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1.
Open Biol ; 12(5): 210317, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35506205

RESUMO

Exosomes, a subset of small extracellular vesicles, carry various nucleic acids, proteins, lipids, amino acids and metabolites. They function as a mode of intercellular communication and molecular transfer. Exosome cargo molecules, including small non-coding RNAs (sncRNAs), are involved in the immune response in various organisms. However, the role of exosome-derived sncRNAs in immune responses in molluscs remains unclear. Here, we aimed to reveal the sncRNAs involved in the immune response during grafting transplantation by the pearl oyster Pinctada fucata. Exosomes were successfully extracted from the P. fucata haemolymph during graft transplantation. Abundant microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) were simultaneously discovered in P. fucata exosomes by small RNA sequencing. The expression patterns of the miRNAs and piRNAs at the grafting and initial stages were not substantially different, but varied significantly between the initial and later stages. Target prediction and functional analysis indicate that these miRNAs and piRNAs are related to immune response upon grafting transplantation, whereas piRNAs may also be associated with transposon silencing by targeting with genome transposon elements. This work provides the basis for a functional understanding of exosome-derived sncRNAs and helps to gain further insight into the PIWI/piRNA pathway function outside of germline cells in molluscs.


Assuntos
Exossomos , MicroRNAs , Pinctada , Pequeno RNA não Traduzido , Animais , Exossomos/genética , Exossomos/metabolismo , Imunidade , MicroRNAs/genética , Pinctada/genética , Pinctada/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
2.
Clin Transl Med ; 12(5): e780, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35522909

RESUMO

BACKGROUND: Cisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism underlying cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participate in tumor metastasis and drug resistance. METHODS: Exosomes isolated from BGC823 and BGC823/DDP culture medium were characterized by transmission electron microscopy and differential ultracentrifugation, and miRNA expression profiles of BGC823 and BGC823/DDP cells derived exosomes were analyzed using miRNA microarray. In vivo and in vitro assays were used to identify roles of exosomal miR-769-5p and clarify the mechanism of exosomal miR-769-5p regulated the crosstalk between sensitive and resistant GC cells. RESULTS: In this study, we found that cisplatin-resistant GC cells communicated with the tumor microenvironment by secreting microvesicles. MiR-769-5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin-resistant patients. The biologically active miR-769-5p could be integrated into exosomes and delivered to sensitive cells, spreading cisplatin resistance. Underlying cellular and molecular mechanism was miR-769-5p targeting CASP9, thus inhibiting the downstream caspase pathway and promoting the degradation of the apoptosis-related protein p53 through the ubiquitin-proteasome pathway. Targeting miR-769-5p with its antagonist to treat cisplatin-resistant GC cells can restore the cisplatin response, confirming that exosomal miR-769-5p can act as a key regulator of cisplatin resistance in GC. CONCLUSIONS: These findings indicate that exosome-transmitted miR-769-5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53. These findings reveal exosomal miR-769-5p derived from drug-resistant cells can be used as a potential therapeutic predictor of anti-tumor chemotherapy to enhance the effect of anti-cancer chemotherapy, which provides a new treatment option for GC.


Assuntos
Exossomos , MicroRNAs , Neoplasias Gástricas , Caspase 9/genética , Caspase 9/metabolismo , Cisplatino/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Microambiente Tumoral , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/uso terapêutico , Ubiquitinação/genética
3.
Mol Cells ; 45(5): 284-290, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35534190

RESUMO

Process of manufacturing therapeutics exosome development for commercialization. The development of exosome treatment starts at the bench, and in order to be commercialized, it goes through the manufacturing, characterization, and formulation stages, production under Good Manufacturing Practice (GMP) conditions for clinical use, and close consultation with regulatory authorities. Exosome, a type of nanoparticles also known as small extracellular vesicles are gaining attention as novel therapeutics for various diseases because of their ability to deliver genetic or bioactive molecules to recipient cells. Although many pharmaceutical companies are gradually developing exosome therapeutics, numerous hurdles remain regarding manufacture of clinical-grade exosomes for therapeutic use. In this mini-review, we will discuss the manufacturing challenges of therapeutic exosomes, including cell line development, upstream cell culture, and downstream purification process. In addition, developing proper formulations for exosome storage and, establishing good manufacturing practice facility for producing therapeutic exosomes remains as challenges for developing clinicalgrade exosomes. However, owing to the lack of consensus regarding the guidelines for manufacturing therapeutic exosomes, close communication between regulators and companies is required for the successful development of exosome therapeutics. This review shares the challenges and perspectives regarding the manufacture and quality control of clinical grade exosomes.


