1,721,005 research outputs found
Possibility of exosome-based coronavirus disease 2019 vaccine (Review)
Get PDFCoronavirus disease 2019 (COVID‑19) is a global pandemic that can have a long‑lasting impact on public health if not properly managed. Ongoing vaccine development trials involve classical molecular strategies based on inactivated or attenuated viruses, single peptides or viral vectors. However, there are multiple issues, such as the risk of reversion to virulence, inability to provide long‑lasting protection and limited protective immunity. To overcome the aforementioned drawbacks of currently available COVID‑19 vaccines, an alternative strategy is required to produce safe and efficacious vaccines that impart long‑term immunity. Exosomes (key intercellular communicators characterized by low immunogenicity, high biocompatibility and innate cargo‑loading capacity) offer a novel approach for effective COVID‑19 vaccine development. An engineered exosome‑based vaccine displaying the four primary structural proteins of SARS‑CoV‑2 (spike, membrane, nucleocapside and envelope proteins) induces humoral and cell mediated immunity and triggers long‑lasting immunity. The present review investigated the prospective use of exosomes in the development of COVID‑19 vaccines; moreover, exosome‑based vaccines may be key to control the COVID‑19 pandemic by providing enhanced protection compared with existing vaccines
Transforming growth factor‑β family and stem cell‑derived exosome therapeutic treatment in osteoarthritis (Review)
Get PDFOsteoarthritis (OA), although extensively researched, still lacks an effective and safe treatment. The only current treatment option available for advanced OA is joint replacement surgery. This surgery may pose the risks of persistent pain, surgical complications and limited implant lifespan. Transforming growth factor (TGF)‑beta has a crucial role in multiple cellular processes such as cell proliferation. Any deterioration in TGF‑beta signaling pathways can have an immense impact on OA. Owing to the crucial role of TGF‑beta in cartilage homeostasis, targeting it could be an alternative therapeutic approach. Additionally, stem cell‑based therapy has recently emerged as an effective treatment strategy that could replace surgery. A number of recent findings suggest that the tissue regeneration effect of stem cells is attributed to the paracrine secretion of anti‑inflammatory and chondroprotective mediators or trophic factors, particularly nanosized extracellular vesicles (i.e., exosomes). Literature searches were performed in the MEDLINE, EMBASE, Cochrane Library and PubMed electronic database for relevant articles published before September 2021. Multiple investigators have confirmed TGF‑beta3 as a promising candidate which has the chondrogenic potential to repair articular cartilage degeneration. Combining TGF‑beta3 with bone morphogenetic proteins‑6, which has synergistic effect on chondrogenesis, with an efficient platform such as exosomes, which themselves possess a chondroprotective function, offers an innovative and more efficient approach to treat injured cartilage. In addition, multiple findings stating the role of exosomes in chondroprotection has also verified a similar fact showing exosomes may be a more favorable choice than the source itself. In the present review, the importance of TGF‑beta family in OA and the possibility of therapeutic treatment using stem cell‑derived exosomes are described
Immunologic responses to an extracellular vesicle-based vaccine expressing the full suite of SARS-CoV-2 structural proteins
No full textIn an attempt to develop a novel extracellular vesicles (EVs)-based vaccine against COVID-19, we designed EVs harboring a full set of SARS-CoV-2 structural proteins. Thus, the receptor-binding domain (RBD) of spike protein (S) of SARS-CoV-2 variant BA.2 or BA.4/5 with the stabilized wild type spike protein backbone, nucleocapsid protein (N) C-terminally fused with CD63, membrane (M), and envelope (E) proteins were stably expressed in 293T cells. Then, cell death-associated EVs were collected from the cells and evaluated for the expression of SARS-CoV-2 structural proteins. As a result, it was confirmed that trimers of spike fusion protein, N, M, and