Exosomal MiRNAs in Pediatric Cancers

MicroRNAs (miRNAs) have generated great attention in oncology as they play a fundamental role in the regulation of gene expression and their aberrant expression is present in almost all types of tumors including pediatric ones. The discovery that miRNAs can be transported by exosomes, which are vesicles of 40–120 nm involved in cellular communication, that are produced by different cell types, and that are present in different biological fluids, has opened the possibility of using exosomal miRNAs as biomarkers. The possibility to diagnose and monitor the progression and response to drugs through molecules that can be easily isolated from biological fluids represents a particularly important aspect in the pediatric context where invasive techniques are often used. In recent years, the idea of liquid biopsy as well as studies on the possible role of exosomal miRNAs as biomarkers have developed greatly. In this review, we report an overview of all the evidences acquired in recent years on the identification of exosomal microRNAs with biomarker potential in pediatric cancers. We discuss the following herein: neuroblastoma, hepatoblastoma, sarcomas (osteosarcoma, Ewing’s sarcoma and rhabdoid tumors, and non-rhabdomyosarcoma soft tissue sarcoma), brain tumors, lymphomas, and leukemias.

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Current Understanding of Exosomal MicroRNAs in Glioma Immune Regulation and Therapeutic Responses

Frontiers in Immunology ◽

10.3389/fimmu.2021.813747 ◽

2022 ◽

Vol 12 ◽

Author(s):

Jinwu Peng ◽

Qiuju Liang ◽

Zhijie Xu ◽

Yuan Cai ◽

Bi Peng ◽

...

Keyword(s):

Immune Regulation ◽

Response Prediction ◽

Cell Types ◽

Clinicopathological Characteristics ◽

The Novel ◽

Multiple Cancer ◽

Exosomal Mirnas ◽

Multiple Cell ◽

Almost All ◽

Therapeutic Responses

Exosomes, the small extracellular vesicles, are released by multiple cell types, including tumor cells, and represent a novel avenue for intercellular communication via transferring diverse biomolecules. Recently, microRNAs (miRNAs) were demonstrated to be enclosed in exosomes and therefore was protected from degradation. Such exosomal miRNAs can be transmitted to recipient cells where they could regulate multiple cancer-associated biological processes. Accumulative evidence suggests that exosomal miRNAs serve essential roles in modifying the glioma immune microenvironment and potentially affecting the malignant behaviors and therapeutic responses. As exosomal miRNAs are detectable in almost all kinds of biofluids and correlated with clinicopathological characteristics of glioma, they might be served as promising biomarkers for gliomas. We reviewed the novel findings regarding the biological functions of exosomal miRNAs during glioma pathogenesis and immune regulation. Furthermore, we elaborated on their potential clinical applications as biomarkers in glioma diagnosis, prognosis and treatment response prediction. Finally, we summarized the accessible databases that can be employed for exosome-associated miRNAs identification and functional exploration of cancers, including glioma.

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Therapeutic Exosomes in Prognosis and Developments of Coronary Artery Disease

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.691548 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ai-Qun Chen ◽

Xiao-Fei Gao ◽

Zhi-Mei Wang ◽

Feng Wang ◽

Shuai Luo ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Cell Types ◽

Biological Functions ◽

Stent Restenosis ◽

Artery Disease ◽

Almost All ◽

Different Cell Types ◽

Insight Into ◽

Systematic Knowledge

Exosomes, with an diameter of 30~150 nm, could be released from almost all types of cells, which contain diverse effective constituent, such as RNAs, proteins, lipids, and so on. In recent years, exosomes have been verified to play an important role in mechanism, diagnosis, treatment, and prognosis of cardiovascular disease, especially coronary artery disease (CAD). Moreover, it has also been shown that exosomes derived from different cell types have various biological functions based on the cell stimulation and microenvironment. However, therapeutic exosomes are currently far away from clinical translation, despite it is full of hope. In this review, we summarize an update of the recent studies and systematic knowledge of therapeutic exosomes in atherosclerosis, myocardial infarction, and in-stent restenosis, which might provide a novel insight into the treatment of CAD and promote the potential clinical application of therapeutic exosomes.