Assuntos
Exossomos , Vesículas Extracelulares , Técnicas de Cultura de Células , Linhagem Celular , Sistemas de Liberação de Medicamentos , Exossomos/metabolismo
4.
Stem Cell Res Ther ; 13(1): 174, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35505403

RESUMO

BACKGROUND: Ocular surface and retinal diseases are widespread problems that cannot be ignored in today's society. However, existing prevention and treatment still have many shortcomings and limitations, and fail to effectively hinder the occurrence and development of them. MAIN BODY: The purpose of this review is to give a detailed description of the potential mechanism of exosomes and autophagy. The eukaryotic endomembrane system refers to a range of membrane-bound organelles in the cytoplasm that are interconnected structurally and functionally, which regionalize and functionalize the cytoplasm to meet the needs of cells under different conditions. Exosomal biogenesis and autophagy are two important components of this system and are connected by lysosomal pathways. Exosomes are extracellular vesicles that contain multiple signaling molecules produced by multivesicular bodies derived from endosomes. Autophagy includes lysosome-dependent degradation and recycling pathways of cells or organelles. Recent studies have revealed that there is a common molecular mechanism between exosomes and autophagy, which have been, respectively, confirmed to involve in ocular surface and retinal diseases. CONCLUSION: The relationship between exosomes and autophagy and is mostly focused on fundus diseases, while a deeper understanding of them will provide new directions for the pathological mechanism, diagnosis, and treatment of ocular surface and retinal diseases.


Assuntos
Exossomos , Vesículas Extracelulares , Doenças Retinianas , Autofagia/fisiologia , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Lisossomos/metabolismo , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Doenças Retinianas/terapia
5.
Transl Neurodegener ; 11(1): 28, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35527262

RESUMO

Neurodegenerative diseases are a heterogeneous group of maladies, characterized by progressive loss of neurons. These diseases involve an intricate pattern of cross-talk between different types of cells to maintain specific signaling pathways. A component of such intercellular cross-talk is the exchange of various types of extracellular vesicles (EVs). Exosomes are a subset of EVs, which are increasingly being known for the role they play in the pathogenesis and progression of neurodegenerative diseases, e.g., synucleinopathies and tauopathies. The ability of the central nervous system exosomes to cross the blood-brain barrier into blood has generated enthusiasm in their study as potential biomarkers. However, the lack of standardized, efficient, and ultra-sensitive methods for the isolation and detection of brain-derived exosomes has hampered the development of effective biomarkers. Exosomes mirror heterogeneous biological changes that occur during the progression of these incurable illnesses, potentially offering a more comprehensive outlook of neurodegenerative disease diagnosis, progression and treatment. In this review, we aim to discuss the challenges and opportunities of peripheral biofluid-based brain-exosomes in the diagnosis and biomarker discovery of Alzheimer's and Parkinson's diseases. In the later part, we discuss the traditional and emerging methods used for the isolation of exosomes and compare their advantages and disadvantages in clinical settings.


Assuntos
Exossomos , Vesículas Extracelulares , Doenças Neurodegenerativas , Biomarcadores , Encéfalo/metabolismo , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Humanos , Doenças Neurodegenerativas/metabolismo
6.
Biomed Res Int ; 2022: 5346091, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35496046

