Browsing by Subject "exosomes"
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Item Exosomes Derived From Bone Mesenchymal Stem Cells Ameliorate Early Inflammatory Responses Following Traumatic Brain Injury(Frontiers Media S.A., 2019-01-24) Ni, Haoqi; Yang, Su; Siaw-Debrah, Felix; Hu, Jiangnan; Wu, Ke; He, Zibin; Yang, Jianjing; Pan, Sishi; Lin, Xiao; Ye, Haotuo; Xu, Zhu; Wang, Fan; Jin, Kunlin; Zhuge, Qichuan; Huang, LijieTraumatic brain injury (TBI) is a leading cause of mortality and disability worldwide. Although treatment guidelines have been developed, no best treatment option or medicine for this condition exists. Recently, mesenchymal stem cells (MSCs)-derived exosomes have shown lots of promise for the treatment of brain disorders, with some results highlighting the neuroprotective effects through neurogenesis and angiogenesis after TBI. However, studies focusing on the role of exosomes in the early stages of neuroinflammation post-TBI are not sufficient. In this study, we investigated the role of bone mesenchymal stem cells (BMSCs)-exosomes in attenuating neuroinflammation at an early stage post-TBI and explored the potential regulatory neuroprotective mechanism. We administered 30 mug protein of BMSCs-exosomes or an equal volume of phosphate-buffered saline (PBS) via the retro-orbital route into C57BL/6 male mice 15 min after controlled cortical impact (CCI)-induced TBI. The results showed that the administration of BMSCs-exosomes reduced the lesion size and improved the neurobehavioral performance assessed by modified Neurological Severity Score (mNSS) and rotarod test. In addition, BMSCs-exosomes inhibited the expression of proapoptosis protein Bcl-2-associated X protein (BAX) and proinflammation cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta, while enhancing the expression of the anti-apoptosis protein B-cell lymphoma 2 (BCL-2). Furthermore, BMSCs-exosomes modulated microglia/macrophage polarization by downregulating the expression of inducible nitric oxide synthase (INOS) and upregulating the expression of clusters of differentiation 206 (CD206) and arginase-1 (Arg1). In summary, our result shows that BMSCs-exosomes serve a neuroprotective function by inhibiting early neuroinflammation in TBI mice through modulating the polarization of microglia/macrophages. Further research into this may serve as a potential therapeutic strategy for the future treatment of TBI.Item Peripheral Circulating Exosomal miRNAs Potentially Contribute to the Regulation of Molecular Signaling Networks in Aging(MDPI, 2020-03-11) Zhang, Hongxia; Jin, KunlinPeople are living longer than ever. Consequently, they have a greater chance for developing a functional impairment or aging-related disease, such as a neurodegenerative disease, later in life. Thus, it is important to identify and understand mechanisms underlying aging as well as the potential for rejuvenation. Therefore, we used next-generation sequencing to identify differentially expressed microRNAs (miRNAs) in serum exosomes isolated from young (three-month-old) and old (22-month-old) rats and then used bioinformatics to explore candidate genes and aging-related pathways. We identified 2844 mRNAs and 68 miRNAs that were differentially expressed with age. TargetScan revealed that 19 of these miRNAs are predicated to target the 766 mRNAs. Pathways analysis revealed signaling components targeted by these miRNAs: mTOR, AMPK, eNOS, IGF, PTEN, p53, integrins, and growth hormone. In addition, the most frequently predicted target genes regulated by these miRNAs were EIF4EBP1, insulin receptor, PDK1, PTEN, paxillin, and IGF-1 receptor. These signaling pathways and target genes may play critical roles in regulating aging and lifespan, thereby validating our analysis. Understanding the causes of aging and the underlying mechanisms may lead to interventions that could reverse certain aging processes and slow development of aging-related diseases.Item Phosphorlyation of Annexin A2 is essential for its association with exosomes and for migration, invasion and proliferation in triple negative breast cancer(2018-12) Desai, Priyanka P.; Vishwanatha, Jamboor K.; Basha, Riyaz; Chaudhary, PankajExosomes are membrane enclosed small vesicles that range from 40-120 nm in size and participate in cell-cell communication by transferring proteins to other cells. Annexin A2 (AnxA2), a calcium-dependent phospholipid binding protein, is present on the surface of the exosomes. AnxA2 phosphorylation plays an essential role in many physiological conditions by forming a heterotetrameric complex with p11 or S100A10 on the cell surface. We demonstrate here that the phosphorylation at Tyrosine (Tyr)-23 in the N-terminal region of AnxA2 is consequential for its association with the cell surface. This association increases the migratory, invasive and proliferative capacity of MDA-MB-231 triple negative breast cancer (TNBC) cells. An increase in cell surface AnxA2 further leads to a stronger association of AnxA2 with the exosomal surface. We also demonstrate that AnxA2 enriched exosomes promote proliferative and invasive characteristics of a different recipient cell [CAL (Centre Antoine Lacassagne) - 148]. These results demonstrate that Tyr23 phosphorylation of AnxA2 is pivotal for its association with exosomes and for imparting more malignant characteristics to the other breast cancer cells. Thus, AnxA2 could be used as a targeting approach for developing a