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Exo-miRNAs as a New Tool for Liquid Biopsy in Lung Cancer

Cancers ◽

10.3390/cancers11060888 ◽

2019 ◽

Vol 11 (6) ◽

pp. 888 ◽

Cited By ~ 13

Author(s):

Orazio Fortunato ◽

Patrizia Gasparini ◽

Mattia Boeri ◽

Gabriella Sozzi

Keyword(s):

Lung Cancer ◽

Liquid Biopsy ◽

Biological Fluids ◽

Lung Cancer Screening ◽

Cell Types ◽

Lung Carcinogenesis ◽

Lung Cancer Diagnosis ◽

Diagnosis Of Lung Cancer ◽

Exosomal Mirna ◽

Different Cell Types

Lung cancer is the predominant cause of cancer-related deaths. The high mortality rates are mainly due to the lack of diagnosis before the cancer is at a late stage. Liquid biopsy is a promising technique that could allow early diagnosis of lung cancer and better treatment selection for patients. Cell-free microRNAs have been detected in biological fluids, such as serum and plasma, and are considered interesting biomarkers for lung cancer screening and detection. Exosomes are nanovesicles of 30–150 nm and can be released by different cell types within the tumor microenvironment. Their exosomal composition reflects that of their parental cells and could be potentially useful as a biomarker for lung cancer diagnosis. This review summarizes the state-of-the-art of circulating microRNAs (miRNAs) in lung cancer, focusing on their potential use in clinical practice. Moreover, we describe the importance of exosomal miRNA cargo in lung cancer detection and their potential role during lung carcinogenesis. Finally, we discuss our experience with the analysis of circulating exosomal miRNAs in the bioMILD screening trial.

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Exosomes and cardiovascular cell–cell communication

Essays in Biochemistry ◽

10.1042/ebc20170081 ◽

2018 ◽

Vol 62 (2) ◽

pp. 193-204 ◽

Cited By ~ 14

Author(s):

Adam J. Poe ◽

Anne A. Knowlton

Keyword(s):

Biological Fluids ◽

Cell Communication ◽

Cell Types ◽

Cardiac Cells ◽

The Body ◽

Biologically Active ◽

Surrounding Tissue ◽

Intercellular Signaling ◽

Cardiac Damage ◽

Almost All

Exosomes have become an important player in intercellular signaling. These lipid microvesicles can stably transfer miRNA, protein, and other molecules between cells and circulate throughout the body. Exosomes are released by almost all cell types and are present in most if not all biological fluids. The biologically active cargo carried by exosomes can alter the phenotype of recipient cells. Exosomes increasingly are recognized as having an important role in the progression and treatment of cardiac disease states. Injured cardiac cells can release exosomes with important pathological effects on surrounding tissue, in addition to effecting other organs. But of equal interest is the possible benefit(s) conferred by exosomes released from stem cells for use in treatment and possible repair of cardiac damage.

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Turnover of the carboxy-terminal tyrosine of alpha-tubulin and means of reaching elevated levels of detyrosination in living cells

Journal of Cell Science ◽

10.1242/jcs.88.2.185 ◽

1987 ◽

Vol 88 (2) ◽

pp. 185-203

Author(s):

J. Wehland ◽

K. Weber

Keyword(s):

Primary Cultures ◽

Neuroblastoma Cells ◽

Cell Types ◽

Morphological Transformation ◽

Alpha Tubulin ◽

Tubulin Antibodies ◽

Cell Processes ◽

Carboxy Terminal ◽

Almost All ◽

Different Cell Types

Monoclonal antibodies specific for either the tyrosinated (Tyr) or the detyrosinated (Glu) form of alpha-tubulin were elicited with synthetic peptides spanning the carboxy-terminal sequences of the two forms. While almost all microtubules (MTs) are usually of the Tyr-tubulin type (Tyr-rich MTs) some MTs containing noticeable amounts of Glu-tubulin (Glu-rich MTs) were found in many but not all cell lines studied. Glu-rich MTs seemed absent from proliferating CHO and N115 neuroblastoma cells. When differentiation of these cells was initiated by the addition of forskolin for CHO, or by serum deprivation for N115, elevated levels of microtubular Glu-tubulin were observed. In differentiated N115 cells Glu-tubulin was restricted to MT of elongated cell processes and was not found in growth cones and many MT of the cell body. Elevated levels of Glu-tubulin were also characteristic of other differentiated cell types, including neurones and myotubes but were not found in glial cells, astrocytes and fibroblasts in the same primary cultures. Additional experiments suggested that the restricted distribution of Glu-tubulin is the result of MT subsets with different stabilities. Results with mitotic drugs indicated that detyrosination occurs on MTs rather than on soluble tubulin and that stabilization of MTs usually favours the detyrosination process. Evidence for a functional alpha-tubulin cycle involving an inherent carboxypeptidase and a recharging ligase was apparent in 3T3 cells from the preponderance of Glu-rich MTs induced by taxol treatment or the micro-injection of certain antibodies either protecting the detyrosinated form (Glu-tubulin antibodies) or inhibiting retyrosination (ligase antibodies). As the same treatment of CHO cells resulted in comparable arrays of Glu-rich MTs only when forskolin was also present, different cell types may differ in the level of active carboxypeptidase. The results are discussed in terms of possible functions of the tyrosination/detyrosination cycle of alpha-tubulin. While most results can be explained on the basis of ‘older’ and, consequently, more detyrosinated MTs, others raise the possibility that cyclic-AMP-dependent events and certain environmental influences known to induce either a morphological transformation or a differentiation event may influence the carboxypeptidase inherent in the alpha-tubulin cycle.