RESUMO

Background: Ovarian cancer (OvCa), the deadliest gynaecological malignancy, is associated with poor prognosis and high mortality rate. Ovarian cancer has been related with CA-125 and metabolic reprogramming by SIRT1 leading to metastasis with the involvement of exosomes. Methods: Clinicopathological data of OvCa patients were collected to perform the analysis. Patients' samples were collected during surgery for immunohistochemistry and flow cytometric analysis of SIRT1, HIF-1α, exosomal markers (CD81 and CD63), ki-67, and PAS staining for glycogen deposition. Adjacent normal and tumor tissues were collected as per the CA-125 levels. Results: CA-125, a vital diagnostic marker, has shown significant correlation with body mass index (BMI) (P = 0.0153), tumor type (P = 0.0029), ascites level, ascites malignancy, degree of dissemination, tumor differentiation, FIGO stage, TNM stage, laterality, and tumor size at P < 0.0001. Since significant correlation was associated with BMI and degree of dissemination, as disclosed by IHC analysis, metabolic marker SIRT1 (P = 0.0003), HIF-1α (P < 0.0001), exosomal marker CD81 (P < 0.0001), ki-67 status (P = 0.0034), and glycogen deposition (P <0.0001) were expressed more in tumor tissues as compared to the normal ones. ROC analysis of CA-125 had shown 327.7 U/ml has the best cutoff point with 82.4% sensitivity and specificity of 52.3%. In addition, Kaplan-Meier plots of CA-125 (P < 0.0001), BMI (P = 0.001), degree of dissemination (P < 0.0001), and ascites level (P <0.0001) reflected significant correlation with overall survival (OS). Upon multivariate Cox-regression analysis for overall survival (OS), BMI (P = 0.008, HR 1.759, 95% CI 1.156-2.677), ascites malignancy (P = 0.032, HR 0.336, 95% CI 0.124-0.911), and degree of dissemination (P = 0.004, HR 1.994, 95% CI 1.251-3.178) were significant proving to be independent indicators of the disease. Conclusion: Clinicopathological parameters like BMI, degree of dissemination, and ascites level along with CA-125 can be prognostic factors for the disease. Levels of CA-125 can depict the metabolic and metastatic factors. Thus, by targeting SIRT1 and assessing exosomal concentrations to overcome metastasis and glycogen deposition, individualized treatment strategy could be designed. In-depth studies are still required.


Assuntos
Exossomos , Neoplasias Ovarianas , Ascite , Antígeno Ca-125 , Carcinoma Epitelial do Ovário , Exossomos/metabolismo , Feminino , Glicogênio , Humanos , Antígeno Ki-67 , Mucinas , Prognóstico , Sirtuína 1/metabolismo
7.
Cell Death Dis ; 13(5): 426, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501306

RESUMO

Clear evidence shows that tumors could secrete microRNAs (miRNAs) via exosomes to modulate the tumor microenvironment (TME). However, the mechanisms sorting specific miRNAs into exosomes are still unclear. In order to study the biological function and characterization of exosomal miRNAs, we performed whole-transcriptome sequencing in 59 patients' whole-course cerebrospinal fluid (CSF) small extracellular vesicles (sEV) and matched glioma tissue samples. The results demonstrate that miRNAs could be divided into exosome-enriched miRNAs (ExomiRNAs) and intracellular-retained miRNAs (CLmiRNAs), and exosome-enriched miRNAs generally play a dual role. Among them, miR-1298-5p was enriched in CSF exosomes and suppressed glioma progression in vitro and vivo experiments. Interestingly, exosomal miR-1298-5p could promote the immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) to facilitate glioma. Therefore, we found miR-1298-5p had different effects on glioma cells and MDSCs. Mechanically, downstream signaling pathway analyses showed that miR-1298-5p plays distinct roles in glioma cells and MDSCs via targeting SETD7 and MSH2, respectively. Moreover, reverse verification was performed on the intracellular-retained miRNA miR-9-5p. Thus, we confirmed that tumor-suppressive miRNAs in glioma cells could be eliminated through exosomes and target tumor-associated immune cells to induce tumor-promoting phenotypes. Glioma could get double benefit from it. These findings uncover the mechanisms that glioma selectively sorts miRNAs into exosomes and modulates tumor immunity.


Assuntos
Exossomos , Glioma , MicroRNAs , Células Supressoras Mieloides , Movimento Celular , Exossomos/metabolismo , Glioma/patologia , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Células Supressoras Mieloides/metabolismo , Microambiente Tumoral/genética
8.
BMC Genomics ; 23(1): 355, 2022 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-35525953

RESUMO

BACKGROUND: The mechanisms through which Mycobacterium tuberculosis evades immune surveillance during tuberculosis (TB) infection remain complex. Previous studies have found that Mycobacteria can manipulate the miRNAs of host cells to promote their survival during host-pathogen interactions, and most of these effects occur at the cellular miRNA level. We attempted to investigate the possible related mechanisms at the exosomal miRNA level. RESULTS: High-throughput sequencing revealed that Bacillus Calmette-Guérin (BCG) infection could alter the composition of the macrophage exosome content, and the expression levels of miRNAs in exosomes derived from the cell culture media of macrophages showed significant differences between the BCG-infected and non-infected groups. Compared with the non-infected group, 20 exosomal miRNAs were up-regulated and 7 exosomal miRNAs were down-regulated in the infection group (p < 0.05), of which mmu-miR-27b-3p, mmu-miR-93-5p, mmu-miR-25-3p, mmu-miR-1198-5p, mmu-let-7c-5p and let-7a-5p were significantly up-regulated. A bioinformatic analysis indicated that these differentially expressed exosomal miRNAs were involved in multiple biological processes and pathways. The target genes of top six miRNAs in up-regulated groups were positively correlated with the regulation of apoptosis. CONCLUSIONS: The expression profile of miRNA in exosomes derived from macrophage were altered after Mycobacterium Bovis Bacillus Calmette-Guérin infection, and the differentially expressed miRNAs were involved in multiple biological processes and signalling pathways. The top six up-regulated miRNAs and their targeted genes were predominantly correlated with the regulation of apoptosis.