E were successfully loaded in the EVs. In an intramuscular injection model of mice, the inoculation of 50 mug EVs resulted in significant IgG antibody responses to S after the booster injection and neutralized the entry of S-pseudotyped VSVs. Anti-nucleocapsid antibodies were efficiently increased in mice primarily injected with 25 or 50 mug EVs, showing further increased values after booster dosages. Memory CD4(+) T(H1) cells and CD8(+) T(C) cells against S and N proteins was generated in mice that received a booster-immunization with all dosages (10, 25, or 50 mug) of EVs. Additionally, T cells responses against M and E peptides were increased in booster-immunized mice that received 50 mug of EVs. Taken together, this work proved feasibility of EVs expressing SARS-CoV-2 proteins as a universal vaccine candidate, potentially offering protection against emerging SARS-CoV-2 variants and future pandemics
The LRRK2-G2019S mutation attenuates repair of brain injury partially by reducing the release of osteopontin-containing monocytic exosome-like vesicles
No full textBackground: Brain injury has been suggested as a risk factor for neurodegenerative diseases. Accordingly, defects in the brain's intrinsic capacity to repair injury may result in the accumulation of damage and a progressive loss of brain function. The G2019S (GS) mutation in LRRK2 (leucine rich repeat kinase 2) is the most prevalent genetic alteration in Parkinson's disease (PD). Here, we sought to investigate how this LRRK2-GS mutation affects repair of the injured brain. Methods: Brain injury was induced by stereotaxic injection of ATP, a damage-associated molecular pattern (DAMP) component, into the striatum of wild-type (WT) and LRRK2-GS mice. Effects of the LRRK2-GS mutation on brain injury and the recovery from injury were examined by analyzing the molecular and cellular behavior of neurons, astrocytes, and monocytes. Results: Damaged neurons express osteopontin (OPN), a factor associated with brain repair. Following ATP-induced damage, monocytes entered injured brains, phagocytosing damaged neurons and producing exosome-like vesicles (EVs) containing OPN through activation of the inflammasome and subsequent pyroptosis. Following EV production, neurons and astrocytes processes elongated towards injured cores. In LRRK2-GS mice, OPN expression and monocytic pyroptosis were decreased compared with that in WT mice, resulting in diminished release of OPN-containing EVs and attenuated elongation of neuron and astrocyte processes. In addition, exosomes prepared from injured LRRK2-GS brains induced neurite outgrowth less efficiently than those from injured WT brains. Conclusions: The LRRK2-GS mutation delays repair of injured brains through reduced expression of OPN and diminished release of OPN-containing EVs from monocytes. These findings suggest that the LRRK2-GS mutation may promote the development of PD by delaying the repair of brain injury
Exosomal delivery of TRAIL and miR-335 for the treatment of hepatocellular carcinoma (Review)
No full textLiver cancer is the sixth most prevalent type of cancer worldwide and accounts for the third most frequent cause of cancer-associated mortality. Conventional anticancer drugs display limited efficacy owing to their short half-life, poor solubility and inefficient drug delivery. Despite advancements being made in drug discovery and development for the treatment of hepatocellular carcinoma (HCC), drug inefficacy and drug continue to pose significant obstacles to effective treatment. Therefore, it is imperative that novel treatment strategies be developed with the aim of developing anticancer treatments without any side-effects and with long-term durability. Extracellular vesicles, such as exosomes, intercellular communication agents which have the ability to carry heterogenous molecules with high penetrability, low immunogenicity and longer durability, may provide a versatile natural delivery system. The present review article illustrates the innovative treatment strategy using exosomes as a delivery agent for two distinct anticancer candidates, i.e., tumor necrosis factor-related apoptosis-inducing ligand and microRNA-335. The aim of the present review was to present a unique strategy for the development of an exceptional anticancer treatment therapy exploiting exosomes as a delivery vehicle which may be used for HCC
