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1.
An Bras Dermatol ; 100(1): 121-130, 2025.
Artigo em Inglês | MEDLINE | ID: mdl-39562240

RESUMO

Exosomes are extracellular nanovesicles secreted by several cells in the human and animal body. Consisting of a lipid membrane and encapsulated proteins, they contain biologically active substances such as proteins, DNA, RNA, transcription factors, and metabolites. Discovered in the 1980s, exosomes play an important role in cell-to-cell communication and immune function. They vary in size, content, and function depending on the cell of origin. Exosomes have attracted interest in the field of Dermatology due to their potential applications in the treatment of scars, skin rejuvenation, hair regeneration, and other dermatological conditions. However, further clinical studies are needed to prove their efficacy and safety. Regulatory issues also need to be considered, as the use of exosomes in cosmetics and medical treatments is not yet fully approved in some countries. Moreover, it is important to understand the risks and side effects associated with the use of exosomes before their clinical use. Although promising, more research is needed to explore the full potential of exosomes in Medicine and Dermatology.


Assuntos
Dermatologia , Exossomos , Humanos , Dermatopatias/terapia , Rejuvenescimento/fisiologia , Comunicação Celular/fisiologia
2.
Stem Cell Res Ther ; 15(1): 466, 2024 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-39639397

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) derived from gestational tissues offer a promising avenue for prenatal intervention in congenital malformations although their application is hampered by concerns related to cellular plasticity and the need for invasive, high-risk surgical procedures. Here, we present naturally occurring exosomes (EXOs) isolated from amniotic fluid-derived MSCs (AF-MSCs) and their mimetic analogs (MIMs) as viable, reproducible, and stable alternatives. These nanovesicles present a minimally invasive therapeutic option, addressing the limitations of MSC-based treatments while retaining therapeutic efficacy. METHODS: MIMs were generated from AF-MSCs by combining sequential filtration steps through filter membranes with different porosity and size exclusion chromatography columns. A physicochemical, structural, and molecular comparison was conducted with exosomes (EXOs) released from the same batch of cells. Additionally, their distribution patterns in female mice were evaluated following in vivo administration, along with an assessment of their safety profile throughout gestation in a mouse strain predisposed to neural tube defects (NTDs). The possibility to exploit both formulations as mRNA-therapeutics was explored by evaluating cell uptake in two different cell types(fibroblasts, and macrophages) and mRNA functionality overtime in an in vitro experimental setting as well as in an ex vivo, whole embryo culture using pregnant C57BL6 dams. RESULTS: Molecular and physiochemical characterization showed no differences between EXOs and MIMs, with MIMs determining a threefold greater yield. Biodistribution patterns following intraperitoneal administration were comparable between the two particle types, with the uterus being among targeted organs. No toxic effects were observed in the dams during gestation, nor were there any malformations or significant differences in the number of viable versus dead fetuses detected. MIMs delivered a more intense and prolonged expression of mRNA encoding for green fluorescent protein in macrophages and fibroblasts. An ex-vivo whole embryo culture demonstrated that MIMs mainly accumulate at the level of the yolk sac, while EXOs reach the embryo. CONCLUSIONS: The present data confirms the potential application of EXOs and MIMs as suitable tools for prevention and treatment of NTDs and proposes MIMs as prospective vehicles to prevent congenital malformations caused by in utero exposure to drugs.


Assuntos
Líquido Amniótico , Células-Tronco Mesenquimais , Líquido Amniótico/citologia , Líquido Amniótico/metabolismo , Animais , Feminino , Camundongos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Humanos , Exossomos/metabolismo , Gravidez , Defeitos do Tubo Neural/metabolismo , Diferenciação Celular/efeitos dos fármacos
3.
Int J Mol Sci ; 25(22)2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39596356