Assuntos
Exossomos , MicroRNAs , Mycobacterium bovis , Tuberculose , Vacina BCG , Biologia Computacional , Exossomos/genética , Exossomos/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mycobacterium bovis/genética , Análise de Sequência de RNA , Tuberculose/genética , Tuberculose/veterinária
9.
Stem Cell Res Ther ; 13(1): 138, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35365226

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) therapy is a novel treatment strategy for cancer and a wide range of diseases with an excessive immune response such as ulcerative colitis (UC), due to its powerful immunomodulatory properties and its capacity for tissue regeneration and repair. One of the promising therapeutic options can focus on MSC-secreted exosomes (MSC-Exo), which have been identified as a type of paracrine interaction. In light of a wide variety of recent experimental studies, the present review aims to seek the recent research advances of therapies based on the MSC-Exo for treating UC and colorectal cancer (CRC). METHODS: A systematic literature search in MEDLINE, Scopus, and Google Scholar was performed from inception to December 2021 using the terms [("colorectal cancer" OR "bowel cancer" OR "colon cancer" OR "rectal cancer") AND (exosome) AND (stem cell) AND ("inflammatory bowel disease" OR "Crohn's disease" OR "colitis")] in titles and abstracts. FINDINGS: Exosomes derived from various sources of MSCs, including human umbilical cord-derived MSCs (hUC-MSCs), human adipose-derived MSCs (hAD-MSCs), human bone marrow-derived MSCs (hBM-MSCs), and olfactory ecto-MSCs (OE-MSCs), have shown the protective role against UC and CRC. Exosomes from hUC-MSCs, hBM-MSCs, AD-MSCs, and OE-MSCs have been found to ameliorate the experimental UC through suppressing inflammatory cells including macrophages, Th1/Th17 cells, reducing the expression of proinflammatory cytokines, as well as inducing the anti-inflammatory function of Treg and Th2 cells and enhancing the expression of anti-inflammatory cytokines. In addition, hBM-MSC-Exo and hUC-MSC-Exo containing tumor-suppressive miRs (miR-3940-5p/miR-22-3p/miR-16-5p) have been shown to suppress proliferation, migration, and invasion of CRC cells via regulation of RAP2B/PI3K/AKT signaling pathway and ITGA2/ITGA6. KEY MESSAGES: The MSC-Exo can exert beneficial effects on UC and CRC through two different mechanisms including modulating immune responses and inducing anti-tumor responses, respectively.


Assuntos
Colite Ulcerativa , Neoplasias Colorretais , Exossomos , Células-Tronco Mesenquimais , Colite Ulcerativa/terapia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Exossomos/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas rap de Ligação ao GTP/metabolismo
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 30(2): 583-592, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35396001

RESUMO

OBJECTIVE: To investigate the changes of gene sequencing and proteomics of apheresis platelet (AP) exosomes in different storage periods and predict the function of AP exosomes in different storage periods. METHODS: Platelets at different storage periods of 0 day (D0), 3 day (D3) and 5 day (D5) were collected, exosomes were extracted with Gradient centrifugation; gene sequencing and proteomic analysis were used to analyze the exosomes, and biological functions of platelet exosomes were analyzed and predicted by bioinformatics. Liquid mass spectrometry (LMS) was used to detect the changes and function prediction of exosomes proteins. The small RNA sequencing library was prepared, and the constructed library was sequenced and bioinformatics technology was used for data analysis. RESULTS: AP exosome iTRAQ protein analysis showed that AP exosomes stored in D3 with 55 up-regulated proteins and 94 down-regulated proteins (P<0.05, FC<0.83 or FC>1.2), while AP exosomes stored in D5 with 292 up-regulated proteins and 53 down-regulated proteins (P<0.05, FC<0.83 or FC>1.2) as compared with D0. KEGG pathway analysis showed that the proteins were mainly involved in transport and metabolism, immune system, cancer, membrane transport and other processes. There were statistically significant differences between AP exosome miRNAs in different storage days (P<0.01). The number of miRNA up-regulated and down-regulated was 374 and 255 as compared with the number of platelet exosomes miRNA stored in D3 and D0, while that was 297 and 242 in D5 and D0, and 252 and 327 in D5 and D3, respectively. The target genes of differential platelet exosome miRNAs were analyzed by GO enrichment. Target genes of differential miRNA were mainly involved in membrane composition, mainly played molecular functions binding to proteins, and participated in biological processes of transcriptional regulation. CONCLUSION: The exosome differential proteins and miRNAs in D5 are significantly different from those in the D0 of APs, and they are involved in various biological processes.