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Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms21197002 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7002

Author(s):

Christiana Magkrioti ◽

Eleanna Kaffe ◽

Elli-Anna Stylianaki ◽

Camelia Sidahmet ◽

Georgia Melagraki ◽

...

Keyword(s):

In Silico ◽

Rational Design ◽

Inflammatory Diseases ◽

Molecular Model ◽

Biological Fluids ◽

Cell Types ◽

Phase Iii ◽

Priority List ◽

Model Docking ◽

Almost All

Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids, largely responsible for extracellular lysophosphatidic acid (LPA) production. LPA is a bioactive growth-factor-like lysophospholipid that exerts pleiotropic effects in almost all cell types, exerted through at least six G-protein-coupled receptors (LPAR1-6). Increased ATX expression has been detected in different chronic inflammatory diseases, while genetic or pharmacological studies have established ATX as a promising therapeutic target, exemplified by the ongoing phase III clinical trial for idiopathic pulmonary fibrosis. In this report, we employed an in silico drug discovery workflow, aiming at the identification of structurally novel series of ATX inhibitors that would be amenable to further optimization. Towards this end, a virtual screening protocol was applied involving the search into molecular databases for new small molecules potentially binding to ATX. The crystal structure of ATX in complex with a known inhibitor (HA-155) was used as a molecular model docking reference, yielding a priority list of 30 small molecule ATX inhibitors, validated by a well-established enzymatic assay of ATX activity. The two most potent, novel and structurally different compounds were further structurally optimized by deploying further in silico tools, resulting to the overall identification of six new ATX inhibitors that belong to distinct chemical classes than existing inhibitors, expanding the arsenal of chemical scaffolds and allowing further rational design.

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Exosomes and Micro-RNAs in Aging Process

Biomedicines ◽

10.3390/biomedicines9080968 ◽

2021 ◽

Vol 9 (8) ◽

pp. 968

Author(s):

Yousra Hamdan ◽

Loubna Mazini ◽

Gabriel Malka

Keyword(s):

Messenger Rna ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Biological Fluids ◽

Cell Types ◽

Exosome Biogenesis ◽

Age Related ◽

Micro Rnas ◽

Underlying Mechanisms ◽

Almost All

Exosomes are the main actors of intercellular communications and have gained great interest in the new cell-free regenerative medicine. These nanoparticles are secreted by almost all cell types and contain lipids, cytokines, growth factors, messenger RNA, and different non-coding RNA, especially micro-RNAs (mi-RNAs). Exosomes’ cargo is released in the neighboring microenvironment but is also expected to act on distant tissues or organs. Different biological processes such as cell development, growth and repair, senescence, migration, immunomodulation, and aging, among others, are mediated by exosomes and principally exosome-derived mi-RNAs. Moreover, their therapeutic potential has been proved and reinforced by their use as biomarkers for disease diagnostics and progression. Evidence has increasingly shown that exosome-derived mi-RNAs are key regulators of age-related diseases, and their involvement in longevity is becoming a promising issue. For instance, mi-RNAs such as mi-RNA-21, mi-RNA-29, and mi-RNA-34 modulate tissue functionality and regeneration by targeting different tissues and involving different pathways but might also interfere with long life expectancy. Human mi-RNAs profiling is effectively related to the biological fluids that are reported differently between young and old individuals. However, their underlying mechanisms modulating cell senescence and aging are still not fully understood, and little was reported on the involvement of mi-RNAs in cell or tissue longevity. In this review, we summarize exosome biogenesis and mi-RNA synthesis and loading mechanism into exosomes’ cargo. Additionally, we highlight the molecular mechanisms of exosomes and exosome-derived mi-RNA regulation in the different aging processes.

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CaMelia: imputation in single-cell methylomes based on local similarities between cells

Bioinformatics ◽

10.1093/bioinformatics/btab029 ◽

2021 ◽

Author(s):

Jianxiong Tang ◽

Jianxiao Zou ◽

Mei Fan ◽

Qi Tian ◽

Jiyang Zhang ◽

...