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and memory loss. While the precise causes of AD remain unclear, emerging evidence suggests that messenger RNA (mRNA) dysregulation contributes to AD pathology and risk. This study examined exosomal mRNA expression profiles of 15 individuals diagnosed with AD and 15 healthy controls from Barranquilla, Colombia. Utilizing advanced bioinformatics and machine learning (ML) techniques, we identified differentially expressed mRNAs and assessed their predictive power for AD diagnosis and AD age of onset (ADAOO). Our results showed that ENST00000331581 (CADM1) and ENST00000382258 (TNFRSF19) were significantly upregulated in AD patients. Key predictors for AD diagnosis included ENST00000311550 (GABRB3), ENST00000278765 (GGTLC1), ENST00000331581 (CADM1), ENST00000372572 (FOXJ3), and ENST00000636358 (ACY1), achieving > 90% accuracy in both training and testing datasets. For ADAOO, ENST00000340552 (LIMK2) expression correlated with a delay of ~12.6 years, while ENST00000304677 (RNASE6), ENST00000640218 (HNRNPU), ENST00000602017 (PPP5D1), ENST00000224950 (STN1), and ENST00000322088 (PPP2R1A) emerged as the most important predictors. ENST00000304677 (RNASE6) and ENST00000602017 (PPP5D1) showed promising predictive accuracy in unseen data. These findings suggest that mRNA expression profiles may serve as effective biomarkers for AD diagnosis and ADAOO, providing a cost-efficient and minimally invasive tool for early detection and monitoring. Further research is needed to validate these results in larger, diverse cohorts and explore the biological roles of the identified mRNAs in AD pathogenesis.


Assuntos
Idade de Início , Doença de Alzheimer , Biomarcadores , Exossomos , RNA Mensageiro , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Feminino , Masculino , Exossomos/genética , Exossomos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Aprendizado de Máquina , Perfilação da Expressão Gênica/métodos , Estudos de Casos e Controles , Pessoa de Meia-Idade
4.
Int J Nanomedicine ; 19: 10725-10743, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39469450

RESUMO

Introduction: The meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain. Methods: We employed superparamagnetic iron oxide nanoparticles (SPIONs), exosomes loaded with SPIONs, gold nanorods, and Chinese ink nanoparticles. SPIONs were prepared via chemical coprecipitation, while exosomes were isolated from the B16F10 melanoma cell line through the Exo-Spin column protocol and loaded with SPIONs through electroporation. Gold nanorods were functionalized with polyethylene glycol. We utilized C57BL/6 mice for post-mortem and in vivo procedures. To evaluate the retrograde directional flow, we injected each nanoparticle solution in the deep cervical lymph node. The head and neck were fixed for magnetic resonance imaging and histological analysis. Results: Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within the deep cervical lymph nodes post-mortem and in vivo, exclusively through lymphatic structures. Discussion: The functional anatomy of dural lymphatics has been found to be conserved between mice and humans, suggesting that our findings may have significant implications for advancing targeted drug delivery systems using nanoparticles. Understanding the retrograde transport of nanoparticles through the meningeal lymphatic network could lead to novel therapeutic approaches in nanomedicine, offering new insights into fluid dynamics in both physiological and neuropathological contexts. Further research into this pathway may unlock new strategies for treating neurological diseases or enhancing drug delivery to the brain.


Assuntos
Encéfalo , Ouro , Meninges , Camundongos Endogâmicos C57BL , Animais , Encéfalo/metabolismo , Ouro/química , Ouro/farmacocinética , Linhagem Celular Tumoral , Camundongos , Meninges/metabolismo , Vasos Linfáticos/metabolismo , Exossomos/química , Exossomos/metabolismo , Nanopartículas Magnéticas de Óxido de Ferro/química , Nanopartículas de Magnetita/química , Melanoma Experimental/metabolismo , Pescoço , Imageamento por Ressonância Magnética/métodos , Linfonodos/metabolismo
5.
Exp Cell Res ; 442(1): 114211, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39147261