Apoptotic cell-derived exosomes: messages from dying cells
Get PDFApoptosis, a type of programmed cell death that plays a key role in both healthy and pathological conditions, releases extracellular vesicles such as apoptotic bodies and microvesicles, but exosome release due to apoptosis is not yet commonly accepted. Here, the reports demonstrating the presence of apoptotic exosomes and their roles in inflammation and immune responses are summarized, together with a general summary of apoptosis and extracellular vesicles. In conclusion, apoptosis is not just a 'silent' type of cell death but an active form of communication from dying cells to live cells through exosomes
Clonal expansion of T-cells in measles
No full textSome autoimmune complications such as postinfectious encephalomyelitis are associated with immunologic abnormalities induced by measles virus infection. To address the superantigenic stimulation in measles which might be related with autoimmune complications, T-cells bearing the TCRBV5S2 or TCRBV8 chains and the expression of activation markers were analyzed by monoclonal antibodies. To estimate clonal expansions, the CDR3 length profile in T-cells bearing the TCRBVSS2 or TCRBV8 chains was analyzed by two-stage PCR. Results showed that the expression of DR molecules in CD3(+) cells was increased significantly in measles patients (19.6 +/- 20.7%) compared to healthy children (2.9 +/- 1.4%). The mean percentage (7.1 +/- 4.4%) of T-cells bearing the TCRBV8 chain was increased in measles patients compared to healthy children (5.6 +/- 3.1%). The percentage of T-cells bearing the TCRBVSS2 chain in measles patients (3.0 +/- 1.2%) was similar to that in healthy children (2.7 +/- 0.6%). By analysis of the CDR3 length we found that there was no evidence of clonal expansions in T-cells bearing the TCRBV8 chain and that there were clonal expansions in T-cells bearing the TCRBV5S2 chain. These data suggest a conventional antigenic stimulation with T-cells bearing the TCRBVSS2 chain and a superantigenic stimulation with T-cells bearing the TCRBV8 chain may occur in the acute stage of measles infection. (C) 1998 Elsevier Science B.V. All rights reserved
Update on Extracellular Vesicle-Based Vaccines and Therapeutics to Combat COVID-19
Get PDFThe COVID-19 pandemic has had a deep impact on people worldwide since late 2019 when SARS-CoV-2 was first identified in Wuhan, China. In addition to its effect on public health, it has affected humans in various aspects of life, including social, economic, cultural, and political. It is also true that researchers have made vigorous efforts to overcome COVID-19 throughout the world, but they still have a long way to go. Accordingly, innumerable therapeutics and vaccine candidates have been studied for their efficacies and have been tried clinically in a very short span of time. For example, the versatility of extracellular vesicles, which are membrane-bound particles released from all types of cells, have recently been highlighted in terms of their effectiveness, biocompatibility, and safety in the fight against COVID-19. Thus, here, we tried to explain the use of extracellular vesicles as therapeutics and for the development of vaccines against COVID-19. Along with the mechanisms and a comprehensive background of their application in trapping the coronavirus or controlling the cytokine storm, we also discuss the obstacles to the clinical use of extracellular vesicles and how these could be resolved in the future
An Alternatively Spliced Sirtuin 2 Isoform 5 Inhibits Hepatitis B Virus Replication from cccDNA by Repressing Epigenetic Modifications Made by Histone Lysine Methyltransferases