Assuntos
Remoção de Componentes Sanguíneos , Exossomos , MicroRNAs , Plaquetas/metabolismo , Exossomos/genética , Exossomos/metabolismo , Humanos , MicroRNAs/genética , Proteômica
11.
Front Endocrinol (Lausanne) ; 13: 830466, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35399949

RESUMO

Background: The prevalence of diabetic microvascular diseases has increased significantly worldwide, the most common of which are diabetic nephropathy (DN) and diabetic retinopathy (DR). Microvascular endothelial cells are thought to be major targets of hyperglycemic damage, while the underlying mechanism of diffuse endothelial dysfunction in multiple organs needs to be further investigated. Aim: The aim of this study is to explore the endothelial dysfunction mechanisms of serum exosomes (SExos) extracted from DR and DN (DRDN) patients. Methods: In this study, human glomerular endothelial cells (HGECs) were used as the cell model. Metabolomics ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and proteomics tandem mass tag (TMT)-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) together with bioinformatics, the correlation analysis, and the joint pathway analysis were employed to discover the underlying mechanisms of endothelial dysfunction caused by patient's SExos. Results: It can be assumed that serum exosomes extracted by DRDN patients might cause endothelial dysfunction mainly by upregulating alpha subunit of the coagulation factor fibrinogen (FIBA) and downregulating 1-methylhistidine (1-MH). Bioinformatics analysis pointed to an important role in reducing excess cysteine and methionine metabolism. Conclusion: FIBA overexpression and 1-MH loss may be linked to the pathogenicity of diabetic endothelial dysfunction in DR/DN, implying that a cohort study is needed to further investigate the role of FIBA and 1-MH in the development of DN and DR, as well as the related pathways between the two proteins.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Retinopatia Diabética , Exossomos , Cromatografia Líquida , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Células Endoteliais/metabolismo , Exossomos/metabolismo , Humanos , Metabolômica , Proteômica , Espectrometria de Massas em Tandem
12.
Int J Nanomedicine ; 17: 1577-1592, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35400999

RESUMO

Purpose: Angiogenesis is required for improving myocardial function and is a key factor in long-term prognosis after an acute myocardial infarction (AMI). Although exosomes are known to play a crucial role in angiogenesis, the role of peripheral exosomes in angiogenic signal transduction in patients with AMI remains unclear. Here, we explored the effect of exosomes extracted from the peripheral serum of AMI patients on angiogenesis and elucidated the downstream pathways. Patients and Methods: Serum exosomes were obtained from patients with AMI (AMI-Exo) and healthy individuals (Con-Exo). The exosomes were cocultured with human umbilical vein endothelial cells (HUVECs) in vitro, with aortic rings ex vivo, and were used to treat mouse hind-limb ischemia and mouse AMI model in vivo. Results: AMI-Exo raised HUVEC proliferation, tube formation, and migration, and enhanced microvessel sprouting from aortic rings compared to Con-Exo, both in vitro and ex vivo. Quantitative reverse transcription-polymerase chain reaction revealed that the abundance of miR-126-3p, a crucial regulator of angiogenesis, was increased in AMI-Exo. The inhibition of miR-126-3p decreased the benefits of AMI-Exo treatment, and miR-126-3p upregulation enhanced the benefits of Con-Exo treatment in HUVECs, aortic rings, the mouse hind-limb ischemia model, and the mouse AMI model. Knockdown and overexpression analyses revealed that miR-126-3p regulated angiogenesis in HUVECs by directly targeting tuberous sclerosis complex 1 (TSC1). Moreover, we found that miR-126-3p could inhibit TSC1 expression, which further activated mTORC1 signaling and increased HIF-1α and VEGFA expression, ultimately promoting angiogenesis. Conclusion: Collectively, our results provide a novel understanding of the function of exosomes in angiogenesis post AMI. We demonstrated that exosomes from the peripheral serum of AMI patients promote angiogenesis via the miR-126-3p/TSC1/mTORC1/HIF-1α signaling pathway.


