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Pharmaceutics Nov 2022Neurological diseases remain some of the major causes of death and disability in the world. Few types of drugs and insufficient delivery across the blood-brain barrier... (Review)
Review
Neurological diseases remain some of the major causes of death and disability in the world. Few types of drugs and insufficient delivery across the blood-brain barrier limit the treatment of neurological disorders. The past two decades have seen the rapid development of extracellular vesicle-based therapeutics in many fields. As the physiological and pathophysiological roles of extracellular vesicles are recognized in neurological diseases, they have become promising therapeutics and targets for therapeutic interventions. Moreover, advanced nanomedicine technologies have explored the potential of extracellular vesicles as drug delivery systems in neurological diseases. In this review, we discussed the preclinical strategies for extracellular vesicle-based therapeutics in neurological disorders and the struggles involved in their clinical application.
PubMed: 36559145
DOI: 10.3390/pharmaceutics14122652 -
Frontiers in Cardiovascular Medicine 2022Cardiovascular diseases rank the highest incidence and mortality worldwide. As the most common type of cardiovascular disease, myocardial infarction causes high... (Review)
Review
Cardiovascular diseases rank the highest incidence and mortality worldwide. As the most common type of cardiovascular disease, myocardial infarction causes high morbidity and mortality. Recent studies have revealed that extracellular vesicles, including exosomes, show great potential as a promising cell-free therapy for the treatment of myocardial infarction. However, low heart-targeting efficiency and short plasma half-life have hampered the clinical translation of extracellular vesicle therapy. Currently, four major types of strategies aiming at enhancing target efficiency have been developed, including modifying EV surface, suppressing non-target absorption, increasing the uptake efficiency of target cells, and utilizing a hydrogel patch. This presented review summarizes the current research aimed at EV heart targeting and discusses the challenges and opportunities in EV therapy, which will be beneficial for the development of effective heart-targeting strategies.
PubMed: 36704471
DOI: 10.3389/fcvm.2022.1041481 -
Acta Neuropathologica Apr 2021The neuronal protein α-synuclein (αS) is central to the pathogenesis of Parkinson's disease and other progressive brain diseases such as Lewy body dementia and... (Review)
Review
The neuronal protein α-synuclein (αS) is central to the pathogenesis of Parkinson's disease and other progressive brain diseases such as Lewy body dementia and multiple system atrophy. These diseases, collectively referred to as 'synucleinopathies', have long been considered purely proteinopathies: diseases characterized by the misfolding of a protein into small and large aggregates mainly consisting of that protein (in this case: α-synuclein). However, recent morphological insights into Lewy bodies, the hallmark neuropathology of human synucleinopathies, suggests these lesions are also rich in vesicles and other membranous organelles. Moreover, αS physiology and pathology are both strongly associated with various aspects of intracellular vesicle trafficking and lipid biology. αS physiologically binds to synaptic and other small vesicles, and several functions of αS in regulating vesicle biology have been proposed. Familial PD-linked αS excess and missense mutations have been shown to impair vesicle trafficking and alter lipid homeostasis. On the other hand, vesicle trafficking and lipid-related genes have emerged as Parkinson's risk factors, suggesting a bidirectional relationship. The answer to the question "Does abnormal αS accumulation cause impaired vesicle trafficking and lipid dyshomeostasis or is αS aggregation the consequence of such impairments?" may be "Both". Here, we review current knowledge of the αS-lipid and αS-vesicle trafficking interplay, with a special focus on Parkinson's disease and Lewy body dementia.
Topics: Animals; Cytoplasmic Vesicles; Humans; Lipid Metabolism; Protein Aggregation, Pathological; Protein Transport; Synucleinopathies; alpha-Synuclein
PubMed: 32607605
DOI: 10.1007/s00401-020-02177-z -
Biomedicines Jul 2022Within 1 millisecond of action potential arrival at presynaptic terminals voltage-gated Ca channels open. The Ca channels are linked to synaptic vesicles which are... (Review)
Review
Within 1 millisecond of action potential arrival at presynaptic terminals voltage-gated Ca channels open. The Ca channels are linked to synaptic vesicles which are tethered by active zone proteins. Ca entrance into the active zone triggers: (1) the fusion of the vesicle and exocytosis, (2) the replenishment of the active zone with vesicles for incoming exocytosis, and (3) various types of endocytosis for vesicle reuse, dependent on the pattern of firing. These time-dependent vesicle dynamics are controlled by presynaptic Ca sensor proteins, regulating active zone scaffold proteins, fusion machinery proteins, motor proteins, endocytic proteins, several enzymes, and even Ca channels, following the decay of Ca concentration after the action potential. Here, I summarize the Ca-dependent protein controls of synchronous and asynchronous vesicle release, rapid replenishment of the active zone, endocytosis, and short-term plasticity within 100 msec after the action potential. Furthermore, I discuss the contribution of active zone proteins to presynaptic plasticity and to homeostatic readjustment during and after intense activity, in addition to activity-dependent endocytosis.
