Molecular and cellular therapies最新文献

{"title":"MiR-223 regulates the differentiation of immature neurons.","authors":"Maged M Harraz, Jin-Chong Xu, Noah Guiberson, Ted M Dawson, Valina L Dawson","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>Small non-coding microRNA RNA molecules can regulate stem cell function. The role of microRNAs in neural stem/progenitor cells (NS/PCs) differentiation is not entirely clear.</p><p><strong>Methods: </strong>MiRNA profiling, loss and gain of function studies coupled with dendritic tree development morphometric analysis and calcium influx imaging were utilized to investigate the role of micoRNA-223 in differentiating NS/PCs.</p><p><strong>Results: </strong>MiRNA profiling in human NS/PCs before and after differentiation in vitro reveals modulation of miRNAs following differentiation of NS/PCs. MiR-223, a microRNA well characterized as a hematopoietic-specific miRNA was identified. Cell-autonomous inhibition of miR-223 in the adult mouse dentate gyrus NS/PCs led to a significant increase in immature neurons soma size, dendritic tree total length, branch number per neuron and complexity, while neuronal migration in the dentate gyrus remained unaffected. Overexpression of miR-223 decreased dendritic tree total length, branch number and complexity in neurons differentiated from human embryonic stem cells (hESCs). Inhibition of miR-223 enhanced N-methyl-D-aspartate (NMDA) induced calcium influx in human neurons differentiated from NS/PCs.</p><p><strong>Conclusions: </strong>Taken together, these findings indicate that miR-223 regulates the differentiation of neurons derived from NS/PCs.</p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32817158","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":"Molecular mechanisms of tissue inhibitor of metalloproteinase 2 in the tumor microenvironment.","authors":"Taylor C Remillard, Gennady Bratslavsky, Sandra Jensen-Taubman, William G Stetler-Stevenson, Dimitra Bourboulia","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>There has been a recent paradigm shift in the way we target cancer, drawing a greater focus on the role of the tumor microenvironment (TME) in cancer development, progression and metastasis. Within the TME, there is a crosstalk in signaling and communication between the malignant cells and the surrounding extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteases that have the ability to degrade the matrix surrounding a tumor and mediate tumor growth, angiogenesis and metastatic disease. Their endogenous inhibitors, the Tissue Inhibitors of Metalloproteinases (TIMPs), primarily function to prevent degradation of the ECM via inhibition of MMPs. However, recent studies demonstrate that TIMP family members also possess MMP-independent functions. One TIMP member in particular, TIMP-2, has many distinct properties and functions, that occur independent of MMP inhibition, including the inhibition of tumor growth and reduction of angiogenesis through decreased endothelial cell proliferation and migration. The MMP-independent molecular mechanisms and signaling pathways elicited by TIMP-2 in the TME are described in this review. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"17"},"PeriodicalIF":0.0,"publicationDate":"2014-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33247333","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":"MicroRNAs: short non-coding players in cancer chemoresistance.","authors":"Sara Donzelli, Federica Mori, Francesca Biagioni, Teresa Bellissimo, Claudio Pulito, Paola Muti, Sabrina Strano, Giovanni Blandino","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Chemoresistance is one of the main problems in the therapy of cancer. There are a number of different molecular mechanisms through which a cancer cell acquires resistance to a specific treatment, such as alterations in drug uptake, drug metabolism and drug targets. There are several lines of evidence showing that miRNAs are involved in drug sensitivity of cancer cells in different tumor types and by different treatments. In this review, we provide an overview of the more recent and significant findings on the role of miRNAs in cancer cell drug resistance. In particular, we focus on specific miRNA mechanisms of action that in various steps lead from drug cell sensitivity to drug cell resistance. We also provide evidence on how miRNA profiling may unveil relevant predictive biomarkers for therapy outcomes. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"16"},"PeriodicalIF":0.0,"publicationDate":"2014-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33373744","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":"Role of solute carriers in response to anticancer drugs.","authors":"Qing Li, Yan Shu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Membrane transporters play critical roles in moving a variety of anticancer drugs across cancer cell membrane, thereby determining chemotherapy efficacy and/or toxicity. The retention of anticancer drugs in cancer cells is the result of net function of efflux and influx transporters. The ATP-binding cassette (ABC) transporters are mainly the efflux transporters expressing at cancer cells, conferring the chemo-resistance in various malignant tumors, which has been well documented over the past decades. However, the function of influx transporters, in particular the solute carriers (SLC) in cancer cells, has only been recently well recognized to have significant impact on cancer therapy. The SLC transporters not only directly bring anticancer agents into cancer cells but also serve as the uptake mediators of essential nutrients for tumor growth and survival. In this review, we concentrate on the interaction of SLC transporters with anticancer drugs and nutrients, and their impact on chemo-sensitivity or -resistance of cancer cells. The differential expression patterns of SLC transporters between normal and tumor tissues may be well utilized to achieve specific delivery of chemotherapeutic agents. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"15"},"PeriodicalIF":0.0,"publicationDate":"2014-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33373743","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":"Extracellular matrix macromolecules: potential tools and targets in cancer gene therapy.","authors":"Annele Sainio, Hannu Järveläinen","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Tumour cells create their own microenvironment where they closely interact with a variety of soluble and non-soluble molecules, different cells and numerous other components within the extracellular matrix (ECM). Interaction between tumour cells and the ECM is bidirectional leading to either progression or inhibition of tumourigenesis. Therefore, development of novel therapies targeted primarily to tumour microenvironment (TME) is highly rational. Here, we give a short overview of different macromolecules of the ECM and introduce mechanisms whereby they contribute to tumourigenesis within the TME. Furthermore, we present examples of individual ECM macromolecules as regulators of cell behaviour during tumourigenesis. Finally, we focus on novel strategies of using ECM macromolecules as tools or targets in cancer gene therapy in the future. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"14"},"PeriodicalIF":0.0,"publicationDate":"2014-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33373742","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":"Directed cardiomyogenesis of autologous human induced pluripotent stem cells recruited to infarcted myocardium with bioengineered antibodies.","authors":"Marek Malecki, Emily Putzer, Chelsea Sabo, Afsoon Foorohar, Carol Quach, Chris Stampe, Michael Beauchaine, Raf Malecki, Xenia Tombokan, Mark Anderson","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Objective: </strong>Myocardial infarctions constitute a major factor contributing to non-natural mortality world-wide. Clinical trials of myocardial regenerative therapy, currently pursued by cardiac surgeons, involve administration of stem cells into the hearts of patients suffering from myocardial infarctions. Unfortunately, surgical acquisition of these cells from bone marrow or heart is traumatic, retention of these cells to sites of therapeutic interventions is low, and directed differentiation of these cells <i>in situ</i> into cardiomyocytes is difficult. The specific aims of this work were: (1) to generate autologous, human, pluripotent, induced stem cells (ahiPSCs) from the peripheral blood of the patients suffering myocardial infarctions; (2) to bioengineer heterospecific antibodies (htAbs) and use them for recruitment of the ahiPSCs to infarcted myocardium; (3) to initiate <i>in situ</i> directed cardiomyogenesis of the ahiPSCs retained to infarcted myocardium.</p><p><strong>Methods: </strong>Peripheral blood was drawn from six patients scheduled for heart transplants. Mononuclear cells were isolated and reprogrammed, with plasmids carrying six genes (<i>NANOG, POU5F1, SOX2, KLF4, LIN28A, MYC</i>), to yield the ahiPSCs. Cardiac tissues were excised from the injured hearts of the patients, who received transplants during orthotopic surgery. These tissues were used to prepare <i>in vitro</i> models of stem cell therapy of infarcted myocardium. The htAbs were bioengineered, which simultaneously targeted receptors displayed on pluripotent stem cells (SSEA-4, SSEA-3, TRA-1-60, TRA-1-81) and proteins of myocardial sarcomeres (myosin, α-actinin, actin, titin). They were used to bridge the ahiPSCs to the infarcted myocardium. The retained ahiPSCs were directed with bone morphogenetic proteins and nicotinamides to differentiate towards myocardial lineage.</p><p><strong>Results: </strong>The patients' mononuclear cells were efficiently reprogrammed into the ahiPSCs. These ahiPSCs were administered to infarcted myocardium in <i>in vitro</i> models. They were recruited to and retained at the treated myocardium with higher efficacy and specificity, if were preceded with the htAbs, than with isotype antibodies or plain buffers. The retained cells differentiated into cardiomyocytes.</p><p><strong>Conclusions: </strong>The proof of concept has been attained<i>,</i> for reprogramming the patients' blood mononuclear cells (PBMCs) into the ahiPSCs, recruiting these cells to infarcted myocardium, and initiating their cardiomyogenesis. This novel strategy is ready to support the ongoing clinical trials aimed at regeneration of infarcted myocardium.</p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32593504","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":"Advances toward regenerative medicine in the central nervous system: challenges in making stem cell therapy a viable clinical strategy.","authors":"Elizabeth A Stoll","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Over recent years, there has been a great deal of interest in the prospects of stem cell-based therapies for the treatment of nervous system disorders. The eagerness of scientists, clinicians, and spin-out companies to develop new therapies led to premature clinical trials in human patients, and now the initial excitement has largely turned to skepticism. Rather than embracing a defeatist attitude or pressing blindly ahead, I argue it is time to evaluate the challenges encountered by regenerative medicine in the central nervous system and the progress that is being made to solve these problems. In the twenty years since the adult brain was discovered to have an endogenous regenerative capacity, much basic research has been done to elucidate mechanisms controlling proliferation and cellular identity; how stem cells may be directed into neuronal lineages; genetic, pharmacological, and behavioral interventions that modulate neurogenic activity; and the exact nature of limitations to regeneration in the adult, aged, diseased and injured CNS. These findings should prove valuable in designing realistic clinical strategies to improve the prospects of stem cell-based therapies. In this review, I discuss how basic research continues to play a critical role in identifying both barriers and potential routes to regenerative therapy in the CNS. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"12"},"PeriodicalIF":0.0,"publicationDate":"2014-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33373741","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-wide analysis of primary peripheral blood mononuclear cells from HIV + patients-pre-and post- HAART show immune activation and inflammation the main drivers of host gene expression.","authors":"Viviane N da Conceicao, Wayne B Dyer, Kaushal Gandhi, Priyanka Gupta, Nitin K Saksena","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>Although the host gene expression in the context of HIV has been explored by several studies, it remains unclear how HIV is able to manipulate and subvert host gene machinery before and after highly active antiretroviral therapy (HAART) in the same individual. In order to define the underlying pharmaco-genomic basis of HIV control during HAART and genomic basis of immune deterioration prior to HAART initiation, we performed a genome-wide expression analysis using primary peripheral blood mononuclear cells (PBMC) derived from 14 HIV + subjects pre-highly active antiretroviral therapy (HAART) (time point-1 or TP1) with detectable plasma viremia and post-HAART (time point-2 or TP2) with effective control of plasma viremia (<40 HIV RNA copies/mL of plasma).</p><p><strong>Methods: </strong>Genomic RNA extracted from the PBMCs was used in microarray analysis using HT-12V3 Illumina chips. Illumina®BeadStudio Software was used to obtain differentially expressed (DE) genes. Only the genes with p value <0.01 and FDR of <5% were considered for analysis. Pathway analysis was performed in MetaCore™ to derive functional annotations. Functionally significant genes were validated by qRT-PCR.</p><p><strong>Results: </strong>Between TP1 and TP2, 234 genes were differentially expressed (DE). During viremic phase (TP1), there was an orchestrated and coordinated up-regulation of immune, inflammation and antiviral genes, consistent with HIV infection and immune activation, which comprised of genes mainly involved in antiviral action of interferons and their signalling. In contrast, the therapy-mediated control phase (TP2) showed systematic down-regulation of these pathways, suggesting that the reduction in plasma viremia with HAART has a considerable influence on reducing the immune activation, thereby implying a definitive role of HIV in subverting the human gene machinery.</p><p><strong>Conclusions: </strong>This is the first study to show the evidence for the differential regulation of gene expression between the untreated and treated time points, suggesting that gene expression is a consequence of cellular activation during plasma viremia. Affirmation to these observations comes from down-modulation of genes involved in cellular activation and inflammation upon initiation of HAART coinciding with below detectable levels of plasma viremia.</p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"11"},"PeriodicalIF":0.0,"publicationDate":"2014-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33373740","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":"The macrophage: a therapeutic target in HIV-1 infection.","authors":"Amit Kumar, Georges Herbein","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Human immunodeficiency virus (HIV) is still a serious global health concern responsible for more than 25 million deaths in last three decades. More than 34 million people are living with HIV infection. Macrophages and CD4+ T cells are the principal targets of HIV-1. The pathogenesis of HIV-1 takes different routes in macrophages and CD4+ T cells. Macrophages are resistant to the cytopathic effect of HIV-1 and produce virus for longer periods of time. In addition, macrophages being present in every organ system thus can disseminate virus to the different anatomical sites leading to the formation of viral sanctuaries. Complete cure of HIV-1 needs better understanding of viral pathogenesis in these reservoirs and implementation of knowledge into robust therapeutic products. In this review we will focus on the unique relationship between HIV-1 and macrophages. Furthermore, we will describe how successful antiretroviral therapy (ART) is in suppressing HIV and novel molecular and cellular strategies against HIV-1 in macrophages. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"10"},"PeriodicalIF":0.0,"publicationDate":"2014-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33373739","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":"\"Much ado to achieve nothing: prospects for curing HIV infection\".","authors":"Andrew D Badley","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Currently there is significant scientific effort being directed at developing ways to create either a sterilizing cure, or functional cure for HIV infection. Multiple approaches are being evaluated under the broad headings of gene therapy, immune based interventions, and treatments which depend upon HIV reactivation from latency to cause the death of cells which harbor the virus. Molecular and Cellular Therapies (MCT) welcomes all manuscripts devoted to increasing our understanding of determinants of affecting a cure for HIV and mechanistic studies determine the cellular and viral interventions necessary for achieving HIV cure. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"9"},"PeriodicalIF":0.0,"publicationDate":"2014-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33373738","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}