Assuntos
Exossomos , MicroRNAs , Infarto do Miocárdio , Esclerose Tuberosa , Animais , Proliferação de Células , Exossomos/genética , Exossomos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Isquemia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Esclerose Tuberosa/metabolismo
13.
Cells ; 11(7)2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35406627

RESUMO

Extracellular vesicles (EVs), including exosomes, are key factors of intercellular communication, performing both local and distant transfers of bioactive molecules. The increasingly obvious role of EVs in carcinogenesis, similarity of molecular signatures with parental cells, precise selection and high stability of cargo molecules make exosomes a promising source of liquid biopsy markers for cancer diagnosis. The uterine cavity fluid, unlike blood, urine and other body fluids commonly used to study EVs, is of local origin and therefore enriched in EVs secreted by cells of the female reproductive tract. Here, we show that EVs, including those corresponding to exosomes, could be isolated from individual samples of uterine aspirates (UA) obtained from epithelial ovarian cancer (EOC) patients and healthy donors using the ultracentrifugation technique. First, the conducted profiling of small RNAs (small RNA-seq) from UA-derived EVs demonstrated the presence of non-coding RNA molecules belonging to various classes. The analysis of the miRNA content in EVs from UA performed on a pilot sample revealed significant differences in the expression levels of a number of miRNAs in EVs obtained from EOC patients compared to healthy individuals. The results open up prospects for using UA-derived EVs as a source of markers for the diagnostics of gynecological cancers, including EOC.


Assuntos
Exossomos , Vesículas Extracelulares , MicroRNAs , Neoplasias , Biomarcadores/metabolismo , Detecção Precoce de Câncer , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Feminino , Humanos , MicroRNAs/metabolismo , Neoplasias/metabolismo , Útero/metabolismo
14.
Cells ; 11(7)2022 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-35406692

RESUMO

Exosomes are small membrane vesicles of endocytic origin containing cytokines, RNAs, growth factors, proteins, lipids, and metabolites. They have been identified as fundamental intercellular communication controllers in several diseases and an enormous volume of data confirmed that exosomes could either sustain or inhibit tumor onset and diffusion in diverse solid and hematological malignancies by paracrine signaling. Thus, exosomes might constitute a promising cell-free tumor treatment alternative. This review focuses on the effects of exosomes in the treatment of tumors, by discussing the most recent and promising data from in vitro and experimental in vivo studies and the few existing clinical trials. Exosomes are extremely promising as transporters of drugs, antagomir, genes, and other therapeutic substances that can be integrated into their core via different procedures. Moreover, exosomes can augment or inhibit non-coding RNAs, change the metabolism of cancer cells, and modify the function of immunologic effectors thus modifying the tumor microenvironment transforming it from pro-tumor to antitumor milieu. Here, we report the development of currently realized exosome modifiers that offer indications for the forthcoming elaboration of other more effective methods capable of enhancing the activity of the exosomes.


Assuntos
Exossomos , Neoplasias Hematológicas , Neoplasias , Comunicação Celular , Exossomos/metabolismo , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/terapia , Humanos , Neoplasias/patologia , Microambiente Tumoral
15.
Int J Mol Sci ; 23(7)2022 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35408909

RESUMO

Exosomes are cell-secreted nanoparticles containing various molecules including small vesicles, microRNAs (miRNAs), messenger RNAs or bioactive proteins which are thought to be of paramount importance for intercellular communication. The unique effects of exosomes in terms of cell penetration capacity, decreased immunogenicity and inherent stability, along with their key role in mediating information exchange among tumor cells and their surrounding tumor microenvironment (TME), render them a promising platform for drug targeted delivery. Compared to synthetic drugs, exosomes boast a plethora of advantages, including higher biocompatibility, lower toxicity and increased ability of tissue infiltration. Nevertheless, the use of artificial exosomes can be limited in practice, partly due to their poor targeting ability and partly due to their limited efficacy. Therefore, efforts have been made to engineer stem cell-derived exosomes in order to increase selectiveness and effectivity, which can then become loaded with various active substances depending on the therapeutic approach followed. Erythropoietin-producing human hepatocellular receptors (EPHs), along with their ligands, the EPH family receptor interacting proteins (ephrins), have been extensively investigated for their key roles in both physiology and cancer pathogenesis. EPHs/ephrins exhibit both tumorigenic and tumor suppressing properties, with their targeting representing a promising, novel therapeutic approach in cancer patients' management. In our review, the use of ephrin-loaded exosomes as a potential therapeutic targeted delivery system in cancer will be discussed.


