ABSTRACT
Alzheimer's disease (AD) is currently incurable and places a large burden on the caregivers of AD patients. In the AD brain, iron is abundant, catalyzing free radicals and impairing neurons. The blood-brain barrier hampers antidementia drug delivery via circulation to the brain, which limits the therapeutic effects of drugs. Here, according to the method described by Gobinda, we synthesized a 16 lysine (K) residue-linked low-density lipoprotein receptor-related protein (LRP)-binding amino acid segment of apolipoprotein E (K16APoE). By mixing this protein with our designed therapeutic peptide HAYED, we successfully transported HAYED into an AD model mouse brain, and the peptide scavenged excess iron and radicals and decreased the necrosis of neurons, thus easing AD.
Subject(s)
Alzheimer Disease/drug therapy , Apolipoproteins E/chemistry , Low Density Lipoprotein Receptor-Related Protein-1/chemistry , Peptides/administration & dosage , Animals , Apolipoproteins E/metabolism , Biological Transport , Blood-Brain Barrier/drug effects , Disease Models, Animal , Humans , Iron/chemistry , Mice , Peptides/chemistryABSTRACT
Cell proliferation was inhibited following forced over-expression of miR-30a in the ovary cancer cell line A2780DX5 and the gastric cancer cell line SGC7901R. Interestingly, miR-30a targets the DNA replication protein RPA1, hinders the replication of DNA and induces DNA fragmentation. Furthermore, ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2) were phosphorylated after DNA damage, which induced p53 expression, thus triggering the S-phase checkpoint, arresting cell cycle progression and ultimately initiating cancer cell apoptosis. Therefore, forced miR-30a over-expression in cancer cells can be a potential way to inhibit tumour development.
Subject(s)
Cell Proliferation/physiology , DNA Replication/physiology , MicroRNAs/physiology , Replication Protein A/metabolism , Apoptosis/genetics , Apoptosis/physiology , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , Cell Cycle/genetics , Cell Cycle/physiology , Cell Line, Tumor , Cell Proliferation/genetics , Cellular Senescence/genetics , Cellular Senescence/physiology , Checkpoint Kinase 2/genetics , Checkpoint Kinase 2/metabolism , Comet Assay , DNA Replication/genetics , Histones/metabolism , Humans , Immunohistochemistry , MicroRNAs/genetics , MicroRNAs/metabolism , RNA Interference/physiology , Replication Protein A/geneticsABSTRACT
We propose a novel approach to fracturing (and denting) brittle materials. To avoid the computational burden imposed by the stringent time step restrictions of explicit methods or with solving nonlinear systems of equations for implicit methods, we treat the material as a fully rigid body in the limit of infinite stiffness. In addition to a triangulated surface mesh and level set volume for collisions, each rigid body is outfitted with a tetrahedral mesh upon which finite element analysis can be carried out to provide a stress map for fracture criteria. We demonstrate that the commonly used stress criteria can lead to arbitrary fracture (especially for stiff materials) and instead propose the notion of a time averaged stress directly into the FEM analysis. When objects fracture, the virtual node algorithm provides new triangle and tetrahedral meshes in a straightforward and robust fashion. Although each new rigid body can be rasterized to obtain a new level set, small shards can be difficult to accurately resolve. Therefore, we propose a novel collision handling technique for treating both rigid bodies and rigid body thin shells represented by only a triangle mesh.