RESUMO

Blood vessel growth and osteogenesis in the skeletal system are coupled; however, fundamental aspects of vascular function in osteoblast-to-osteocyte transition remain unclear. Our study demonstrates that vascular smooth muscle cells (VSMCs), but not endothelial cells, are sufficient to drive bone marrow mesenchymal stromal cell-derived osteoblast-to-osteocyte transition via ß-catenin signaling and exosome-mediated communication. We found that VSMC-derived exosomes are loaded with transcripts encoding proteins associated with the osteocyte phenotype and members of the WNT/ß-catenin signaling pathway. In contrast, endothelial cell-derived exosomes facilitated mature osteoblast differentiation by reprogramming the TGFB1 gene family and osteogenic transcription factors osterix (SP7) and RUNX2. Notably, VSMCs express significant levels of tetraspanins (CD9, CD63, and CD81) and drive the intracellular trafficking of exosomes with a lower membrane zeta potential than those from other cells. Additionally, the high ATP content within these exosomes supports mineralization mechanisms, as ATP is a substrate for alkaline phosphatase. Osteocyte function was further validated by RNA sequencing, revealing activity in genes related to intermittent mineralization and sonic hedgehog signaling, alongside a significant increase in TNFSF11 levels. Our findings unveil a novel role of VSMCs in promoting osteoblast-to-osteocyte transition, thus offering new insights into bone biology and homeostasis, as well as in bone-related diseases. Clinically, these insights could pave the way for innovative therapeutic strategies targeting VSMC-derived exosome pathways to treat bone-related disorders such as osteoporosis. By manipulating these signaling pathways, it may be possible to enhance bone regeneration and improve skeletal health in patients with compromised bone structure and function.


Assuntos
Exossomos , Músculo Liso Vascular , Osteoblastos , Osteócitos , Osteogênese , beta Catenina , Osteoblastos/metabolismo , Osteoblastos/citologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/citologia , Exossomos/metabolismo , Animais , beta Catenina/metabolismo , beta Catenina/genética , Osteócitos/metabolismo , Osteócitos/citologia , Camundongos , Osteogênese/genética , Osteogênese/fisiologia , Miócitos de Músculo Liso/metabolismo , Diferenciação Celular , Humanos , Via de Sinalização Wnt , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Células Cultivadas , Transdução de Sinais , Camundongos Endogâmicos C57BL
6.
Rev. obstet. ginecol. Venezuela ; 84(3): 279-288, Ago. 2024. ilus, tab, graf
Artigo em Espanhol | LILACS, LIVECS | ID: biblio-1570300

RESUMO

Objetivo: Evaluar el efecto de los exosomas como tratamiento alternativo en la restauración del síndrome genitourinario de la menopausia en pacientes que acuden a una consulta ginecológica, en Valencia, Estado Carabobo, en el período junio - agosto de 2023. Métodos: Estudio prospectivo, descriptivo, exploratorio, incluyó tres casos de mujeres con diagnóstico de síndrome genitourinario de la menopausia. Se evaluó la respuesta en cuanto a los síntomas, examen clínico según el índice de salud vaginal, la satisfacción con el tratamiento y la tolerabilidad. Se aplicó el tratamiento con exosomas: 2 cc con técnica de punto a punto en todas las paredes vaginales y 1 cc en el vestíbulo, en 3 sesiones, con intervalo de 15 días. Resultados: La edad de las pacientes estuvo entre 53 y 56 años, con un promedio de tiempo de menopausia de 6,6 años. Previo al tratamiento, había un nivel alto de irritación vaginal (100 %), dolor en el introito (100 %), sequedad vaginal, dispareunia, hipersensibilidad y las no relaciones sexuales (66,67 %). Postratamiento predominó la ausencia de los síntomas: sequedad vaginal, dispareunia, hipersensibilidad y dolor en introito (100 %); irritación vaginal y no relaciones sexuales (66,67 %) (p = 0,0001). La mediana del índice de salud vaginal previa fue 13 (10 ­ 13) y posterior fue 18 (17 ­ 20) (p = 0,0476). La satisfacción y tolerabilidad fue de 66,67 %. Una paciente refirió dolor leve. Conclusión: La terapia con exosomas es eficaz para reducir los síntomas y signos del síndrome genitourinario de la menopausia, y bien tolerado(AU)


