Microglial interaction with beta-amyloid: implications for the pathogenesis of Alzheimer's disease.

The etiology of Alzheimer's disease (AD) involves a significant inflammatory component as evidenced by the presence of elevated levels of a diverse range of proinflammatory molecules in the AD brain. These inflammatory molecules are produced principally by activated microglia, which are found to be clustered within and adjacent to the senile plaque. Moreover, long-term treatment of patients with non-steroidal anti-inflammatory drugs has been shown to reduce risk and incidence of AD and delay disease progression. The microglia respond to beta-amyloid (Abeta) deposition in the brain through the interaction of fibrillar forms of amyloid with cell surface receptors, leading to the activation of intracellular signal transduction cascades. The activation of multiple independent signaling pathways ultimately leads to the induction of proinflammatory gene expression and production of reactive oxygen and nitrogen species. These microglial inflammatory products act in concert to produce neuronal toxicity and death. Therapeutic approaches focused on inhibition of the microglial-mediated local inflammatory response in the AD brain offer new opportunities to intervene in the disease.     

LDL receptor-related protein (LRP) in Alzheimer's disease: towards a unified theory of pathogenesis

To date, mutations in three genes, beta-amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2), have been found to be causally related to familial Alzheimer's disease (AD). In addition, polymorphisms in three other genes (among others), apolipoprotein E (apoE), alpha2-macroglobulin (alpham), and the low density lipoprotein receptor-related protein (LRP), are implicated to contribute to AD pathogenesis. Interestingly, the encoded gene products are all functionally related in various ways to LRP. Specifically apoE, alpha2m, secreted APP, and amyloid beta-protein (Abeta) complexed to either apoE or alpha2m are ligands of LRP. Furthermore, over-expression of presenilin 1 results in decreased expression of LRP. Since levels of many LRP ligands are increased in Alzheimer's disease and LRP and its ligands are present in senile plaques, decreased LRP function may be a central component in AD pathogenesis. This review explores the current knowledge of LRP in AD and its relationship to the other known AD susceptibility markers.     

Apolipoprotein J (clusterin) and Alzheimer's disease

Apolipoprotein J (clusterin) is a ubiquitous multifunctional glycoprotein capable of interacting with a broad spectrum of molecules. In pathological conditions, it is an amyloid associated protein, co-localizing with fibrillar deposits in systemic and localized amyloid disorders. In Alzheimer's disease, the most frequent form of amyloidosis in humans and the major cause of dementia in the elderly, apoJ is present in amyloid plaques and cerebrovascular deposits but is rarely seen in NFT-containing neurons. ApoJ expression is up-regulated in a wide variety of insults and may represent a defense response against local damage to neurons. Four different mechanisms of action could be postulated to explain the role of apoJ as a neuroprotectant during cellular stress: (1) function as an anti-apoptotic signal, (2) protection against oxidative stress, (3) inhibition of the membrane attack complex of complement proteins locally activated as a result of inflammation, and (4) binding to hydrophobic regions of partially unfolded, stressed proteins, and therefore avoiding aggregation in a chaperone-like manner. This review focuses on the association of apoJ in biological fluids with Alzheimer's soluble Abeta. This interaction prevents Abeta aggregation and fibrillization and modulates its blood-brain barrier transport at the cerebrovascular endothelium.     

Cerebrospinal fluid lipoproteins in Alzheimer's disease

Interest in cerebrospinal fluid (CSF) lipoproteins has been stimulated by the association of certain alleles of the human apolipoprotein E gene (APOE) with an increased risk of Alzheimer's disease (AD), and because apolipoprotein E (apoE) is one of the major apolipoproteins in CSF. CSF lipoproteins (d < 1.210 g/ml fraction) are distinct from their plasma counterparts, and in AD patients CSF may contain novel particles. The protein concentration of CSF lipoproteins is reduced in AD patients. Moreover, the molecular distribution of apoE- and apoAII-containing apolipoproteins in CSF is dictated by APOE. The lipid composition suggests that CSF lipoproteins from AD patients may have undergone increased free radical-mediated damage; experimental data support the possibility that this may occur both before and after lipoprotein assembly. Finally, human CSF lipoproteins oxidized ex vivo are neurotoxic to neuronal cells in culture and disrupt microtubule structure, an activity not observed with oxidized bovine CSF lipoproteins. CSF lipoproteins may represent a means whereby apoE influences the outcome of free radical-mediated damage to brain.     

