Molecular and cellular therapies最新文献

{"title":"Cross talk of the first-line defense TLRs with PI3K/Akt pathway, in preconditioning therapeutic approach.","authors":"Fatemeh Pourrajab, Mohammad Baghi Yazdi, Mojtaba Babaei Zarch, Mohammadali Babaei Zarch, Seyedhossein Hekmatimoghaddam","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Toll-like receptor family (TLRs), pattern recognition receptors, is expressed not only on immune cells but also on non-immune cells, including cardiomyocytes, fibroblasts, and vascular endothelial cells. One main function of TLRs in the non-immune system is to regulate apoptosis. TLRs are the central mediators in hepatic, pulmonary, brain, and renal ischemic/reperfusion (I/R) injury. Up-regulation of TLRs and their ligation by either exogenous or endogenous danger signals plays critical roles in ischemia/reperfusion-induced tissue damage. Conventional TLR-NF-κB pathways are markedly activated in failing and ischemic myocardium. Recent studies have identified a cross talk between TLR activation and the PI3K/Akt pathway. The activation of TLRs is proposed to be the most potent preconditioning method after ischemia, to improve the cell survival via the mechanism involved the PI3K/Akt signaling pathway and to attenuate the subsequent TLR-NF-κB pathway stimulation. Thus, TLRs could be a great target in the new treatment approaches for myocardial I/R injury. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"3 ","pages":"4"},"PeriodicalIF":0.0,"publicationDate":"2015-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33370974","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":"Polymeric nanocarriers for the treatment of systemic iron overload.","authors":"Jasmine L Hamilton, Jayachandran N Kizhakkedathu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Desferrioxamine (DFO), deferiprone (L1) and desferasirox (ICL-670) are clinically approved iron chelators used to treat secondary iron overload. Although iron chelators have been utilized since the 1960s and there has been much improvement in available therapy, there is still the need for new drug candidates due to limited long-term efficacy and drug toxicity. Moreover, all currently approved iron chelators are of low molecular weight (MW) (<600 Da) and the objectives reported for the \"ideal\" chelator of low MW, including possessing the ability to promote iron excretion without causing toxic side effects, has proven difficult to realize in practice. With prolonged iron chelator use, patients may develop toxicities or become insensitive. In contrast, the limited research that has been geared towards developing higher MW, polymeric, long circulating iron chelators has shown promise. The inherent potential of polymeric iron chelators toward longer plasma half-lives and reduction in toxicity provides optimism and may be a significant addition to the currently available low MW iron chelators. This article reviews knowledge pertaining to this theme, highlights some unique advantages that these nanomedicines have in treating systemic iron overload as well as their potential utility in the treatment of other disease states. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"3 ","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2015-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33370973","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":"Outlook on PI3K/AKT/mTOR inhibition in acute leukemia.","authors":"Lars Fransecky, Liliana H Mochmann, Claudia D Baldus","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Technological advances allowing high throughput analyses across numerous cancer tissues have allowed much progress in understanding complex cellular signaling. In the future, the genetic landscape in cancer may have more clinical relevance than diagnosis based on tumor origin. This progress has emphasized PI3K/AKT/mTOR, among others, as a central signaling center of cancer development due to its governing control in cellular growth, survival, and metabolism. The discovery of high frequencies of mutations in the PI3K/AKT/mTOR pathway in different cancer entities has sparked interest to inhibit elements of this pathway. In acute leukemia pharmacological interruption has yet to achieve desirable efficacy as targetable downstream mutations in PI3K/AKT/mTOR are absent. Nevertheless, mutations in membrane-associated genes upstream of PI3K/AKT/mTOR are frequent in acute leukemia and are associated with aberrant activation of PI3K/AKT/mTOR thus providing a good rationale for further exploration. This review attempts to summarize key findings leading to aberrant activation and to reflect on both promises and challenges of targeting PI3K/AKT/mTOR in acute leukemia. Our emphasis lies on the insights gained through high-throughput data acquisition that open up new avenues for identifying specific subgroups of acute leukemia as ideal candidates for PI3K/AKT/mTOR targeted therapy. