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1.
Yonsei Med J ; 61(9): 750-761, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32882759

RESUMO

PURPOSE: Gastric cancer (GC) is a malignant tumor with a high mortality rate. Drug resistance is a major obstacle to GC therapy. This study aimed to investigate the role and mechanism of exosomal circPRRX1 in doxorubicin resistance in GC. MATERIALS AND METHODS: HGC-27 and AGS cells were exposed to different doses of doxorubicin to construct doxorubicin-resistant cell lines. Levels of circPRRX1, miR-3064-5p, and nonreceptor tyrosine phosphatase 14 (PTPN14) were detected by quantitative real-time PCR or Western blot assay. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, transwell, and Western blot assays were used to explore the function of circPRRX1 in GC cells. Interactions among circPRRX1, miR-3064-5p, and PTPN14 were confirmed by dual-luciferase reporter assay. The in vivo function of circPRRX1 was analyzed in a xenograft tumor model. RESULTS: CircPRRX1 was highly expressed in doxorubicin-resistant GC cell lines. Knockdown of circPRRX1 reversed doxorubicin resistance in doxorubicin-resistant GC cells. Additionally, extracellular circPRRX1 was carried by exosomes to spread doxorubicin resistance. CircPRRX1 silencing reduced doxorubicin resistance by targeting miR-3064-5p or regulating PTPN14. In GC patients, high levels of circPRRX1 in serum exosomes were associated with poor responses to doxorubicin treatment. Moreover, depletion of circPRRX1 reduced doxorubicin resistance in vivo. CONCLUSION: CircPRRX1 strengthened doxorubicin resistance by modulating miR-3064-5p/PTPN14 signaling and might be a therapeutic target for GC patients.


Assuntos
Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio , Humanos , MicroRNAs/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
2.
Cells ; 9(9)2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32887260

RESUMO

We have previously shown that the combination of radiotherapy with human umbilical-cord-derived mesenchymal stromal/stem cells (MSCs) cell therapy significantly reduces the size of the xenotumors in mice, both in the directly irradiated tumor and in the distant nonirradiated tumor or its metastasis. We have also shown that exosomes secreted from MSCs preirradiated with 2 Gy are quantitatively, functionally and qualitatively different from the exosomes secreted from nonirradiated mesenchymal cells, and also that proteins, exosomes and microvesicles secreted by MSCs suffer a significant change when the cells are activated or nonactivated, with the amount of protein present in the exosomes of the preirradiated cells being 1.5 times greater compared to those from nonirradiated cells. This finding correlates with a dramatic increase in the antitumor activity of the radiotherapy when is combined with MSCs or with preirradiated mesenchymal stromal/stem cells (MSCs*). After the proteomic analysis of the load of the exosomes released from both irradiated and nonirradiated cells, we conclude that annexin A1 is the most important and significant difference between the exosomes released by the cells in either status. Knowing the role of annexin A1 in the control of hypoxia and inflammation that is characteristic of acute respiratory-distress syndrome (ARDS), we designed a hypothetical therapeutic strategy, based on the transplantation of mesenchymal stromal/stem cells stimulated with radiation, to alleviate the symptoms of patients who, due to pneumonia caused by SARS-CoV-2, require to be admitted to an intensive care unit for patients with life-threatening conditions. With this hypothesis, we seek to improve the patients' respiratory capacity and increase the expectations of their cure.


Assuntos
Raios gama , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos da radiação , Síndrome do Desconforto Respiratório do Adulto/terapia , Anexina A1/metabolismo , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Exossomos/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Pandemias , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Síndrome do Desconforto Respiratório do Adulto/virologia
3.
Cells ; 9(9)2020 09 02.
Artigo em Inglês | MEDLINE | ID: covidwho-742752