Variant Creutzfeldt-Jakob disease: immunocytochemical studies and image analysis

Variant Creutzfeldt-Jakob disease (vCJD) is a recently identified human prion disease that appears to arise from exposure to the bovine spongiform encephalopathy agent. The clinical features and neuropathology of vCJD are distinctive, particularly the patterns of PrP(sc) accumulation in the brain. PrP immunocytochemistry has also demonstrated the accumulation of PrP(sc) in tissues outside the central nervous system, including sensory ganglia and lymphoid tissues. These observations have allowed the use of tonsillar biopsy as an investigation to aid the diagnosis of vCJD, since accumulation of PrP(sc) in lymphoid tissues does not occur in other forms of human prion disease. The patterns of PrP(sc) accumulation in vCJD can be studied by image analysis techniques, using both quantitative and qualitative approaches. Preliminary results of textural analysis are presented, which indicate that this approach can be used to discriminate and study the unique features of PrP(sc) accumulation in the brain in vCJD. This technique has major potential as a research tool in human prion diseases, particularly for the characterisation of disease phenotype in large series of cases.     

Apolipoprotein E immunoreactivity in neurons and neurofibrillary degeneration of aged non-demented and Alzheimer's disease patients

Apolipoprotein E (ApoE) genotype is a risk factor for Alzheimer's disease (AD) but its relationship with neurofibrillary degeneration remains obscure. To further analyze this relationship, hippocampal, entorhinal, temporopolar, and insular cortices of 10 non-demented and 7 Alzheimer disease brains were studied with both light and electron microscopy. Focus was directed on pretangles and neurons starting to accumulate tangles. ApoE immunolabeling in neurons and tangles was independent of ApoE individual genotype. The majority of the neurons in all of the brains were ApoE-negative, but virtually every brain also contained groups of ApoE-immunoreactive neurons, with diffuse cytoplasmic labeling. Most of the ApoE-positive tangles were extracellular, but a few tangles were shown to be intraneuronal when studied ultrastructurally. No ApoE immunoreactivity was found in neuropil threads, as well as in neurites associated with senile plaques. Double protocols with both AT-8 and anti-ApoE antibodies, performed to determine whether ApoE-positive neurons were pretangle neurons, did not detect cytoplasmic AT-8 in ApoE-positive neurons. Though careful electron microscopy studies found ApoE reaction product in an occasional ApoE-positive pretangle-like neuron and a few intracellular tangles, these findings do not support that ApoE is necessary for the accumulation of hyperphosphorylated tau protein. The more consistent colocalization of anti-ApoE and AT-8 in extracellular tangles reveals that ApoE mainly binds to tangles once they are in the extracellular space, in a manner similar to that described for amyloid fibrils.     

Evaluating the function of hippocampal subregions with high-resolution MRI in Alzheimer's disease and aging