Assuntos
Exossomos , Neoplasias , Biomarcadores , Efrinas/metabolismo , Exossomos/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptores da Família Eph/metabolismo , Receptores da Eritropoetina , Microambiente Tumoral
16.
Int J Mol Sci ; 23(7)2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35408980

RESUMO

Pancreatic Ductal Adenocarcinoma (PDAC) constitutes a leading cause of cancer death globally. Its mortality remains unaltered despite the considerable scientific progress made in the fields of diagnostics and treatment. Exosomes comprise of small extracellular vesicles secreted by nearly all cells; their cargo contains a vast array of biomolecules, such as proteins and microRNAs. It is currently established that their role as messengers is central to a plethora of both physiologic and pathologic processes. Accumulating data have shed light on their contributions to carcinogenesis, metastasis, and immunological response. Meanwhile, the advancement of personalized targeted therapies into everyday clinical practice necessitates the development of cost-efficient treatment approaches. The role of exosomes is currently being extensively investigated towards this direction. This review aims to summarize the current pre-clinical and clinical evidence regarding the effects of exosomal applications in the timely diagnosis, prognosis, and therapeutic management of pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático , Exossomos , Neoplasias Pancreáticas , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Exossomos/metabolismo , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia
17.
Bioengineered ; 13(4): 9901-9915, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35412945

RESUMO

Fractures are frequently encountered diseases troubling the senior population, and the research on fracture repair and the exploration of effective treatment methods are of great significance. This study aimed to clarify the effect of human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hUMSC-EVs) on the proliferation and osteogenic differentiation of autologous bone marrow stem cells (ABMSCs). The two kinds of cells were co-cultured firstly, 5-Ethynyl-2'- deoxyuridine (EDU) staining and alizarin red staining were used to detect the proliferation and osteogenic differentiation of ABMSCs. The exosomes of hUMSCs were subsequently extracted to process ABMSCs to further test the effect on the cells. The EDU positive rate of ABMSCs and Collagen II expression were elevated, whereas the TdT-mediated dUTP nick end labeling (TUNEL) positive rate and Matrix Metallopeptidase 13 (MMP13) were markedly decreased after the co-culture of hUMSCs and ABMSCs using Transwell chamber assays. The results indicated that hUMSCs could increase the proliferation of ABMSCs, reduce apoptosis, and promote matrix metabolism. The hUMSCs exosomes were separated and added to ABMSCs. As the exosomes content increased, the proliferation of ABMSCs increased simultaneously, and ABMSCs apoptosis decreased. Meanwhile, ABMSCs that migrated to the submembrane increased compared with untreated ABMSCs. Western blot, qPCR and immunofluorescence results revealed that increased exosomes contents promoted the expression of ABMSCs anabolic-related indicators gradually, while decreased the expression of catabolism-related indicators gradually. The previously described results indicated that hUMSCs promoted the proliferation and osteogenic differentiation of ABMSCs by secreting exosomes.


Assuntos
Exossomos , Células-Tronco Mesenquimais , Células da Medula Óssea , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Exossomos/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Cordão Umbilical
18.
Front Immunol ; 13: 871096, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35444638

RESUMO

The pathogenesis of the prototypical chronic autoimmune disorder primary Sjögren syndrome (pSS) has been thought to be B-cell-centric, based on serum autoantibodies, the increased risk of B cell lymphoma, and altered B cell subsets in patients with pSS. Over the last 10 years, therapies targeting B cells have been investigated for pSS; however, current evidence for the efficacy of B cell targeted therapies in pSS is still sparse. Mesenchymal stem cells (MSCs) might represent a promising strategy for cell therapy of autoimmune diseases via regulation of immune cells. MSC-released exosomes carry various bioactive molecules and thus have been studied in MSC-based therapy. The newly discovered labial gland MSCs (LGMSCs) have exhibited enhanced performance. Herein, we aimed to determine the effects of LGMSC-derived exosomes (LGMSC-Exos) on the symptoms of a mouse model of pSS and their regulatory effect and mechanism on B cell subsets. In vivo, treatment of the spontaneous mouse model of pSS with LGMSC-Exos resulted in reduced inflammatory infiltration and restored saliva secretion in salivary glands. In vitro, coculture of LGMSC-Exos with peripheral blood mononuclear cells of patients with pSS markedly reduced the proportions of CD19+CD20-CD27+CD38+ plasma cells among peripheral blood mononuclear cells. Further investigations provided evidence that LGMSC-Exo-derived microRNA-125b affected plasma cells of pSS by directly binding to its target gene, PRDM1 (PR domain zinc finger protein 1, also known as BLIMP1), which might be developed as a target to treat pSS. Overall, these findings provided a possible exploitable therapeutic target in pSS and provide new insights into the potential therapeutic application of exosomes in pSS and other disease mediated by B-cells.