Get PDFSirtuin 2 (Sirt2), an NAD(+)-dependent protein deacetylase, deacetylates tubulin, AKT, and other proteins. Previously, we showed that Sirt2 isoform 1 (Sirt2.1) increased replication of hepatitis B virus (HBV). Here, we show that HBV replication upregulates the expression of Sirt2 primary and alternatively spliced transcripts and their respective isoforms, 1, 2, and 5. Since Sirt2 isoform 5 (Sirt2.5) is a catalytically inactive nuclear protein with a spliced-out nuclear export signal (NES), we speculated that its different localization affects its activity. The overexpression of Sirt2.5 reduced expression of HBV mRNAs, replicative intermediate DNAs, and covalently closed circular DNA (cccDNA), an activity opposite that of Sirt2.1 and Sirt2.2. Unlike the Sirt2.1-AKT interaction, the Sirt2.5-AKT interaction was weakened by HBV replication. Unlike Sirt2.1, Sirt2.5 activated the AKT/GSK-3beta/beta-catenin signaling pathway very weakly and independently of HBV replication. When the NES and an N-terminal truncated catalytic domain were added to the Sirt2.5 construct, it localized in the cytoplasm and increased HBV replication (like Sirt2.1 and Sirt2.2). Chromatin immunoprecipitation assays revealed that more Sirt2.5 was recruited to cccDNA than Sirt2.1. The recruitment of histone lysine methyltransferases (HKMTs), such as SETDB1, SUV39H1, EZH2, and PR-Set7, and their respective transcriptional repressive markers, H3K9me3, H3K27me3, and H4K20me1, to cccDNA also increased in Sirt2.5-overexpressing cells. Among these, the Sirt2.5-PR-Set7 and -SETDB1 interactions increased upon HBV replication. These results demonstrate that Sirt2.5 reduces cccDNA levels and viral transcription through epigenetic modification of cccDNA via direct and/or indirect association with HKMTs, thereby exhibiting anti-HBV activity.IMPORTANCE Sirt2, a predominant cytoplasmic alpha-tubulin deacetylase, promotes the growth of hepatocellular carcinoma; indeed, HBV replication increases Sirt2 expression, and overexpression of Sirt2 is associated with hepatic fibrosis and epithelial-to-mesenchymal transition. Increased amounts of Sirt2 isoforms 1, 2, and 5 upon HBV replication might further upregulate HBV replication, leading to a vicious cycle of virus replication/disease progression. However, we show here that catalytically inactive nuclear Sirt2.5 antagonizes the effects of Sirt2.1 and Sirt2.2 on HBV replication, thereby inhibiting cccDNA level, transcription of cccDNA, and subsequent synthesis of replicative intermediate DNA. More Sirt2.5 was recruited to cccDNA than Sirt2.1, thereby increasing epigenetic modification by depositing transcriptional repressive markers, possibly through direct and/or indirect association with histone lysine methyltransferases, such as SETDB1, SUV39H1, EZH2, and/or PR-Set7, which represses HBV transcription. Thus, Sirt2.5 might provide a functional cure for HBV by silencing the transcription of HBV
Neutrophil Extracellular Traps May Contribute to the Pathogenesis in Adult-onset Still Disease
No full textOBJECTIVE: Release of neutrophil extracellular traps (NET) has been described as an effector mechanism of polymorphonuclear neutrophils in several inflammatory diseases. Thus, this study was performed to evaluate the role of NET in the pathogenesis of adult-onset Still disease (AOSD).
METHODS: We determined the serum levels of NET molecules and investigated their associations with clinical disease activities in patients with AOSD. Further, we analyzed the differences in the NETosis response in AOSD patients compared to healthy controls (HC). To explore the in vivo involvement of NET in AOSD, we performed immunohistochemical analysis of skin and lymph node (LN) biopsies for proteins related to NET in patients with active AOSD.
RESULTS: Serum levels of cell-free DNA, myeloperoxidase (MPO)-DNA complex, and alpha-defensin were significantly increased in patients with AOSD compared to HC. Serum levels of the NET molecules, cell-free DNA, MPO-DNA, and alpha-defensin were correlated with several disease activity markers for AOSD. In followup of patients with AOSD after treatment with corticosteroid, the levels of cell-free DNA and alpha-defensin decreased significantly. On immunohistochemistry, neutrophil elastase-positive and MPO-positive inflammatory cells were detected in skin and LN of patients with AOSD, and were expressed in fiber form in the lesions. The serum from patients with active AOSD induced NETosis in neutrophils from HC. NET molecules induced interleukin 1beta production in monocytes, representing a novel mechanism in the pathogenesis of AOSD.
CONCLUSION: The findings presented here suggest that NET may contribute to the inflammatory response and pathogenesis in AOSD
- …