RESUMO

We have previously shown that the combination of radiotherapy with human umbilical-cord-derived mesenchymal stromal/stem cells (MSCs) cell therapy significantly reduces the size of the xenotumors in mice, both in the directly irradiated tumor and in the distant nonirradiated tumor or its metastasis. We have also shown that exosomes secreted from MSCs preirradiated with 2 Gy are quantitatively, functionally and qualitatively different from the exosomes secreted from nonirradiated mesenchymal cells, and also that proteins, exosomes and microvesicles secreted by MSCs suffer a significant change when the cells are activated or nonactivated, with the amount of protein present in the exosomes of the preirradiated cells being 1.5 times greater compared to those from nonirradiated cells. This finding correlates with a dramatic increase in the antitumor activity of the radiotherapy when is combined with MSCs or with preirradiated mesenchymal stromal/stem cells (MSCs*). After the proteomic analysis of the load of the exosomes released from both irradiated and nonirradiated cells, we conclude that annexin A1 is the most important and significant difference between the exosomes released by the cells in either status. Knowing the role of annexin A1 in the control of hypoxia and inflammation that is characteristic of acute respiratory-distress syndrome (ARDS), we designed a hypothetical therapeutic strategy, based on the transplantation of mesenchymal stromal/stem cells stimulated with radiation, to alleviate the symptoms of patients who, due to pneumonia caused by SARS-CoV-2, require to be admitted to an intensive care unit for patients with life-threatening conditions. With this hypothesis, we seek to improve the patients' respiratory capacity and increase the expectations of their cure.


Assuntos
Raios gama , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos da radiação , Síndrome do Desconforto Respiratório do Adulto/terapia , Anexina A1/metabolismo , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Exossomos/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Pandemias , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/patologia , Síndrome do Desconforto Respiratório do Adulto/virologia
4.
Cells ; 9(9)2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32859053

RESUMO

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising of exosomes, apoptotic bodies, and microvesicles. Of the extracellular vesicles, exosomes are the most widely sorted and extensively explored for their contents and function. The size of the nanovesicular structures (exosomes) range from 30 to 140 nm and are present in various biological fluids such as saliva, plasma, urine etc. These cargo-laden extracellular vesicles arise from endosome-derived multivesicular bodies and are known to carry proteins and nucleic acids. Exosomes are involved in multiple physiological and pathological processes, including cellular senescence. Exosomes mediate signaling crosstalk and play a critical role in cell-cell communications. Exosomes have evolved as potential biomarkers for aging-related diseases. Aging, a physiological process, involves a progressive decline of function of organs with a loss of homeostasis and increasing probability of illness and death. The review focuses on the classic view of exosome biogenesis, biology, and age-associated changes. Owing to their ability to transport biological information among cells, the review also discusses the interplay of senescent cell-derived exosomes with the aging process, including the susceptibility of the aging population to COVID-19 infections.


Assuntos
Envelhecimento/metabolismo , Doenças Cardiovasculares/metabolismo , Comunicação Celular , Senescência Celular , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/metabolismo , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Doenças Neurodegenerativas/metabolismo , Pneumonia Viral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Betacoronavirus , Biomarcadores/metabolismo , Infecções por Coronavirus/virologia , Humanos , Camundongos , Pandemias , Pneumonia Viral/virologia
5.
PLoS One ; 15(8): e0237044, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745122

RESUMO

Human norovirus (HuNoV) is a leading cause of acute gastroenteritis. Outbreaks normally occur via the fecal-oral route. HuNoV infection is thought to occur by viral particle transmission, but increasing evidence suggests a function for exosomes in HuNoV infection. HuNoV is contained within stool-derived exosomes, and exosome-associated HuNoV has been shown to replicate in human intestinal enteroids. In this study, we examine exosome-associated HuNoV infection of Vero cells and show that exosomes containing HuNoV may attach, infect, and be passaged in Vero cells. These findings support earlier findings and have implications for developing HuNoV disease intervention strategies.


Assuntos
Infecções por Caliciviridae/metabolismo , Infecções por Caliciviridae/transmissão , Exossomos/metabolismo , Animais , Infecções por Caliciviridae/genética , Criança , Pré-Escolar , Chlorocebus aethiops , Enterocolite/virologia , Exossomos/genética , Fezes/virologia , Feminino , Gastroenterite/virologia , Humanos , Masculino , Norovirus/patogenicidade , Células Vero , Vírion
6.
Life Sci ; 258: 118226, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32771555