Memory ability declines in older age groups. There is a growing list of physiological processes that target the hippocampal formation in an age-related fashion, and some might underlie the hippocampal component of memory decline. The hippocampal formation is comprised of separate subregions, and physiological processes differentially target these subregions. The ability to evaluate the functional integrity of individual subregions-performing subregional analysis-is a major clinical goal since it can aid in the diagnosis of memory decline, as well as in elucidating mechanisms of disease and testing potential interventions. Because of its superior spatial resolution, magnetic resonance imaging (MRI) is best suited to accomplish this goal. Despite limited success, most functional MRI (fMRI) protocols have difficulty in performing complete subregional analysis of the hippocampal formation. Here we address sources of difficulty by (1) generating T2* -weighted maps of the hippocampal formation with sub-millimeter resolution; and (2) by adapting an approach used by animal investigators to identify the hippocampal subregions using anatomical landmarks. The protocol is tested in patients with Alzheimer's disease and in healthy controls, in an effort to determine whether it can detect neuronal dysfunction. Results showed diminished signal in the hippocampal formation of patients with Alzheimer's disease (AD) compared to controls, and multivariate analysis showed that this difference was most prominent in the entorhinal cortex. The protocol can be used to perform subregional analysis of the hippocampal formation. Testing the protocol in other clinical populations is needed to demonstrate its efficacy in evaluating the neuronal integrity of all hippocampal subregions.     

Combinatory effect of hesperetin and mesenchymal stem cells on the deteriorated lipid profile,heart and kidney functions and antioxidant activity in STZ-induced diabetic rats

This study aimed to assess the effect of hesperetin and/or bone marrow-derived mesenchymal stem cells (BM-MSCs) on disturbed lipid profile, heart and kidney functions, oxidative stress and antioxidant defense system in streptozotocin (STZ)-induced diabetic rats. Type 1 diabetes mellitus (T1DM) was induced in male Wistar rats by injecting 40 mg/kg body weight (b.w.) STZ dissolved in citrate buffer (pH 4.5). The diabetic rats were treated with hesperetin orally administered at dose 20 mg/kg b.w., BM-MSCs intravenously injected at a dose of 1 x 106 cells/ rat/week and their combination for 6 weeks. The diabetic rats exhibited lipid abnormalities manifested by elevated serum levels of total cholesterol, triglycerides, LDL-cholesterol and VLDL-cholesterol and lowered HDL-cholesterol as well as elevated liver cholesterol and triglycerides content in association with the resultant fasting and postprandial hyperglycemia and insulin deficiency. The heart function biomarkers including CK-MB, AST and LDH activities as well as levels of kidney function parameters, creatinine, and urea, were significantly raised in the serum of diabetic rats. These changes were concomitant with abnormal redox balance represented by elevated lipid peroxidation, decreased glutathione content, and suppressed antioxidant enzyme activities in both heart and kidney of diabetic rats. The previous deleterious alterations were significantly ameliorated after the treatment of diabetic rats with hesperetin and BM-MSCs singly or in combination; the treatment with hesperetin together with BM-MSCs was the most potent. Based on these findings, it can be concluded that the use of hesperetin with BM-MSCs may have more additive therapeutic value than their uses singly in T1DM. In addition, the ameliorative effects of hesperetin and BM-MSCs on lipid profile and heart and kidney functions in diabetic rats may be mediated, at least in part, via their suppressive effects on oxidative stress and ameliorative effects on the antioxidant defense system secondary to improvement in the hyperglycemia and insulin secretory response.     

保证安全，保护环境，促进特种加工技术的持续发展

综述了特种加工,如电火花加工,电解加工,激光加工等加工过程中可能产生的有害有毒气体,废弃物,电磁辐射等危害因素,并列举了相应的防治措施,对电气安全,防火防焊等极为重要的安全生产问题,进行了专门论述,提出了预防措施,对保护环境,保证安全生产有一定的指导作用。     

Immunocytochemical analysis of connexin expression in the healthy and diseased cardiovascular system