Keyword(s):

Single Cell ◽

Regulation Of Gene Expression ◽

Cell Types ◽

Supplementary Information ◽

Gradient Boosting ◽

Raw Data ◽

Boosting Method ◽

Cell Subpopulations ◽

Downstream Analysis ◽

Almost All

Abstract Motivation Single-cell DNA methylation sequencing detects methylation levels with single-cell resolution, while this technology is upgrading our understanding of the regulation of gene expression through epigenetic modifications. Meanwhile, almost all current technologies suffer from the inherent problem of detecting low coverage of the number of CpGs. Therefore, addressing the inherent sparsity of raw data is essential for quantitative analysis of the whole genome. Results Here, we reported CaMelia, a CatBoost gradient boosting method for predicting the missing methylation states based on the locally paired similarity of intercellular methylation patterns. On real single-cell methylation datasets, CaMelia yielded significant imputation performance gains over previous methods. Furthermore, applying the imputed data to the downstream analysis of cell-type identification, we found that CaMelia helped to discover more intercellular differentially methylated loci that were masked by the sparsity in raw data, and the clustering results demonstrated that CaMelia could preserve cell-cell relationships and improve the identification of cell types and cell subpopulations. Availability and implementation Python code is available at https://github.com/JxTang-bioinformatics/CaMelia. Supplementary information Supplementary data are available at Bioinformatics online.

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Targeting GRK5 for Treating Chronic Degenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22041920 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1920

Author(s):

Federica Marzano ◽

Antonio Rapacciuolo ◽

Nicola Ferrara ◽

Giuseppe Rengo ◽

Walter J. Koch ◽

...

Keyword(s):

Neurological Diseases ◽

Cell Types ◽

Cardiac Cells ◽

Multifunctional Protein ◽

Surface Receptors ◽

Extracellular Signals ◽

Degenerative Disorders ◽

Almost All ◽

Related Proteins ◽

Different Cell Types

G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors and they are responsible for the transduction of extracellular signals, regulating almost all aspects of mammalian physiology. These receptors are specifically regulated by a family of serine/threonine kinases, called GPCR kinases (GRKs). Given the biological role of GPCRs, it is not surprising that GRKs are also involved in several pathophysiological processes. Particular importance is emerging for GRK5, which is a multifunctional protein, expressed in different cell types, and it has been found located in single or multiple subcellular compartments. For instance, when anchored to the plasma membrane, GRK5 exerts its canonical function, regulating GPCRs. However, under certain conditions (e.g., pro-hypertrophic stimuli), GRK5 translocates to the nucleus of cells where it can interact with non-GPCR-related proteins as well as DNA itself to promote “non-canonical” signaling, including gene transcription. Importantly, due to these actions, several studies have demonstrated that GRK5 has a pivotal role in the pathogenesis of chronic-degenerative disorders. This is true in the cardiac cells, tumor cells, and neurons. For this reason, in this review article, we will inform the readers of the most recent evidence that supports the importance of targeting GRK5 to prevent the development or progression of cancer, cardiovascular, and neurological diseases.

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Platelet Toll-Like Receptors: Bridging Inflammation and Immunity

Blood ◽

10.1182/blood.v128.22.sci-45.sci-45 ◽

2016 ◽

Vol 128 (22) ◽

pp. SCI-45-SCI-45

Author(s):

Paul Kubes

Keyword(s):

Immune Cells ◽

Conflicts Of Interest ◽

Detection System ◽

Vascular Dysfunction ◽

Cell Types ◽

Neutrophil Extracellular Traps ◽

Extracellular Traps ◽

Almost All ◽

Different Cell Types

Abstract Since the discovery that there is a series of pattern recognition receptors that allow the immune system to detect pathogens, there has been a lot of work to elucidate the signaling molecules that contribute to this detection system. Although the cell types involved would seem to be just as important, our understanding of which cells are critical remains less well explored. Using intravital imaging to visualize the different cell types, we were surprised to find that in almost all conditions that we examined, platelets were rapidly recruited to afflicted tissues. Under some conditions, platelets bound vascular macrophage including Kupffer cells and helped contain bacteria. These were instantaneous responses. At later times, platelets bound neutrophils and induced the production of neutrophil extracellular traps (NETs) that helped to catch bacteria as well as viruses but did induce some local vascular injury. In some scenarios, platelets bound endothelial cells and whether this was to wall off and contain infections or a hijacking of platelets by bacteria to induce vascular dysfunction and poor perfusion remains unclear. Visualizing platelets in sterile injury also revealed important contributions to helping recruit other immune cells that help to heal. The role of the platelet as an effector in infections and inflammation will be discussed. Disclosures No relevant conflicts of interest to declare.

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