treatment of TNBC.Item Salivary Exosomes in Health and Disease: Future Prospects in the Eye(MDPI, 2023-04-14) Liu, Angela; Hefley, Brenna; Escandon, Paulina; Nicholas, Sarah E.; Karamichos, DimitriosExosomes are a group of vesicles that package and transport DNA, RNA, proteins, and lipids to recipient cells. They can be derived from blood, saliva, urine, and/or other biological tissues. Their impact on several diseases, such as neurodegenerative, autoimmune, and ocular diseases, have been reported, but not fully unraveled. The exosomes that are derived from saliva are less studied, but offer significant advantages over exosomes from other sources, due to their accessibility and ease of collection. Thus, their role in the pathophysiology of diseases is largely unknown. In the context of ocular diseases, salivary exosomes have been under-utilized, thus creating an enormous gap in the literature. The current review discusses the state of exosomes research on systemic and ocular diseases and highlights the role and potential of salivary exosomes as future ocular therapeutic vehicles.Item The role of exosomes and microRNA in Astrocyte-mediated HIV-1 Tat neurotoxicity(2016-08-01) Rahimian, Pejman; Johnny J. HeHuman immunodeficiency virus invades the central nervous system (CNS) soon after the initial infection, often leading to neurological complications including cognitive and motor dysfunction, which have been collectively termed HIV/neuroAIDS. The introduction of combination antiretroviral therapy in the mid-1990’s led to reduced viral replication, improved immune function and increased life expectancy among HIV-infected individuals. As a result, the incidence of the most severe form of cognitive impairment due to HIV, so called HIV-associated dementia, reduced dramatically. However, the treatment regimen was not successful in protecting the patients from neuroAIDS as more discrete forms of CNS dysfunction, so-called minor cognitive motor disorders, have become more common. HIV-1 Tat protein is an indispensable factor for successful transcription and replication of the viral genome. Aside from nucleus-bound functions, Tat is diffusely and unconventionally secreted outside of infected cells and contributes immensely to the pathology of neuroAIDS as a potent neurotoxin. The presence of Tat in the CNS despite the implementation of combination anti-retroviral therapy and the strong correlation of pathological hallmarks of neuroAIDS with continued Tat expression in CNS cells warrant a thorough understanding of the partially explained unconventional secretion mechanism(s) by Tat. Exosomal secretion of cargo has been established as an extremely efficient pathway of glia-neuron communications and astrocytes have been shown to utilize this delivery mechanism for the provision of neurotrophic factors and danger-associated molecular patterns to neurons. My dissertation research consisted of two parts. In the first part, we investigated the possibility of exosomal association and distribution of Tat protein from astrocytes and its delivery to neurons. We demonstrated significant presence of HIV-1 Tat in exosomes derived from Tat-expressing primary astrocytes, astrocytoma cell lines, and HIV-infected T cells. We further showed that exosome-associated Tat from Tat-expressing astrocytes was capable of causing neurite shortening and neuron death, further supporting that this new form of extracellular Tat is biologically active. Lastly, we constructed a Tat mutant deleted of its basic domain and determined the role of the basic domain in Tat trafficking into exosomes. Basic domain-deleted Tat exhibited no apparent effects on Tat trafficking into exosomes, while maintained its dominant negative function in Tat-mediated LTR transactivation. Taken together, these results show a significant fraction of Tat is secreted and present in the form of exosomes and may contribute to the stability of extracellular Tat and broaden the spectrum of its target cells. In the second part, we investigated the mechanism of neurite shortening by Tat. Dendritic pruning and synaptic loss of neurons are the most prominent pathological hallmarks of neuroAIDS in the cART era. Although Tat has been implicated in the synaptodendritic damage to neurons, the exact mechanisms of this injury by Tat have not yet been elucidated. Several important controllers of dendritic plasticity have been shown to be post-transcriptionally regulated by a brain-enriched microRNA, miR-132, which is abundantly expressed in the brains of the HIV-infected individuals with cognitive impairment. We found significant induction of miR-132 in both astrocytic and neuronal cell lines following Tat transfection. Tat expression in primary astrocytes from our doxycycline-inducible Tat transgenic mice (iTat) and HIV-infected primary human astrocytes also led to significant upregulation of this microRNA. We confirmed the repression of miR-132 target genes involved in the regulation of dendritic length following Tat expression. Using a basic-domain-deletion mutant of Tat we further demonstrated that Tat-induced miR-132 expression involved CREB phosphorylation. Lastly, we showed that following Tat expression in astrocytes, exosome-associated miR-132 was significantly increased and caused neurite shortening in primary mouse cortical neurons. Taken together, these results demonstrate for the first time the role of miR-132 in Tat-induced damage of the dendritic arbor.