Gap junctions play essential roles in the normal function of the heart and arteries, mediating the spread of the electrical impulse that stimulates synchronized contraction of the cardiac chambers, and contributing to co-ordination of activities between cells of the arterial wall. In common with other multicellular systems, cardiovascular tissues express multiple connexin isotypes that confer distinctive channel properties. This review highlights how state-of-the-art immunocytochemical and cellular imaging techniques, as part of a multidisciplinary approach in gap junction research, have advanced our understanding of connexin diversity in cardiovascular cell function in health and disease. In the heart, spatially defined patterns of expression of three connexin isotypes-connexin43, connexin40, and connexin45-underlie the precisely orchestrated patterns of current flow governing the normal cardiac rhythm. Derangement of gap junction organization and/or reduced expression of connexin43 are associated with arrhythmic tendency in the diseased human ventricle, and high levels of connexin40 in the atrium are associated with increased risk of developing atrial fibrillation after coronary by-pass surgery. In the major arteries, endothelial gap junctions may simultaneously express three connexin isotypes, connexin40, connexin37, and connexin43; underlying medial smooth muscle, by contrast, predominantly expresses connexin43, with connexin45 additionally expressed at restricted sites. In normal arterial smooth muscle, the abundance of connexin43 gap junctions varies according to vascular site, and shows an inverse relationship with desmin expression and positive correlation with the quantity of extracellular matrix. Increased connexin43 expression between smooth muscle cells is closely linked to phenotypic transformation in early human coronary atherosclerosis and in the response of the arterial wall to injury. Current evidence thus suggests that gap junctions in both their guises, as pathways for cell-to-cell signaling in the vessel wall and as pathways for impulse conduction in the heart, contribute to the initial pathogenesis and eventual clinical manifestation of human cardiovascular disease.     

复合超声心动图筛查孕早期胎儿先天心脏病的应用价值

目的:采用复合超声心动图在孕早期对胎儿心脏进行检查,并结合跟踪随访或尸体解剖结果评估其在胎儿先天心脏病筛查中的应用价值.方法:选取2019年3月-2020年10月于本院进行胎儿心脏病筛查的孕早期孕妇进行研究,共对3458例胎儿进行心脏检查,根据是否具备先天心脏病高危因素将胎儿分为高危组(n=1032)与低危组(n=24...     

Pharmacotherapeutics and molecular docking studies of alpha-synuclein modulators as promising therapeutics for Parkinson’s disease

Parkinson’s disease (PD) is an age-related neurodegenerative ailment that affects dopamine-producing neurons in a specific area of the brain called the substantia nigra of the ventral midbrain. It is clinically characterized by movement disorder and marked with unusual synaptic protein alpha-synuclein accumulation in the brain. To date, only a few Food and Drug Administration (FDA) approved drugs are available on the market for the treatment of PD. Nonetheless, these drugs show parasympathomimetic related adverse events and remarkably higher toxicity; hence, it is important to find more efficacious molecules to treat PD. In our study, We chosen 22 natural compounds as inhibitors that potentially block the alpha-synuclein clump—the pathological hallmark of PD—and provide new avenues for its treatment. Most of these molecules exhibited good pharmacokinetic behaviors, making them decisively favorable drug candidates to cure PD. Molecular docking studies were performed to investigate the binding interactions between natural compounds and alpha-synuclein as anti-Parkinson drug targets. Among the examined compounds, curcumin and piperine emerged as promising phytochemicals with the highest binding affinity, key residual stable bindings and showed a good inhibitory features. Thus, the present study indicates that curcumin and piperine hold the potential to be developed as treatment options against PD. Experimental validations are needed for insights into their mechanism of action and potential clinical application.     

Effects of Additives on the Friction of Steel on Steel. II. Additive-Base Oil Interactions

The steel-on-steel friction characteristics imparted by an oil-additive blend depend on the combination of friction-modifying additive, oxidation inhibitor, and base oil used in the blend. Increased refining of mineral oils generally enhanced the friction modifier effectiveness. The results with synthetic fluids generally fell within the mineral oil range. Free-radical inhibitor-type oxidation inhibitors enhanced or reduced the effect of friction-modifying additives whereas peroxide decomposer-type oxidation inhibitors did not. The magnitude and direction of the base oil-inhibitor interaction effect varied markedly depending on which friction-modifying additive was used. The results suggest that limited base oil oxidation may be essential for additive response.     

Microglia and prion disease.