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"3 ","pages":"2"},"PeriodicalIF":0.0,"publicationDate":"2015-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33370972","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 Wnt/β-catenin pathway in human fibrotic-like diseases and its eligibility as a therapeutic target.","authors":"Maria Vittoria Enzo, Marco Rastrelli, Carlo Riccardo Rossi, Uros Hladnik, Daniela Segat","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The canonical Wnt signaling pathway is involved in a variety of biological processes like cell proliferation, cell polarity, and cell fate determination. This pathway has been extensively investigated as its deregulation is linked to different diseases, including various types of cancer, skeletal defects, birth defect disorders (including neural tube defects), metabolic diseases, neurodegenerative disorders and several fibrotic diseases like desmoid tumors. In the \"on state\", beta-catenin, the key effector of Wnt signaling, enters the nucleus where it binds to the members of the TCF-LEF family of transcription factors and exerts its effect on gene transcription. Disease development can be caused by direct or indirect alterations of the Wnt/β-catenin signaling. In the first case germline or somatic mutations of the Wnt components are associated to several diseases such as the familial adenomatous polyposis (FAP) - caused by germline mutations of the tumor suppressor adenomatous polyposis coli gene (APC) - and the desmoid-like fibromatosis, a sporadic tumor associated with somatic mutations of the β-catenin gene (CTNNB1). In the second case, epigenetic modifications and microenvironmental factors have been demonstrated to play a key role in Wnt pathway activation. The natural autocrine Wnt signaling acts through agonists and antagonists competing for the Wnt receptors. Anomalies in this regulation, whichever is their etiology, are an important part in the pathogenesis of Wnt pathway linked diseases. An example is promoter hypermethylation of Wnt antagonists, such as SFRPs, that causes gene silencing preventing their function and consequently leading to the activation of the Wnt pathway. Microenvironmental factors, such as the extracellular matrix, growth factors and inflammatory mediators, represent another type of indirect mechanism that influence Wnt pathway activation. A favorable microenvironment can lead to aberrant fibroblasts activation and accumulation of ECM proteins with subsequent tissue fibrosis that can evolve in fibrotic disease or tumor. Since the development and progression of several diseases is the outcome of the Wnt pathway cross-talk with other signaling pathways and inflammatory factors, it is important to consider not only direct inhibitors of the Wnt signaling pathway but also inhibitors of microenvironmental factors as promising therapeutic approaches for several tumors of fibrotic origin. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"3 ","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2015-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33370971","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":"Platelet dysfunction in injured patients.","authors":"Noelle N Saillant, Carrie A Sims","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A renewed understanding of Trauma Induced Coagulopathy (TIC) has implicated platelets as a crucial mediator and potential therapeutic target in hemostasis. While the importance of abnormal coagulation tests is well described in trauma, there is a paucity of data regarding the role of platelets in coagulopathy. New coagulation models, namely the cell-based-model of hemostasis, have refocused attention toward the platelet and endothelium as key regulators of clot formation. Although platelet dysfunction has been associated with worse outcomes in trauma, the mechanisms which platelet dysfunction contributes to coagulopathy are poorly understood. The goal of this review article is to outline recent advances in understanding hemostasis and the ensuing cellular dysfunction that contributes to the exsanguination of a critically injured patient. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"37"},"PeriodicalIF":0.0,"publicationDate":"2014-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33370970","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":"Targeting the Wnt/β-catenin pathway in endometriosis: a potentially effective approach for treatment and prevention.","authors":"Sachiko Matsuzaki, Revaz Botchorishvili, Jean Luc Pouly, Michel Canis","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Endometriosis is a chronic, estrogen-dependent disease associated with infertility and pelvic pain. Endometriosis is defined by the presence of extra-uterine endometrial tissue. It affects approximately 10% of reproductive-aged women. However, the underlying etiology, pathogenesis and pathophysiology remain to be fully elucidated. Knowledge of these factors is indispensable for the development of targeted therapies for prevention and treatment of endometriosis. Several studies, including those from our laboratory, have suggested that aberrant activation of the Wnt/β-catenin pathway may be involved in the pathophysiology of endometriosis. This is a review of the literature focused on the aberrant activation of the Wnt/β-catenin pathway in patients with endometriosis, and on how targeting the Wnt/targeting pathway may be a potentially effective approach for treating and/or preventing endometriosis. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"36"},"PeriodicalIF":0.0,"publicationDate":"2014-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33252802","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":"A critical evaluation of PI3K inhibition in Glioblastoma and Neuroblastoma therapy.","authors":"Mike-Andrew Westhoff, Georg Karpel-Massler, Oliver Brühl, Stefanie Enzenmüller, Katia La Ferla-Brühl, Markus D Siegelin, Lisa Nonnenmacher, Klaus-Michael Debatin","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Members of the PI3K/Akt/mTor signaling cascade are among the most frequently altered proteins in cancer, yet the therapeutic application of pharmacological inhibitors of this signaling network, either as monotherapy or in combination therapy (CT) has so far not been particularly successful. In this review we will focus on the role of PI3K/Akt/mTOR in two distinct tumors, Glioblastoma multiforme (GBM), an adult brain tumor which frequently exhibits PTEN inactivation, and Neuroblastoma (NB), a childhood malignancy that affects the central nervous system and does not harbor any classic alterations in PI3K/Akt signaling. We will argue that inhibitors of PI3K/Akt signaling can be components for potentially promising new CTs in both tumor entities, but further understanding of the signal cascade's complexity is essential for successful implementation of these CTs. Importantly, failure to do this might lead to severe adverse effects, such as treatment failure and enhanced therapy resistance. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"32"},"PeriodicalIF":0.0,"publicationDate":"2014-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33252369","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":"Aptamer technology for tracking cells' status & function.","authors":"Christian Wiraja, David Yeo, Daniel Lio, Louai Labanieh, Mengrou Lu, Weian Zhao, Chenjie Xu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>In fields such as cancer biology and regenerative medicine, obtaining information regarding cell bio-distribution, tropism, status, and other cellular functions are highly desired. Understanding cancer behaviors including metastasis is important for developing effective cancer treatments, while assessing the fate of therapeutic cells following implantation is critical to validate the efficacy and efficiency of the therapy. For visualization purposes with medical imaging modalities (e.g. magnetic resonance imaging), cells can be labeled with contrast agents (e.g. iron-oxide nanoparticles), which allows their identification from the surrounding environment. Despite the success of revealing cell biodistribution in vivo, most of the existing agents do not provide information about the status and functions of cells following transplantation. The emergence of aptamers, single-stranded RNA or DNA oligonucleotides of 15 to 60 bases in length, is a promising solution to address this need. When aptamers bind specifically to their cognate molecules, they undergo conformational changes which can be transduced into a change of imaging contrast (e.g. optical, magnetic resonance). Thus by monitoring this signal change, researchers can obtain information about the expression of the target molecules (e.g. mRNA, surface markers, cell metabolites), which offer clues regarding cell status/function in a non-invasive manner. In this review, we summarize recent efforts to utilize aptamers as biosensors for monitoring the status and function of transplanted cells. We focus on cancer cell tracking for cancer study, stem cell tracking for regenerative medicine, and immune cell (e.g. dendritic cells) tracking for immune therapy. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"33"},"PeriodicalIF":0.0,"publicationDate":"2014-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33252801","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":"Neural stem cells: ready for therapeutic applications?","authors":"Simona Casarosa, Yuri Bozzi, Luciano Conti","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Neural stem cells (NSCs) offer a unique and powerful tool for basic research and regenerative medicine. However, the challenges that scientists face in the comprehension of the biology and physiological function of these cells are still many. Deciphering NSCs fundamental biological aspects represents indeed a crucial step to control NSCs fate and functional integration following transplantation, and is essential for a safe and appropriate use of NSCs in injury/disease conditions. In this review, we focus on the biological properties of NSCs and discuss how these cells may be exploited to provide effective therapies for neurological disorders. We also review and discuss ongoing NSC-based clinical trials for these diseases. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"31"},"PeriodicalIF":0.0,"publicationDate":"2014-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33252368","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":"Targeting the Wnt pathways for therapies.","authors":"Artem Blagodatski, Dmitry Poteryaev, Vladimir L Katanaev","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The Wnt/β-catenin signaling pathway is crucial in animal development from sponges to humans. Its activity in the adulthood is less general, with exceptions having huge medical importance. Namely, improper activation of this pathway is carcinogenic in many tissues, most notably in the colon, liver and the breast. On the other hand, the Wnt/β-catenin signaling must be re-activated in cases of tissue damage, and insufficient activation results in regeneration failure and degeneration. These both medically important implications are unified by the emerging importance of this signaling pathway in the control of proliferation of various types of stem cells, crucial for tissue regeneration and, in case of cancer stem cells - cancer progression and relapse. This article aims at briefly reviewing the current state of knowledge in the field of Wnt signaling, followed by a detailed discussion of current medical developments targeting distinct branches of the Wnt pathway for anti-cancer and pro-regeneration therapies. </p>","PeriodicalId":90271,"journal":{"name":"Molecular and cellular therapies","volume":"2 ","pages":"28"},"PeriodicalIF":0.0,"publicationDate":"2014-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33252367","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}