Assuntos
Doenças Autoimunes , Exossomos , Células-Tronco Mesenquimais , MicroRNAs , Síndrome de Sjogren , Animais , Exossomos/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , MicroRNAs/genética , Plasmócitos/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/genética , Síndrome de Sjogren/terapia
19.
Front Immunol ; 13: 824188, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35444652

RESUMO

Exosomes are small extracellular vesicles that are secreted by almost all types of cells and exist in almost all extracellular spaces. As an important mediator of intercellular communication, exosomes encapsulate the miRNA, lncRNA, cirRNA, mRNA, cytokine, enzyme, lipid, and other components from the cytoplasm into its closed single membrane structure and transfer them to recipient units in an autocrine, paracrine, or endocrine manner. Hypoxia is a state of low oxygen tension and is involved in many pathological processes. Hypoxia influences the size, quantity, and expression of exosome cargos. Exosomes derived from hypoxic tumor cells transfer genetics, proteins, and lipids to the recipient units to exert pleiotropic effects. Different donor cells produce different cargo contents, target different recipient units and lead to different biological effects. Hypoxic exosomes derived from tumor cells uptaken by normoxic tumor cells lead to promoted proliferation, migration, and invasion; uptaken by extracellular space or liver lead to promoted metastasis; uptaken by endothelial cells lead to promoted angiogenesis; uptaken by immune cells lead to promoted macrophage polarization and changed tumor immune microenvironment. In addition to various types of tumors, hypoxic exosomes also participate in the development of diseases in the cardiovascular system, neuron system, respiratory system, hematology system, endocrine system, urinary system, reproduction system, and skeletomuscular system. Understanding the special characteristics of hypoxic exosomes provide new insight into elaborating the pathogenesis of hypoxia related disease. This review summarizes hypoxia induced cargo changes and the biological effects of hypoxic exosomes in tumors and non-malignant diseases in different systems.


Assuntos
Exossomos , Neoplasias , Comunicação Celular , Células Endoteliais/metabolismo , Exossomos/metabolismo , Humanos , Hipóxia/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral
20.
J Extracell Vesicles ; 11(4): e12211, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35411723

RESUMO

Tumour cells are characterized by having lost their differentiation state. They constitutively secrete small extracellular vesicles (sEV) called exosomes when they come from late endosomes. Dendrogenin A (DDA) is an endogenous tumour suppressor cholesterol-derived metabolite. It is a new class of ligand of the nuclear Liver X receptors (LXR) which regulate cholesterol homeostasis and immunity. We hypothesized that DDA, which induces tumour cell differentiation, inhibition of tumour growth and immune cell infiltration into tumours, could functionally modify sEV secreted by tumour cells. Here, we have shown that DDA differentiates tumour cells by acting on the LXRß. This results in an increased production of sEV (DDA-sEV) which includes exosomes. The DDA-sEV secreted from DDA-treated cells were characterized for their content and activity in comparison to sEV secreted from control cells (C-sEV). DDA-sEV were enriched, relatively to C-sEV, in several proteins and lipids such as differentiation antigens, "eat-me" signals, lipidated LC3 and the endosomal phospholipid bis(monoacylglycero)phosphate, which stimulates dendritic cell maturation and a Th1 T lymphocyte polarization. Moreover, DDA-sEV inhibited the growth of tumours implanted into immunocompetent mice compared to control conditions. This study reveals a pharmacological control through a nuclear receptor of exosome-enriched tumour sEV secretion, composition and immune function. Targeting the LXR may be a novel way to reprogram tumour cells and sEV to stimulate immunity against cancer.


Assuntos
Exossomos , Neoplasias , Animais , Colestanóis , Colesterol/metabolismo , Exossomos/metabolismo , Imidazóis , Receptores X do Fígado/metabolismo , Camundongos , Neoplasias/tratamento farmacológico
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