Gliosis is one of the hallmarks of the prion diseases. Prion diseases are fatal neurodegenerative conditions of low incidence made famous by both the hypothesis that a protein acts as the infectious agent without involvement of nucleic acid and the speculative idea that a disease of cattle, BSE, has spread to humans from the ingestion of prion-infected beef. Despite these unproved hypotheses, the aetiology of the prion diseases remains unsolved. The rapid degenerative course of the disease is preceded by a long incubation period with little or no symptoms. The rapid neurodegeneration in the disease follows from increased deposition of an abnormal isoform of a normal neuronal protein. Co-incident with the appearance of this abnormal protein is the activation of large numbers of microglia. Studies in cell culture with both the abnormal prion protein and a peptide-mimic suggest that neuronal degeneration occurs because of two concurrent effects. First, there is a reduction in neuronal resistance to toxic insults and, second, there is an increase in the production of toxic substances such as reactive oxygen species by microglia and a decrease in glutamate clearance by astrocytes. Microglia activated by the abnormal form of the prion protein also release cytokines, which stimulate changes in astrocytes such as proliferation. The implication of this is that microglia may play a major role in initiating the pathological changes in prion disease. This review discusses the role of microglia in these changes.     

Influence of lipoproteins on microglial degradation of Alzheimer's amyloid beta-protein

Amyloid beta-protein (Abeta), the major component of plaques in Alzheimer's disease, is a small hydrophobic protein that is carried on apolipoprotein E (ApoE)- and ApoJ-containing lipoprotein particles in plasma and cerebrospinal fluid (CSF). Microglia, the scavenger cells of the CNS, take up and degrade Abeta via lipoprotein receptors including scavenger receptors A and B, and possibly via other receptors. Lipoproteins, ApoE, and ApoJ influence the uptake and degradation of Abeta in vitro and in vivo. Differences in ApoE-E4, -E3, and -E2 isoforms with respect to Abeta binding to lipoproteins and delivery to cells, including microglia, may contribute to the increased risk of Alzheimer's disease for people with an APOE4 genotype and to risk reduction with APOE2.     

The role of periodontal disease in atherosclerotic cardiovascular disease

Atherosclerotic cardiovascular disease (ASCVD) includes a group of disorders of the heart and blood vessels and accounts for major morbidity and premature death worldwide. Periodontitis is a chronic inflammatory disease with the gradual destruction of supporting tissues around the teeth, including gingiva, periodontal ligament, alveolar bone, and cementum. Periodontitis has been found to potentially increase the risk of ASCVD. Generally, oral microorganisms and inflammation are the major factors for periodontitis to the incidence of ASCVD. Recently, evidence has shown that the loss of masticatory function is another important factor of periodontitis to the incidence of ASCVD. In this review, we illustrate the recent finding of the relationship between periodontitis and ASCVD, from a microscale perspective-oral microorganisms, inflammation, and tooth loss. With the high prevalence of periodontitis, it is important to add oral therapy as a regular ASCVD prevention strategy. Regular dental visits could be a helpful strategy for ASCVD patients or general medical practitioners.     

Anti-TNF therapies in rheumatoid arthritis, Crohn's disease, sepsis, and myelodysplastic syndromes

An attempt has been made in this article to summarize the state-of-the-art clinical experience with the use of anti-TNF therapies in four diseased states with special emphasis on myelodysplastic syndromes. Given the central role of TNF-alpha in initiating and perpetuating the chronic damage produced in the diseased organs by controlling a cascade of pro-inflammatory cytokines, as well as its acute role in sepsis, theoretically speaking, neutralization of this peptide was a natural therapeutic choice. Results of the initial clinical trials appear encouraging and sometimes dramatic in their efficacy. The mechanism of response however, is interesting in that even when TNF-alpha is directly targeted by a monoclonal antibody, the resulting benefits can frequently not be attributed to TNF suppression alone. Rather, it appears that a more general effect on the T-lymphocytes is also contributing to the responses being seen. This raises the new possibility of combining anti-cytokine and anti-T-cell strategies to treat at least the more chronic diseases such as Crohn's disease and myelodysplastic syndromes. Continued clinical trials testing these strategies are clearly warranted.