Objective: To evaluate the effect of exosomes as an alternative treatment in the restoration of genitourinary syndrome of menopause in patients attending a gynecological consultation in Valencia, Carabobo State, in the period June - August 2023. Methods: A prospective, descriptive, exploratory study included three cases of women diagnosed with genitourinary syndrome of menopause. Response was assessed in terms of symptoms, clinical examination according to vaginal health index, satisfaction with treatment and tolerability. Treatment with exosomes was applied: 2 cc with point-to-point technique on all vaginal walls and 1 cc in the vestibule, in 3 sessions, with an interval of 15 days. Results: The age of the patients was between 53 and 56 years, with a mean menopause time of 6.6 years. Prior to treatment, there was a high level of vaginal irritation (100%), pain in the introitus (100%), vaginal dryness, dyspareunia, hypersensitivity and non-sexual intercourse (66.67%). Post-treatment, the absence of symptoms predominated: vaginal dryness, dyspareunia, hypersensitivity and pain in the introitus (100%); vaginal irritation and no sexual intercourse (66.67%) (p = 0.0001). The median index of previous vaginal health was 13 (10 ­ 13) and subsequent was 18 (17 ­ 20) (p = 0.0476). Satisfaction and tolerability was 66.67%. One patient reported mild pain. Conclusion: Exosome therapy is effective in reducing the symptoms and signs of genitourinary syndrome of menopause, and well tolerated(AU)


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Terapias Complementares , Menopausa , Terapia de Reposição Hormonal , Exossomos , Perimenopausa , Estrogênios , Ácido Hialurônico
7.
Clinics (Sao Paulo) ; 79: 100441, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38976936

RESUMO

OBJECTIVE: This study aimed to identify differentially expressed microRNAs (miRNAs) in exosomes derived from the blood plasma of Rheumatoid Arthritis (RA) patients and explore their clinical significance and biological roles. METHODS: Illumina high-throughput sequencing was employed to measure miRNA expression levels in plasma exosomes, followed by validation using qRT-PCR. The correlation between exosomal miRNAs and disease activity was systematically analyzed. Additionally, the pathogenic effects of RA exosomes were investigated through bioinformatics analysis and in vitro experiments. RESULTS: Significantly reduced levels of exosomal miR-144-3p and miR-30b-5p were observed in RA patients, which were negatively correlated with DAS28 scores and anti-CCP antibody levels. ROC curve analysis showed that miR-144-3p and miR-30b-5p in plasma exosomes could effectively distinguish RA patients from healthy controls, with AUC values of 0.725 and 0.773, respectively. Combining bioinformatics analysis and in vitro experiments, it was demonstrated that plasma exosomes contribute to ongoing autoantibody production in RA by promoting B-cell differentiation and antibody production. CONCLUSION: The present study indicates that plasma exosomes from RA patients may be potentially pathogenic. Exosomal miR-144-3p and miR-30b-5p exhibit significant decreases in RA patients and are associated with disease activity, suggesting their potential as valuable biomarkers for RA.


Assuntos
Artrite Reumatoide , Linfócitos B , Exossomos , MicroRNAs , Humanos , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , MicroRNAs/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Linfócitos B/imunologia , Estudos de Casos e Controles , Adulto , Biomarcadores/sangue , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real
8.
Biotechnol Lett ; 46(5): 907-924, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38900338

RESUMO

Mesenchymal stem/stromal cells (MSC) play a pivotal role in regenerative therapies. Recent studies show that factors secreted by MSC can replicate their biological activity, driving the emergence of cell-free therapy, likely to surpass stem cell therapy. Patents are an objective measure of R&D and innovation activities, and patent mapping allows us to verify the state of the art and technology, anticipate trends, and identify emerging lines of research. This review performed a search on Derwent World Patents Index™ and retrieved 269 patent families related to the MSC-derived cell-free products. Analysis reveals an exponential increase in patents from the mid-2010s, primarily focusing on exosomes. The patent's contents offer a great diversity of applications and associated technologies by using the products as medicinal agents or drug delivery systems. Nevertheless, numerous application branches remain unexplored, suggesting vast potential for cell-free technologies alone or combined with other approaches.