RESUMO

AIM: Colorectal carcinoma (CRC) is one of the most prevalent cancers throughout the world. Circulating serum-derived microRNAs (miRNAs, miRs) can be used as non-invasive biomarkers for CRC diagnosis. This study aimed to identify a panel of six serum exosomal miRNAs as novel diagnostic biomarkers for CRC. MAIN METHODS: Exosomes were isolated and characterized from the conditioned media of the human colon adenocarcinoma cells (HCT-116 and Caco2). Sera were isolated from peripheral blood of 45 CRC and also 45 healthy individuals. The expression levels and diagnostic value of candidate circulating miRNAs (miR-19a, miR-20a, miR-150, miR-143, miR-145, and let-7a) were measured through quantitative real-time PCR. Receiver operating characteristic (ROC) curves were applied to evaluate the diagnostic accuracy of selected miRNAs. The association of candidate miRNAs and clinicopathological characteristics e.g. tumor node metastasis (TNM) staging and lymph node metastasis (LNM) were further evaluated. KEY FINDINGS: Circulating serum miR-19a, miR-20a, miR-150, and let-7a were significantly up-regulated in CRC patients, while miR-143 and miR-145 showed a significant down-regulation. The higher levels of miR-143 and miR-145 in patients with TNM stage I-II were detected, whereas miR-19a, miR-20a, miR-150, and let-7a were highly expressed in TNM stage III. The expression levels of miR-19a, miR-20a, and miR-150 were positively correlated with LNM status, while the expression levels of miR-143 and miR-145 were lower in patients with LNM. Area under the ROC curves of miR-19a, miR-20a, miR-150, miR-143, miR-145, and let-7a were 0.87, 0.83, 0.75, 0.76, 0.78 and 0.71, respectively. SIGNIFICANCE: We established a panel of six-circulating miRNA signature (i.e. miR-19a, miR-20a, miR-143, miR-145, miR-150, and let-7a) in serum as a non-invasive biomarker for CRC diagnosis. These findings confirm that serum-derived miRNAs have a strong potential to be a diagnostic biomarker for patients with CRC.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , MicroRNAs/sangue , MicroRNAs/genética , Adulto , Idoso , Células CACO-2 , Exossomos/genética , Exossomos/metabolismo , Feminino , Redes Reguladoras de Genes/genética , Células HCT116 , Humanos , Masculino , Pessoa de Meia-Idade
7.
Cells ; 9(9)2020 08 26.
Artigo em Inglês | MEDLINE | ID: covidwho-730307

RESUMO

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising of exosomes, apoptotic bodies, and microvesicles. Of the extracellular vesicles, exosomes are the most widely sorted and extensively explored for their contents and function. The size of the nanovesicular structures (exosomes) range from 30 to 140 nm and are present in various biological fluids such as saliva, plasma, urine etc. These cargo-laden extracellular vesicles arise from endosome-derived multivesicular bodies and are known to carry proteins and nucleic acids. Exosomes are involved in multiple physiological and pathological processes, including cellular senescence. Exosomes mediate signaling crosstalk and play a critical role in cell-cell communications. Exosomes have evolved as potential biomarkers for aging-related diseases. Aging, a physiological process, involves a progressive decline of function of organs with a loss of homeostasis and increasing probability of illness and death. The review focuses on the classic view of exosome biogenesis, biology, and age-associated changes. Owing to their ability to transport biological information among cells, the review also discusses the interplay of senescent cell-derived exosomes with the aging process, including the susceptibility of the aging population to COVID-19 infections.


Assuntos
Envelhecimento/metabolismo , Doenças Cardiovasculares/metabolismo , Comunicação Celular , Senescência Celular , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/metabolismo , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Doenças Neurodegenerativas/metabolismo , Pneumonia Viral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Betacoronavirus , Biomarcadores/metabolismo , Infecções por Coronavirus/virologia , Humanos , Camundongos , Pandemias , Pneumonia Viral/virologia
9.
Cell Metab ; 32(2): 188-202.e5, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32610096

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Exossomos/metabolismo , Gangliosídeo G(M3)/sangue , Gangliosídeos/sangue , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Diglicerídeos/sangue , Feminino , Humanos , Masculino , Metaboloma/fisiologia , Metabolômica/métodos , Pessoa de Meia-Idade , Pandemias , Esfingomielinas/sangue , Espectrometria de Massas em Tandem , Adulto Jovem
10.
Cell Prolif ; 53(8): e12830, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32608556

