Molecular Medicine & Therapeutics最新文献

{"title":"Novel Combinatorial Therapeutic Targeting of PAI-1 (SERPINE1) Gene Expression in Alzheimer's Disease.","authors":"Stacie M Kutz,&nbsp;Craig E Higgins,&nbsp;Paul J Higgins","doi":"10.4172/2324-8769.1000106","DOIUrl":"https://doi.org/10.4172/2324-8769.1000106","url":null,"abstract":"<p><p>Accumulation of neurotoxic amyloid peptides (Aβ) in the brain, generated by β-site proteolytic processing of the amyloid precursor protein (APP), is the hallmark pathophysiologic feature of Alzheimer's disease. The plasmin-activating cascade, in which urokinase (uPA) and tissue-type (tPA) plasminogen activators convert plasminogen to the broad-spectrum protease plasmin, appears to serve a protective, Aβ-clearing, role in the central nervous system. Plasmin degrades Aβ and catalyzes α- site APP proteolysis generating nontoxic peptides. Plasmin activation in the brain is negatively regulated by the fast-acting clade E serine protease inhibitor (SERPIN) plasminogen activator inhibitor type-1 (PAI-1; SERPINE1) resulting in Aβ accumulation. PAI-1 and its major physiological inducer TGF-β1, moreover, are both increased in Alzheimer's disease models and implicated in the etiology and progression of human neurodegenerative disorders. Current findings support the hypothesis that targeting of PAI-1 function (by small molecule drugs) and/or gene expression (by histone deacetylase inhibitors) may constitute a clinically-relevant molecular approach to the therapy of neurodegenerative diseases associated with increased PAI-1 levels.</p>","PeriodicalId":89825,"journal":{"name":"Molecular Medicine & Therapeutics","volume":"1 2","pages":"106"},"PeriodicalIF":0.0,"publicationDate":"2012-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703665/pdf/nihms-437778.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31216634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-Scale Mapping of MicroRNA Signatures in Human Embryonic Stem Cell Neurogenesis.","authors":"Xuejun H Parsons,&nbsp;James F Parsons,&nbsp;Dennis A Moore","doi":"10.4172/2324-8769.1000105","DOIUrl":"https://doi.org/10.4172/2324-8769.1000105","url":null,"abstract":"<p><p>To date, lacking of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing effective cell-based therapies against a wide range of neurological disorders. Derivation of human embryonic stem cells (hESCs) provides a powerful tool to investigate the molecular controls in human embryonic neurogenesis as well as an unlimited source to generate the diversity of human neuronal cell types in the developing CNS for repair. However, realizing the developmental and therapeutic potential of hESCs has been hindered by conventional multi-lineage differentiation of pluripotent cells, which is uncontrollable, inefficient, highly variable, difficult to reproduce and scale-up. We recently identified retinoic acid (RA) as sufficient to induce the specification of neuroectoderm direct from the pluripotent state of hESCs under defined platform and trigger progression to human neuronal progenitors (hESC-I hNuPs) and neurons (hESC-I hNus) in the developing CNS with high efficiency, which enables hESC neuronal lineage-specific differentiation and opens the door to investigate human embryonic neurogenesis using the hESC model system. In this study, genome-scale profiling of microRNA (miRNA) differential expression patterns in hESC neuronal lineage-specific progression was used to identify molecular signatures of human embryonic neurogenesis. These in vitro neuroectoderm-derived human neuronal cells have acquired a neuron al identity by down-regulating pluripotence-associated miRNAs and inducing the expression of miRNAs linked to regulating human CNS development to high levels in a stage-specific manner, including silencing of the prominent pluripotence-associated hsa-miR-302 family and drastic expression increases of the Hox hsa-miR-10 and let-7 miRNAs. Following transplantation, hESC-I hNuPs engrafted and yielded well-integrated neurons at a high prevalence within neurogenic regions of the brain. In 3D culture, these hESC-I hNuPs proceeded to express subtype neuronal markers, such as dopaminergic and motor neurons, demonstrating their therapeutic potential for CNS repair. Our study provides critical insight into molecular neurogenesis in human embryonic development as well as offers an adequate human neurogenic cell source in high purity and large quantity for scale-up CNS regeneration.