抵抗在其中的催化作用。     

The Potential Role of Rho GTPases in Alzheimer's Disease Pathogenesis

Alzheimer's disease (AD) is characterized by a wide loss of synapses and dendritic spines. Despite extensive efforts, the molecular mechanisms driving this detrimental alteration have not yet been determined. Among the factors potentially mediating this loss of neuronal connectivity, the contribution of Rho GTPases is of particular interest. This family of proteins is classically considered a key regulator of actin cytoskeleton remodeling and dendritic spine maintenance, but new insights into the complex dynamics of its regulation have recently determined how its signaling cascade is still largely unknown, both in physiological and pathological conditions. Here, we review the growing evidence supporting the potential involvement of Rho GTPases in spine loss, which is a unanimously recognized hallmark of early AD pathogenesis. We also discuss some new insights into Rho GTPase signaling framework that might explain several controversial results that have been published. The study of the connection between AD and Rho GTPases represents a quite unchartered avenue that holds therapeutic potential.     

The Role of PTEN in Chronic Growth Hormone-Induced Hepatic Insulin Resistance

Chronic growth hormone (GH) therapy has been shown to cause insulin resistance, but the mechanism remains unknown. PTEN, a tumor suppressor gene, is a major negative regulator of insulin signaling. In this study, we explored the effect of chronic GH on insulin signaling in the context of PTEN function. Balb/c healthy mice were given recombinant human or bovine GH intraperitoneally for 3 weeks. We found that phosphorylation of Akt was significantly decreased in chronic GH group and the expression of PTEN was significantly increased. We further examined this effect in the streptozotocin-induced Type I diabetic mouse model, in which endogenous insulin secretion was disrupted. Insulin/PI3K/Akt signaling was impaired. However, different from the observation in healthy mice, the expression of PTEN did not increase. Similarly, PTEN expression did not significantly increase in chronic GH-treated mice with hypoinsulinemia induced by prolonged fasting. We conducted in-vitro experiments in HepG2 cells to validate our in-vivo findings. Long-term exposure to GH caused similar resistance of insulin/PI3K/Akt signaling in HepG2 cells; and over-expression of PTEN enhanced the impairment of insulin signaling. On the other hand, disabling the PTEN gene by transfecting the mutant PTEN construct C124S or siPTEN, disrupted the chronic GH induced insulin resistance. Our data demonstrate that PTEN plays an important role in chronic-GH-induced insulin resistance. These findings may have implication in other pathological insulin resistance.     

New Evidence for the Role of Ceramide in the Development of Hepatic Insulin Resistance

Aim

There are few and contradictory data on the role of excessive accumulation of intracellular sphingolipids, particularly ceramides, in the development of hepatic insulin resistance. In our study we assessed accumulated sphingolipid fractions and clarify the mechanisms of hepatic insulin resistance development as well as involvement of fatty acid and ceramide transporters in this process.

Methods

In culture of primary rat hepatocytes, exposed to high concentration of palmitic acid (0.75mM) during short and prolonged incubation, high performance liquid chromatography was used to assess intra- and extracellular sphingolipid fractions content. Degree of palmitate-induced insulin resistance was estimated by measuring changes in phosphorylation of insulin pathway proteins by western blotting as well as changes in expression of different type of transporters.

Results

In our study short and prolonged exposure of primary hepatocytes to palmitic acid resulted in increased intracellular accumulation of ceramide which inhibited insulin signaling pathway. We observed a significant increase in the expression of fatty-acid transport protein (FATP2) and ceramide transfer protein (CERT) what is consistent with enhanced intracellular ceramide content. The content of extracellular ceramide was increased nearly threefold after short and twofold after long incubation period. Expression of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter (ABCA1) was increased significantly mainly after short palmitate incubation.

Conclusion

Our data showed that increase in intarcellular ceramide content contributes to the development of hepatic insulin resistance. We suggest pivotal role of transporters in facilitating fatty acid influx (FATP2), accumulation of ceramides (CERT) and export to the media (MTP and ABCA1).     

外周5-羟色胺在胰岛素抵抗中的作用研究进展

5-羟色胺（5-HT）作为一种神经递质在中枢神经系统中具有重要的作用,同时在外周组织系统中5-HT也发挥多种重要的生物功能, 如广泛参与机体的糖脂代谢、肝再生、胃肠运动等。综述外周5-HT诱导胰岛素抵抗的作用机制研究新进展,重点介绍5-HT对胰岛素信 号转导、糖脂代谢等方面的影响。     

Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions

Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood-brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis.     

Role of Cytosolic Calcium-Dependent Phospholipase A2 in Alzheimer's Disease Pathogenesis

Phospholipases (PLA2s) are a superfamily of enzymes characterized by the ability to specifically hydrolyze the sn-2 ester bond of phospholipids generating arachidonic acid, utilized in inflammatory responses, and lysophospholipids involved in the control of cell membrane remodeling and fluidity. PLA2s have been so far considered a crucial element in the etiopathogenesis of several neurological diseases such as cerebral ischemia, multiple sclerosis, Parkinson's disease, and Alzheimer's disease (AD). In AD, the role of beta-amyloid (Aβ) fragments is well established although still more elusive are the molecular events of the cascade that from the Aβ accumulation leads to neurodegeneration with its clinical manifestations. However, it is well known that inflammation and alteration of lipid metabolism are common features of AD brains. Findings obtained from in vitro studies, animal models, and human brain imaging analysis point towards cPLA2 as a key molecule in the onset and maintenance of the neurodegenerative mechanism(s) of AD. In this review, we have focused on the molecular and biological evidence of the involvement of cPLA2s in the pathogenesis of AD. An insight into the molecular mechanism(s) underlying the action and the regulation of cPLA2 is of tremendous interest in the pharmaceutical and biotechnology industry in developing selective and potent inhibitors able to modulate the onset and/or the outcome of AD.     

胰岛素降解酶与阿尔兹海默病的发生

阿尔兹海默病（AD）是以脑中β淀粉样蛋白（Aβ）累积和神经纤维缠绕（NFTs）为主要病理特征的神经退行性疾病,而胰岛素降解酶（IDE）是人体内最主要的Aβ降解酶之一。因此,IDE在AD进程中的作用受到了研究人员的广泛关注。大多数研究显示,AD的病理进程伴随着脑中IDE编码基因的表达和IDE活性的下降。IDE敲除动物也能够表现出AD样表型,同时已有研究尝试靶向于IDE进行AD的治疗。本文通过总结IDE在AD患者和AD模型动物脑中表达情况的变化,以及IDE敲除动物的表型,对近期IDE在AD发生中作用的研究进行了总结。