RESUMO

OBJECTIVES: Skin serves as the major interface between the external environment and body which is liable to many kinds of injuries. Mesenchymal stem cell (MSC) therapy has been widely used and became a promising strategy. Pre-treatment with chemical agents, hypoxia or gene modifications can partially protect MSCs against injury, and the pre-treated MSCs show the improved differentiation, homing capacity, survival and paracrine effects regard to attenuating injury. The aim of this study was to investigate whether the exosomes from the educated MSCs contribute to accelerate wound healing process. MATERIALS AND METHODS: We extracted the exosomes from the two educated MSCs and utilized them in the cutaneous wound healing model. The pro-angiogenetic effect of exosomes on endothelial cells was also investigated. RESULTS: We firstly found that MSCs pre-treated by exosomes from neonatal serum significantly improved their biological functions and the effect of therapy. Moreover, we extracted the exosomes from the educated MSCs and utilized them to treat the cutaneous wound model directly. We found that the released exosomes from MSCs which educated by neonatal serum before had the more outstanding performance in therapeutic effect. Mechanistically, we revealed that the recipient endothelial cells (ECs) were targeted and the exosomes promoted their functions to enhance angiogenesis via regulating AKT/eNOS pathway. CONCLUSIONS: Our findings unravelled the positive effect of the upgraded exosomes from the educated MSCs as a promising cell-free therapeutic strategy for cutaneous wound healing.


Assuntos
Exossomos/metabolismo , Células-Tronco Mesenquimais/citologia , Neovascularização Fisiológica/fisiologia , Cicatrização/fisiologia , Animais , Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Camundongos Endogâmicos C57BL , Pele/citologia
11.
PLoS One ; 15(7): e0234614, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649728

RESUMO

Exosomes appear to be effective inter-cellular communicators delivering several types of molecules, such as proteins and RNAs, suggesting that they could influence neural stem cell (NSC) differentiation. Our RNA sequencing studies demonstrated that the RNAs related to cell proliferation and astrocyte differentiation were upregulated in human mesenchymal stem cells (hMSC) when co-cultured with exosomes obtained from the culture medium of human glioma cells (U87). Metallothionein 3 and elastin genes, which are related to cell proliferation, increased 10 and 7.2 fold, respectively. Expression of genes for astrocyte differentiation, such as tumor growth factor alpha, induced protein 3 of the NOTCH1 family, colony stimulating factor and interleukin 6 of the STAT3 family and Hes family bHLH transcription factor 1 also increased by 2.3, 10, 4.7 and 2.9 fold, respectively. We further examined the effects of these exosomes on rat fetal neural stem cell (rNSC) differentiation using the secreted exosomes from U87 glioma cells or exosomes from U87 cells that were stimulated with interleukin 1ß (IL-1ß). The rNSCs, extracted from rat brains at embryonic day 14 (E14), underwent a culture protocol that normally leads to predominant (~90%) differentiation to ODCs. However, in the presence of the exosomes from untreated or IL-1ß-treated U87 cells, significantly more cells differentiated into astrocytes, especially in the presence of exosomes obtained from the IL-1ß-challenged glioma cells. Moreover, glioma-derived exosomes appeared to inhibit rNSC differentiation into ODCs or astrocytes as indicated by a significantly increased population of unlabeled cells. A portion of the resulting astrocytes co-expressed both CD133 and glial fibrillary acidic protein (GFAP) suggesting that exosomes from U87 cells could promote astrocytic differentiation of NSCs with features expected from a transformed cell. Our data clearly demonstrated that exosomes secreted by human glioma cells provide a strong driving force for rat neural stem cells to differentiate into astrocytes, uncovering potential pathways and therapeutic targets that might control this aggressive tumor type.


Assuntos
Astrócitos/metabolismo , Diferenciação Celular/fisiologia , Exossomos/fisiologia , Células-Tronco Neurais/metabolismo , Animais , Astrócitos/fisiologia , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Elastina/metabolismo , Exossomos/metabolismo , Regulação da Expressão Gênica/genética , Glioma/metabolismo , Humanos , Interleucina-6/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/fisiologia , Neurônios/metabolismo , Cultura Primária de Células , Ratos , Fator de Transcrição STAT3/metabolismo
12.
Life Sci ; 257: 118064, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652136

