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      Interplay between exosomes and autophagy machinery in pain management: State of the art

      research-article
      a , a , a , b , c , d , *
      Neurobiology of Pain
      Elsevier
      Autophagy, Neural Exosome, Pain Management, Cell Therapy, NPCs-Exo, NPCs-derived Exo, CESC-Exo, cartilage endplate stem cell-derived Exo, MMP, matrix metalloproteinase, NPCs, nucleus pulposus cells, HSPA8, heat shock protein family A member 8, SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptors, nSMase, ceramide-generating enzyme neutral sphingomyelinases, ESCRT, endosomal sorting complex required for transport, MVBs, multivesicular bodies, LAMP2, lysosomal‑associated membrane protein type 2, TLR4, Toll-like receptor 4, TRAF6, TNF receptor-associated factor 6, MAPK8/JNK, mitogen-activated protein kinase 8p-/c-Jun N-terminal Kinase, NFKB/NF-κB, nuclear factor of kappa light polypeptide gene enhancer in B cells, ER, endoplasmic reticulum, LAT1, large amino acid transporter, LTs, leukotrienes

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          Highlights

          • Despite recent progress regarding inexpensive medications in clinical settings and, many individuals suffer from moderate to severe pain globally.

          • It is thought that understating the close association between these phenomena paves the way to use exosomes as therapeutic bullets to reduce pain under pathological conditions.

          Abstract

          Despite recent progress regarding inexpensive medical approaches, many individuals suffer from moderate to severe pain globally. The discovery and advent of exosomes, as biological nano-sized vesicles, has revolutionized current knowledge about underlying mechanisms associated with several pathological conditions. Indeed, these particles are touted as biological bio-shuttles with the potential to carry specific signaling biomolecules to cells in proximity and remote sites, maintaining cell-to-cell communication in a paracrine manner. A piece of evidence points to an intricate relationship between exosome biogenesis and autophagy signaling pathways at different molecular levels. A close collaboration of autophagic response with exosome release can affect the body’s hemostasis and physiology of different cell types. This review is a preliminary attempt to highlight the possible interface of autophagy flux and exosome biogenesis on pain management with a special focus on neuropathic pain. It is thought that this review article will help us to understand the interplay of autophagic response and exosome biogenesis in the management of pain under pathological conditions. The application of therapies targeting autophagy pathway and exosome abscission can be an alternative strategy in the regulation of pain.

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          Most cited references139

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          Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication

          The ability of exosomes to transfer cargo from donor to acceptor cells, thereby triggering phenotypic changes in the latter, has generated substantial interest in the scientific community. However, the extent to which exosomes differ from other extracellular vesicles in terms of their biogenesis and functions remains ill-defined. Here, we discuss the current knowledge on the specificities of exosomes and other types of extracellular vesicles, and their roles as important agents of cell-to-cell communication.
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            Exosomes Facilitate Therapeutic Targeting of Oncogenic Kras in Pancreatic Cancer

            Summary The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes, extracellular vesicles generated by all cells, are naturally present in the blood. Here we demonstrate that enhanced retention of exosomes in circulation, compared to liposomes, is due to CD47 mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry siRNA or shRNA specific to oncogenic KRASG12D (iExosomes), a common mutation in pancreatic cancer. Compared to liposomes, iExosomes target oncogenic Kras with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. iExosomes treatment suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased their overall survival. Our results inform on a novel approach for direct and specific targeting of oncogenic Kras in tumors using iExosomes.
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              Is Open Access

              Current knowledge on exosome biogenesis and release

              Exosomes are nanosized membrane vesicles released by fusion of an organelle of the endocytic pathway, the multivesicular body, with the plasma membrane. This process was discovered more than 30 years ago, and during these years, exosomes have gone from being considered as cellular waste disposal to mediate a novel mechanism of cell-to-cell communication. The exponential interest in exosomes experienced during recent years is due to their important roles in health and disease and to their potential clinical application in therapy and diagnosis. However, important aspects of the biology of exosomes remain unknown. To explore the use of exosomes in the clinic, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are better understood. We have here summarized what is presently known about how exosomes are formed and released by cells. Moreover, other cellular processes related to exosome biogenesis and release, such as autophagy and lysosomal exocytosis are presented. Finally, methodological aspects related to exosome release studies are discussed.
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                Author and article information

                Contributors
                Journal
                Neurobiol Pain
                Neurobiol Pain
                Neurobiology of Pain
                Elsevier
                2452-073X
                09 June 2022
                Aug-Dec 2022
                09 June 2022
                : 12
                : 100095
                Affiliations
                [a ]Emergency and Trauma Care Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
                [b ]Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
                [c ]Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
                [d ]Road Traffic Injury Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
                Author notes
                [* ]Corresponding author. soleimanpourh@ 123456tbzmed.ac.ir
                Article
                S2452-073X(22)00012-5 100095
                10.1016/j.ynpai.2022.100095
                9198378
                35720640
                c5cad3e1-c158-4d3c-b913-77495fafe729
                © 2022 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 23 April 2022
                : 4 June 2022
                : 4 June 2022
                Categories
                Original Research Article

                autophagy,neural exosome,pain management,cell therapy,npcs-exo, npcs-derived exo,cesc-exo, cartilage endplate stem cell-derived exo,mmp, matrix metalloproteinase,npcs, nucleus pulposus cells,hspa8, heat shock protein family a member 8,snare, soluble n-ethylmaleimide-sensitive factor attachment protein receptors,nsmase, ceramide-generating enzyme neutral sphingomyelinases,escrt, endosomal sorting complex required for transport,mvbs, multivesicular bodies,lamp2, lysosomal‑associated membrane protein type 2,tlr4, toll-like receptor 4,traf6, tnf receptor-associated factor 6,mapk8/jnk, mitogen-activated protein kinase 8p-/c-jun n-terminal kinase,nfkb/nf-κb, nuclear factor of kappa light polypeptide gene enhancer in b cells,er, endoplasmic reticulum,lat1, large amino acid transporter,lts, leukotrienes

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