</p>","PeriodicalId":89825,"journal":{"name":"Molecular Medicine & Therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2012-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609664/pdf/nihms-432745.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40238468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Coronary Vasomotor Function by Reactive Oxygen Species.","authors":"Lih Kuo,&nbsp;Naris Thengchaisri,&nbsp;Travis W Hein","doi":"10.4172/2324-8769.1000101","DOIUrl":"https://doi.org/10.4172/2324-8769.1000101","url":null,"abstract":"<p><p>Overproduction of reactive oxygen species is closely associated with cardiovascular diseases in part by impairing endothelial function and consequently compromising blood flow regulation. Superoxide and hydrogen peroxide are elevated under various disease states with reduced endothelium-derived nitric oxide bioavailability. The oxidative stress elicited by angiotensin II, C-reactive protein and tumor necrosis factor-α is mediated by the activation of different redox signaling pathways in the microvasculature. The upregulation of L-arginine consuming enzyme arginase also contributes to the reduced nitric oxide bioavailability during oxidative stress. Hydrogen peroxide exhibits vasodilator function in the coronary microcirculation and plays an important role in the physiological regulation of coronary blood flow. However, excessive production of hydrogen peroxide impairs endothelial function by reducing L-arginine availability through hydroxyl radical-mediated upregulation of arginase. This review summarizes the current knowledge on the effects superoxide and hydrogen peroxide on vasomotor function regulated by the endothelium-derived nitric oxide and prostacyclin in the coronary microcirculation.</p>","PeriodicalId":89825,"journal":{"name":"Molecular Medicine & Therapeutics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2012-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615426/pdf/nihms437774.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31341176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low Molecular Weight Antagonists of Plasminogen Activator Inhibitor-1: Therapeutic Potential in Cardiovascular Disease.","authors":"Tessa M Simone,&nbsp;Paul J Higgins","doi":"10.4172/2324-8769.1000102","DOIUrl":"https://doi.org/10.4172/2324-8769.1000102","url":null,"abstract":"<p><p>Plasminogen activator inhibitor-1 (PAI-1; SERPINE1) is the major physiologic regulator of the plasmin-based pericellular proteolytic cascade, a modulator of vascular smooth muscle cell (VSMC) migration and a causative factor in cardiovascular disease and restenosis, particularly in the context of increased vessel transforming growth factor- β1 (TGF-β1) levels. PAI-1 limits conversion of plasminogen to plasmin (and, thereby, fibrin degradation) by inhibiting its protease targets urokinase and tissue-type plasminogen activators (uPA, tPA). PAI-1 also has signaling functions and binds to the low density lipoprotein receptor-related protein 1 (LRP1) to regulate LRP1-dependent cell motility that, in turn, contributes to neointima formation. PAI-1/uPA/uPA receptor/LRPI/integrin complexes are endocytosed with subsequent uPAR/LRP1/integrin redistribution to the leading edge, initiating an \"adhesion-detachment-readhesion\" cycle to promote cell migration. PAI-1 also interacts with LRP1 in a uPA/uPAR-independent manner triggering Jak/Stat1 pathway activation to stimulate cell motility. PAI-1 itself is a substrate for extracellular proteases and exists in a \"cleaved\" form which, while unable to interact with uPA and tPA, retains LRP1-binding and migratory activity. These findings suggest that there are multiple mechanisms through which inhibition of PAI-1 may promote cardiovascular health. Several studies have focused on the design, synthesis and preclinical assessment of PAI-1 antagonists including monoclonal antibodies, peptides and low molecular weight (LMW) antagonists. This review discusses the translational impact of LMW PAI-1 antagonists on cardiovascular disease addressing PAI-1-initiated signaling, PAI-1 structure, the design and characteristics of PAI-1-targeting drugs, results of <i>in vitro</i> and <i>in vivo</i> studies, and their clinical implications.</p>","PeriodicalId":89825,"journal":{"name":"Molecular Medicine & Therapeutics","volume":"1 1","pages":"101"},"PeriodicalIF":0.0,"publicationDate":"2012-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737483/pdf/nihms437775.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31650477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}