RESUMO

AIMS: Exosomes contain functional molecules from their cells of origin and can enter recipient cells for intercellular communication. Interferon ß (IFNß) has been shown to induce some lncRNAs to regulate host immune response and play a major role in the positive regulation of the activity of natural killer (NK) cells. We aim to clarify whether IFNß induced exosomes can regulate the cytotoxicity of NK cells by transferring specific lncRNAs into NK cells. MAIN METHODS: Exosomes were isolated from the supernatants of A549 cells with or without IFNß treatment. Co-culture and ELISA assay were used to analyze the effect of exosomes on the cytotoxicity of NK cells. Human transcriptome array (HTA) was performed to analyze the profiling of RNAs wrapped in exosomes. Then subcellular location, qPCR, western blotting, dual-luciferase reporter assay and ELISA were used to determine long noncoding RNAs (lcnRNAs) location, sponge absorb effects, the expression of NKp46 and cytotoxicity of NK cells. KEY FINDINGS: ELISA assay showed IFNß induced exosomes can strengthen the cytotoxicity of NK cells. Through HTA we found the expression levels of 69 lncRNAs were significantly changed within IFNß induced exosomes. Additionally, we found a specific exosomal cargo, linc-EPHA6-1, acted as a competing endogenous RNA (ceRNA) for hsa-miR-4485-5p which subsequently up-regulate one of the natural cytotoxicity receptors (NKp46) expression. Furthermore, we verified over-expression of linc-EPHA6-1 significantly enhances the cytotoxicity of NK cells against A549 cells and Zika virus infected A549 cells. SIGNIFICANCE: Our results demonstrated that IFNß-induced exosomal linc-EPHA6-1 can regulate the cytotoxicity of NK cells.


Assuntos
Células Matadoras Naturais/citologia , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor EphA6/genética , Infecção por Zika virus/virologia , Células A549 , Exossomos/metabolismo , Humanos , Interferon beta/administração & dosagem , Interferon beta/metabolismo , RNA Longo não Codificante/genética , Regulação para Cima
13.
Life Sci ; 257: 118017, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32603821

RESUMO

AIMS: Mesenchymal stem cell (MSC)-derived exosomes (MSCs-exos) regulate biological functions in different diseases, such as liver fibrosis, diabetes, and ischaemic heart injury. However, the function of MSC-derived exosomes on the intestinal barrier and the underlying mechanisms are poorly characterized. MAIN METHODS: The expression of miR-34a/c-5p, miR-29b-3p and Claudin-3 in human normal intestinal tissues and damaged intestinal tissues was evaluated by RT-qPCR. The effect of MSC-secreted exosomes on Claudins in Caco-2 cells was measured by using confocal microscopy, RT-qPCR and Western blot. Dual luciferase reporter assays and RNA immunoprecipitation (RIP) assays were performed to study the interaction between miR-34a/c-5p, miR-29b-3p and Snail. I/R-induced intestinal damage in rats was used to determine the in vivo effect of MSC-exos on intestinal barrier function. KEY FINDINGS: In this study, we found that miR-34a/c-5p, miR-29b-3p and Claudin-3 were downregulated in damaged human intestinal tissues. MSC-exos increased the expression of Claudin-3, Claudin-2 and ZO-1 in Caco-2 cells. Further studies demonstrated that MSC-exos promoted Claudin-3, Claudin-2 and ZO-1 expression in Caco-2 cells by Snail, which was targeted by miR-34a/c-5p and miR-29b-3p. In vivo experiments showed that MSC-derived exosomes could improve I/R-induced intestinal damage through the Snail/Claudins signaling pathway. SIGNIFICANCE: The findings here suggest a novel molecular basis for the therapy of intestinal barrier dysfunction.


Assuntos
Mucosa Intestinal/metabolismo , MicroRNAs/genética , Animais , Condrócitos/metabolismo , Claudinas/metabolismo , Exossomos/genética , Exossomos/metabolismo , Humanos , Intestinos/fisiologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , MicroRNAs/fisiologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo
14.
Life Sci ; 257: 118042, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621926