PubMed: 35884898
DOI: 10.3390/biomedicines10071593 -
Materials Today. Bio Dec 2023Combination immunotherapy of cancer vaccines with immune checkpoint inhibitors (ICIs) represents a promising therapeutic strategy for immunosuppressed and cold tumors....
Combination immunotherapy of cancer vaccines with immune checkpoint inhibitors (ICIs) represents a promising therapeutic strategy for immunosuppressed and cold tumors. However, this strategy still faces challenges, including the limited therapeutic efficacy of cancer vaccines and immune-related adverse events associated with systematic delivery of ICIs. Herein, we demonstrate the antitumor immune response induced by outer membrane vesicle from (Akk-OMV), which exhibites a favorable safety profile, highlighting the potential application as a natural and biocompatible self-adjuvanting vesicle. Utilizing tumor cell-derived exosome as an antigen source and Akk-OMV as a natural adjuvant, we construct a cancer vaccine formulation of extracellular vesicles hybrid lipid nanovesicles (Lipo@HEV) for enhanced prophylactic and therapeutic vaccination by promoting dendritic cell (DC) maturation in lymph node and activating cytotoxic T cell (CTL) response. The Lipo@HEV is further loaded with plasmid to enable gene therapy-mediated PD-L1 blockade upon peritumoral injection. Meanwhile, it penetrates into lymph node to initiate DC maturation and CTL activation, synergistically inhibiting the established tumor. The fabrication of extracellular vesicles hybrid plasmid-loaded lipid nanovesicles reveals a promising gene therapy-guided and vesicle-based hybrid system for therapeutic cancer vaccination and synergistic immunotherapy strategy.
PubMed: 37942423
DOI: 10.1016/j.mtbio.2023.100845 -
Frontiers in Immunology 2020is the causative agent of a severe pneumonia called Legionnaires' disease. The environmental bacterium replicates in free-living amoebae as well as in lung macrophages... (Review)
Review
is the causative agent of a severe pneumonia called Legionnaires' disease. The environmental bacterium replicates in free-living amoebae as well as in lung macrophages in a distinct compartment, the -containing vacuole (LCV). The LCV communicates with a number of cellular vesicle trafficking pathways and is formed by a plethora of secreted bacterial effector proteins, which target host cell proteins and lipids. Phosphoinositide (PI) lipids are pivotal determinants of organelle identity, membrane dynamics and vesicle trafficking. Accordingly, eukaryotic cells tightly regulate the production, turnover, interconversion, and localization of PI lipids. modulates the PI pattern in infected cells for its own benefit by (i) recruiting PI-decorated vesicles, (ii) producing effectors acting as PI interactors, phosphatases, kinases or phospholipases, and (iii) subverting host PI metabolizing enzymes. The PI conversion from PtdIns(3) to PtdIns(4) represents a decisive step during LCV maturation. In this review, we summarize recent progress on elucidating the strategies, by which subverts host PI lipids to promote LCV formation and intracellular replication.
Topics: Bacterial Proteins; Cell Membrane; Endoplasmic Reticulum; Host-Pathogen Interactions; Humans; Legionella pneumophila; Legionnaires' Disease; Macrophages; Phosphatidylinositols; Secretory Vesicles; Transport Vesicles; Vacuoles
PubMed: 32117224
DOI: 10.3389/fimmu.2020.00025 -
Cells Sep 2023The faithful formation and, consequently, function of a synapse requires continuous and tightly controlled delivery of synaptic material. At the presynapse, a variety of... (Review)
Review
The faithful formation and, consequently, function of a synapse requires continuous and tightly controlled delivery of synaptic material. At the presynapse, a variety of proteins with unequal molecular properties are indispensable to compose and control the molecular machinery concerting neurotransmitter release through synaptic vesicle fusion with the presynaptic membrane. As presynaptic proteins are produced mainly in the neuronal soma, they are obliged to traffic along microtubules through the axon to reach the consuming presynapse. This anterograde transport is performed by highly specialised and diverse presynaptic precursor vesicles, membranous organelles able to transport as different proteins such as synaptic vesicle membrane and membrane-associated proteins, cytosolic active zone proteins, ion-channels, and presynaptic membrane proteins, coordinating synaptic vesicle exo- and endocytosis. This review aims to summarise and categorise the diverse and numerous findings describing presynaptic precursor cargo, mode of trafficking, kinesin-based axonal transport and the molecular mechanisms of presynaptic precursor vesicles biogenesis in both vertebrate and invertebrate model systems.
