No abstract available.
Huntington Disease*

No abstract available.
Intussusception*

No abstract available.
Cisplatin* ; Humans ; Nausea* ; Ondansetron* ; Vomiting*

Parkinson's disease (PD) is the second most progressive neurodegenerative disorder of the aging population after Alzheimer’s disease (AD). Defects in the lysosomal systems and mitochondria have been suspected to cause the pathogenesis of PD. Nevertheless, the pathogenesis of PD remains obscure. Abnormal cholesterol metabolism is linked to numerous disorders, including atherosclerosis. The brain contains the highest level of cholesterol in the body and abnormal cholesterol metabolism links also many neurodegenerative disorders such as AD, PD, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). The blood brain barrier effectively prevents uptake of lipoprotein-bound cholesterol from blood circulation. Accordingly, cholesterol level in the brain is independent from that in peripheral tissues. Because cholesterol metabolism in both peripheral tissue and the brain are quite different, cholesterol metabolism associated with neurodegeneration should be examined separately from that in peripheral tissues. Here, we review and compare cholesterol metabolism in the brain and peripheral tissues. Furthermore, the relationship between alterations in cholesterol metabolism and PD pathogenesis is reviewed.
Aging ; Amyotrophic Lateral Sclerosis ; Atherosclerosis ; Blood Circulation ; Blood-Brain Barrier ; Brain ; Cholesterol ; Metabolism ; Mitochondria ; Neurodegenerative Diseases ; Parkinson Disease

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is highly expressed in neurons, and gathering evidence indicates that UCH-L1 may play pathogenic roles in many neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD). Additionally, lipid rafts have attracted interest in neurodegeneration as playing a common role in many neurodegenerative diseases. In the present study, we demonstrated that UCH-L1 associates with lipid rafts as with other PD-associated gene products. In addition, UCH-L1 regulates lipid raft-dependent endocytosis and it is not dependent on the expression and degradation of caveolin-1 or flotillin-1. Finally, UCH-L1 regulates cell-to-cell transmission of α-synuclein. This study provides evidence that many PD-associated gene products share common signaling pathways to explain the pathogenesis of PD.
alpha-Synuclein ; Alzheimer Disease ; Caveolin 1 ; Endocytosis* ; Neurodegenerative Diseases ; Neurons ; Parkinson Disease ; Prion Diseases ; Ubiquitin Thiolesterase* ; Ubiquitin*

Parkinson’s disease (PD) is characterized by the presence of α-synuclein (α-syn) inclusions in the brain and the degeneration of dopamine-producing neurons. There is evidence to suggest that the progression of PD may be due to the prion-like spread of α-syn aggregates, so understanding and limiting α-syn propagation is a key area of research for developing PD treatments. Several cellular and animal model systems have been established to monitor α-syn aggregation and propagation. In this study, we developed an in vitro model using A53T α-syn-EGFP overexpressing SH-SY5Y cells and validated its usefulness for high-throughput screening of potential therapeutic targets. Treatment with preformed recombinant α-syn fibrils induced the formation of aggregation puncta of A53T α-syn-EGFP in these cells, which were analyzed using four indices: number of dots per cell, size of dots, intensity of dots, and percentage of cells containing aggregation puncta. Four indices are reliable indicators of the effectiveness of interventions against α-syn propagation in a one-day treatment model to minimize the screening time. This simple and efficient in vitro model system can be used for high-throughput screening to discover new targets for inhibiting α-syn propagation.

Protein-tyrosine phosphatases (PTPs) constitute a family of receptor-like, and cytoplasmic enzymes, which catalyze the dephosphorylation of phosphotyrosine residues in a variety of receptors and signaling molecules. Together with protein tyrosine kinases (PTKs), PTPs are critically involved in regulating many cellular signaling processes. In this study, diverse compounds were screened for PTP inhibition and selectively screened for inhibitors with the end product inhibition properties. Among phosphate analogues and their derivatives for PTP inhibition, Keggin compounds phosphomolybdate (PM) and phosphotungstate (PT) strongly inhibited both PTP-1B and SHP-1, with K(i) values of 0.06-1.2 micromM in the presence of EDTA. Unlike the vanadium compounds, inhibition potencies of PM and PT were not significantly affected by EDTA. PM and PT were potent, competitive inhibitors for PTPs, but relatively poor inhibitors of Ser/Thr phosphatase. Interestingly, PM and PT did not inhibit alkaline phosphatase at all. The crystal structure of PTP-1B in complex with PM, at 2.0 A resolution, reveals that MoO(3), derived from PM by hydrolysis, binds at the active site. The molybdenium atom of the inhibitor is coordinated with six ligands: three oxo-ligands, two apical water molecules and a S atom of the catalytic cysteine residue. In support of the crystallographic finding, we observed that molybdenium oxides (MoO(3), MoO(2), and MoO(2)Cl(2)) inhibited PTP-1B with IC(50) in the range 5-15 micromM.
Binding, Competitive ; Catalytic Domain ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Edetic Acid/pharmacology ; Enzyme Inhibitors/*pharmacology ; Human ; Inhibitory Concentration 50 ; Kinetics ; Models, Molecular ; Molybdenum/*pharmacology ; Phosphoric Acids/*pharmacology ; Protein Structure, Tertiary ; Protein-Tyrosine-Phosphatase/*antagonists & inhibitors/*chemistry/isolation & purification ; Substrate Specificity ; Tungsten Compounds/*pharmacology

In vivo testings of the monoleaflet polymer valve were performed in seven dogs to prove its blood biocompatibility. The monoleaflet polymer valve used in this study was developed for short-term usage n the ventricular assist device. The frame and leaflet of the polymer valve were made of polyurethane. The inter-aortic valved conduit were implanted in four dogs and the ventriculo-atrial valved conduit was implanted in one dog. The ventricular assist devices with polymer valve were implanted in two dogs. The longest survival was 20 days. Main causes of death were bleeding and infection. To examine the blood compatibility, each blood sample was collected and RBC, WBC, hematocrit, hemoglobin, platelet and lactic acid dehydrogenase were analyzed. These studies thus far demonstrated that, with further development, a reliable and inexpensive polymer valve will be used in the ventricular assist device as short term usage.
Animal Experimentation* ; Animals* ; Blood Platelets ; Cause of Death ; Dogs ; Heart Valves ; Heart-Assist Devices ; Hematocrit ; Hemorrhage ; Lactic Acid ; Oxidoreductases ; Polymers* ; Polyurethanes