RESUMO

AIMS: To investigate the role of bone marrow mesenchymal stem cell (BMSC)-derived exosomes in smoke inhalation lung injury. MAIN METHODS: In this study, we initially isolated exosomes from BMSCs and identified them by western blot and transmission electron microscopy. BMSC-derived exosomes were then used to treat in vitro and in vivo models of smoke inhalation lung injury. Pathologic alterations in lung tissue, the levels of inflammatory factors and apoptosis-related factors, and the expression of HMGB1 and NF-κB were determined to evaluate the therapeutic effect of BMSC-derived exosomes. KEY FINDINGS: We found that BMSC-derived exosomes could alleviate the injury caused by smoke inhalation. Smoke inhalation increased the levels of inflammatory factors and apoptosis-related factors and the expression of HMGB1 and NF-κB, and these increases were reversed by BMSC-derived exosomes. HMGB1 overexpression abrogated the exosome-induced decreases in inflammatory factors, apoptosis-related factors and NF-κB. SIGNIFICANCE: Collectively, these results indicate that BMSC-derived exosomes can effectively alleviate smoke inhalation lung injury by inhibiting the HMGB1/NF-κB pathway, suggesting that exosome, a noncellular therapy, is a potential therapeutic strategy for inhalation lung injury.


Assuntos
Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Lesão por Inalação de Fumaça/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína HMGB1/metabolismo , Inflamação/patologia , Lesão Pulmonar/metabolismo , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fumaça/efeitos adversos , Lesão por Inalação de Fumaça/terapia
15.
Proc Natl Acad Sci U S A ; 117(29): 17429-17437, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32636270

RESUMO

Biogenesis of plant microRNAs (miRNAs) takes place in nuclear dicing bodies (D-bodies), where the ribonulease III-type enzyme Dicer-like 1 (DCL1) processes primary transcripts of miRNAs (pri-miRNAs) into miRNA/miRNA* (*, passenger strand) duplexes from either base-to-loop or loop-to-base directions. Hyponastic Leaves 1 (HYL1), a double-stranded RNA-binding protein, is crucial for efficient and accurate processing. However, whether HYL1 has additional function remains unknown. Here, we report that HYL1 plays a noncanonical role in protecting pri-miRNAs from nuclear exosome attack in addition to ensuring processing. Loss of functions in SOP1 or HEN2, two cofactors of the nucleoplasmic exosome, significantly suppressed the morphological phenotypes of hyl1-2 Remarkably, mature miRNAs generated from loop-to-base processing were partially but preferentially restored in the hyl1 sop1 and hyl1 hen2 double mutants. Accordingly, loop-to-base-processed pri-miRNAs accumulated to higher levels in double mutants. In addition, dysfunction of HEN2, but not of SOP1, in hyl1-2 resulted in overaccumulation of many base-to-loop-processed pri-miRNAs, with most of their respective miRNAs unaffected. In summary, our findings reveal an antagonistic action of exosome in pri-miRNA biogenesis and uncover dual roles of HYL1 in stabilizing and processing of pri-miRNAs.


Assuntos
Núcleo Celular/metabolismo , Exossomos/metabolismo , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Regulação da Expressão Gênica de Plantas , MicroRNAs/genética , Plantas Geneticamente Modificadas , Proteínas de Ligação a RNA/genética , Ribonuclease III
16.
Cancer Sci ; 111(9): 3100-3110, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32639675

RESUMO

Mesenchymal stem cells (MSC) are multipotent stromal cells with the potential to differentiate into several cell types. MSC-based therapy has emerged as a promising strategy for various diseases. Accumulating evidence suggests that the paracrine effects of MSC are partially exerted by the secretion of soluble factors, in particular exosomes. MSC-derived exosomes are involved in intercellular communication through transfer of proteins, RNA, DNA and bioactive lipids, which might constitute a novel intercellular communication mode. This review illustrates the current knowledge on the composition and biological functions as well as the therapeutic potential of MSC-derived exosomes in cancer, with a focus on clinical translation opportunities.


Assuntos
Produtos Biológicos/uso terapêutico , Micropartículas Derivadas de Células/metabolismo , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Comunicação Celular , Microambiente Celular , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Humanos , Imunomodulação
17.
Cell Metab ; 32(2): 188-202.e5, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: covidwho-612608

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Exossomos/metabolismo , Gangliosídeo G(M3)/sangue , Gangliosídeos/sangue , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Diglicerídeos/sangue , Feminino , Humanos , Masculino , Metaboloma/fisiologia , Metabolômica/métodos , Pessoa de Meia-Idade , Pandemias , Esfingomielinas/sangue , Espectrometria de Massas em Tandem , Adulto Jovem
18.
Toxicol Lett ; 331: 188-199, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32569805