PubMed: 37759474
DOI: 10.3390/cells12182248 -
Nature Communications Jan 2023Ectopic expression in fibroblasts of synapsin 1 and synaptophysin is sufficient to generate condensates of vesicles highly reminiscent of synaptic vesicle (SV) clusters...
Ectopic expression in fibroblasts of synapsin 1 and synaptophysin is sufficient to generate condensates of vesicles highly reminiscent of synaptic vesicle (SV) clusters and with liquid-like properties. Here we show that unlike synaptophysin, other major integral SV membrane proteins fail to form condensates with synapsin, but co-assemble into the clusters formed by synaptophysin and synapsin in this ectopic expression system. Another vesicle membrane protein, ATG9A, undergoes activity-dependent exo-endocytosis at synapses, raising questions about the relation of ATG9A traffic to the traffic of SVs. We find that both in fibroblasts and in nerve terminals ATG9A does not co-assemble into synaptophysin-positive vesicle condensates but localizes on a distinct class of vesicles that also assembles with synapsin but into a distinct phase. Our findings suggest that ATG9A undergoes differential sorting relative to SV proteins and also point to a dual role of synapsin in controlling clustering at synapses of SVs and ATG9A vesicles.
Topics: Synaptic Vesicles; Synapsins; Synaptophysin; Synapses; Membrane Proteins
PubMed: 36709207
DOI: 10.1038/s41467-023-36081-3 -
Molecular Biomedicine Sep 2022Intracellular vesicle trafficking is the fundamental process to maintain the homeostasis of membrane-enclosed organelles in eukaryotic cells. These organelles transport... (Review)
Review
Intracellular vesicle trafficking is the fundamental process to maintain the homeostasis of membrane-enclosed organelles in eukaryotic cells. These organelles transport cargo from the donor membrane to the target membrane through the cargo containing vesicles. Vesicle trafficking pathway includes vesicle formation from the donor membrane, vesicle transport, and vesicle fusion with the target membrane. Coat protein mediated vesicle formation is a delicate membrane budding process for cargo molecules selection and package into vesicle carriers. Vesicle transport is a dynamic and specific process for the cargo containing vesicles translocation from the donor membrane to the target membrane. This process requires a group of conserved proteins such as Rab GTPases, motor adaptors, and motor proteins to ensure vesicle transport along cytoskeletal track. Soluble N-ethyl-maleimide-sensitive factor (NSF) attachment protein receptors (SNARE)-mediated vesicle fusion is the final process for vesicle unloading the cargo molecules at the target membrane. To ensure vesicle fusion occurring at a defined position and time pattern in eukaryotic cell, multiple fusogenic proteins, such as synaptotagmin (Syt), complexin (Cpx), Munc13, Munc18 and other tethering factors, cooperate together to precisely regulate the process of vesicle fusion. Dysfunctions of the fusogenic proteins in SNARE-mediated vesicle fusion are closely related to many diseases. Recent studies have suggested that stimulated membrane fusion can be manipulated pharmacologically via disruption the interface between the SNARE complex and Ca sensor protein. Here, we summarize recent insights into the molecular mechanisms of vesicle trafficking, and implications for the development of new therapeutics based on the manipulation of vesicle fusion.
PubMed: 36129576
DOI: 10.1186/s43556-022-00090-3 -
Tissue Engineering and Regenerative... Aug 2021Extracellular vesicles (EVs) are sub-micrometer lipid vesicles secreted from parental cells with their information such as DNA, RNA, and proteins. EVs can deliver their... (Review)
Review
Extracellular vesicles (EVs) are sub-micrometer lipid vesicles secreted from parental cells with their information such as DNA, RNA, and proteins. EVs can deliver their cargo to recipient cells and regulate the signaling pathway of the recipient cells to determine their destiny. Depending on the cargo of EVs, the recipient cells can be changed into abnormal state or be relieved from diseases. Therefore, EVs has been spotlighted as emerging therapeutics in biomedical research. However, slow EV secretion rate is the major limitation for the clinical applications of EVs. EV secretion is highly environmental dependent and can be regulated by various stimulants such as chemicals, oxygen levels, pH, radiation, starvation, and culture methods. To overcome the limitation of low productivity of EVs, EV stimulation methods have been widely studied and applied to massive EV productions. Another strategy is the synthesis of artificial EVs from cells by physical methods such as nitrogen cavitation, extrusion via porous membrane, and sonication. These physical methods disrupt cellular membrane and reassemble the membrane to lipid vesicles containing proteins or drugs. In this review, we will focus on how EV generation can be enhanced and recent advances in large scale EV generation strategies.
Topics: Biological Transport; Cell Membrane; Extracellular Vesicles; Signal Transduction; Sonication
PubMed: 34275103
DOI: 10.1007/s13770-021-00364-x