RESUMO

Methamphetamine (METH) is a highly addictive psychostimulant drug whose abuse can cause many health complications. Our previous studies have shown that METH exposure increases α-synuclein (α-syn) expression. Recently, it was shown that α-syn could be transferred from neurons to astrocytes via exosomes. However, the specific role of astrocytes in α-syn pathology involved in METH neurotoxicity remains unclear. The objective of this study was to determine whether exosomes derived from METH-treated neurons contain pathological α-syn and test the hypothesis that exosomes can transfer pathological α-syn from neurons to astrocytes. To this end, using animal and cell line coculture models, we show that exosomes isolated from METH-treated SH-SY5Y cells contained pathological α-syn. Furthermore, the addition of METH exosomes to the medium of primary cultured astrocytes induced α-syn aggregation and inflammatory responses in astrocytes. Then, we evaluated changes in nuclear receptor related 1 protein (Nurr1) expression and the levels of inflammatory cytokines in primary cultured astrocytes exposed to METH or α-syn. We found that METH or α-syn exposure decreased Nurr1 expression and increased proinflammatory cytokine expression in astrocytes. Our results indicate that α-syn can be transferred from neuronal cells to astrocytes through exosomes. When internalized α-syn accumulated in astrocytes, the cells produced inflammatory responses. Nurr1 may play a crucial role in this process and could be a therapeutic target for inflammatory damage caused by METH.


Assuntos
Astrócitos/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Exossomos/metabolismo , Metanfetamina/toxicidade , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/metabolismo , alfa-Sinucleína/metabolismo , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Hipocampo/citologia , Humanos , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Neurônios/imunologia , Neurônios/metabolismo , Síndromes Neurotóxicas/imunologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Cultura Primária de Células , Sinucleinopatias/imunologia , Sinucleinopatias/metabolismo
19.
Int J Nanomedicine ; 15: 3363-3376, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494135

RESUMO

Introduction: Myocardial infarction (MI) is the leading cause of congestive heart failure and mortality. Hypoxia is an important trigger in the cardiac remodeling of the myocardium in the development and progression of cardiac diseases. Objective: Thus, we aimed to investigate the effect of hypoxia-induced exosomes on cardiac fibroblasts (CFs) and its related mechanisms. Materials and Methods: In this study, we successfully isolated and identified the exosomes from hypoxic cardiomyocytes (CMs). Exosomes derived from hypoxic CMs promoted apoptosis and inhibited proliferation, migration, and invasion in CFs. RNA-Seq assay suggested that long noncoding RNA AK139128 (lncRNA AK139128) was found to overexpress in both hypoxic CMs and CMs-secreting exosomes. After coculturing with CFs, hypoxic exosomes increased the expression of AK139128 in recipient CFs. Moreover, exosomal AK139128 derived from hypoxic CMs stimulated CFs apoptosis and inhibited proliferation, migration, and invasion. Furthermore, the effect of exosomal AK139128 derived from hypoxic CMs could also exacerbate MI in the rat model. Conclusion: Taken together, hypoxia upregulated the level of AK139128 in CMs and exosomes and exosomal AK139128 derived from hypoxic CMs modulated cellular activities of CFs in vitro and in vivo. This study provides a new understanding of the mechanism underlying hypoxia-related cardiac diseases and insight into developing new therapeutic strategies.


Assuntos
Apoptose , Exossomos/metabolismo , Fibroblastos/patologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Hipóxia Celular , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Endocitose , Exossomos/ultraestrutura , Masculino , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Ratos Sprague-Dawley
20.
Cell Prolif ; 53(7): e12857, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32578911

RESUMO

Exosomes are membrane-bound extracellular vesicles that are produced in the endosomal compartment of most mammalian cell types and then released. Exosomes are effective carriers for the intercellular material transfer of material that can influence a series of physiological and pathological processes in recipient cells. Among loaded cargoes, non-coding RNAs (ncRNAs) vary for the exosome-producing cell and its homeostatic state, and characterization of the biogenesis and secretion of exosomal ncRNAs and the functions of these ncRNAs in skeletal muscle myogenesis remain preliminary. In this review, we will describe what is currently known of exosome biogenesis, release and uptake of exosomal ncRNAs, as well as the varied functions of exosomal miRNAs in skeletal muscle myogenesis.


Assuntos
Exossomos/metabolismo , MicroRNAs/metabolismo , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Animais , Humanos
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