Assuntos
Células-Tronco Mesenquimais , Patentes como Assunto , Células-Tronco Mesenquimais/citologia , Humanos , Exossomos , Sistema Livre de Células , Medicina Regenerativa/métodos , Animais
9.
Int J Mol Sci ; 25(10)2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38791505

RESUMO

In contrast to the hypothesis that aging results from cell-autonomous deterioration processes, the programmed longevity theory proposes that aging arises from a partial inactivation of a "longevity program" aimed at maintaining youthfulness in organisms. Supporting this hypothesis, age-related changes in organisms can be reversed by factors circulating in young blood. Concordantly, the endocrine secretion of exosomal microRNAs (miRNAs) by hypothalamic neural stem cells (htNSCs) regulates the aging rate by enhancing physiological fitness in young animals. However, the specific molecular mechanisms through which hypothalamic-derived miRNAs exert their anti-aging effects remain unexplored. Using experimentally validated miRNA-target gene interactions and single-cell transcriptomic data of brain cells during aging and heterochronic parabiosis, we identify the main pathways controlled by these miRNAs and the cell-type-specific gene networks that are altered due to age-related loss of htNSCs and the subsequent decline in specific miRNA levels in the cerebrospinal fluid (CSF). Our bioinformatics analysis suggests that these miRNAs modulate pathways associated with senescence and cellular stress response, targeting crucial genes such as Cdkn2a, Rps27, and Txnip. The oligodendrocyte lineage appears to be the most responsive to age-dependent loss of exosomal miRNA, leading to significant derepression of several miRNA target genes. Furthermore, heterochronic parabiosis can reverse age-related upregulation of specific miRNA-targeted genes, predominantly in brain endothelial cells, including senescence promoting genes such as Cdkn1a and Btg2. Our findings support the presence of an anti-senescence mechanism triggered by the endocrine secretion of htNSC-derived exosomal miRNAs, which is associated with a youthful transcriptional signature.


Assuntos
Envelhecimento , Exossomos , Hipotálamo , MicroRNAs , Células-Tronco Neurais , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Exossomos/metabolismo , Hipotálamo/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Redes Reguladoras de Genes , Senescência Celular/genética , Encéfalo/metabolismo , Camundongos , Parabiose , Oligodendroglia/metabolismo , Transcriptoma , Regulação da Expressão Gênica , Perfilação da Expressão Gênica
10.
Biol Res ; 57(1): 28, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750549

RESUMO

BACKGROUND: The activated microglia have been reported as pillar factors in neuropathic pain (NP) pathology, but the molecules driving pain-inducible microglial activation require further exploration. In this study, we investigated the effect of dorsal root ganglion (DRG)-derived exosomes (Exo) on microglial activation and the related mechanism. METHODS: A mouse model of NP was generated by spinal nerve ligation (SNL), and DRG-derived Exo were extracted. The effects of DRG-Exo on NP and microglial activation in SNL mice were evaluated using behavioral tests, HE staining, immunofluorescence, and western blot. Next, the differentially enriched microRNAs (miRNAs) in DRG-Exo-treated microglia were analyzed using microarrays. RT-qPCR, RNA pull-down, dual-luciferase reporter assay, and immunofluorescence were conducted to verify the binding relation between miR-16-5p and HECTD1. Finally, the effects of ubiquitination modification of HSP90 by HECTD1 on NP progression and microglial activation were investigated by Co-IP, western blot, immunofluorescence assays, and rescue experiments. RESULTS: DRG-Exo aggravated NP resulting from SNL in mice, promoted the activation of microglia in DRG, and increased neuroinflammation. miR-16-5p knockdown in DRG-Exo alleviated the stimulating effects of DRG-Exo on NP and microglial activation. DRG-Exo regulated the ubiquitination of HSP90 through the interaction between miR-16-5p and HECTD1. Ubiquitination alteration of HSP90 was involved in microglial activation during NP. CONCLUSIONS: miR-16-5p shuttled by DRG-Exo regulated the ubiquitination of HSP90 by interacting with HECTD1, thereby contributing to the microglial activation in NP.


Assuntos
Exossomos , Gânglios Espinais , Proteínas de Choque Térmico HSP90 , MicroRNAs , Microglia , Neuralgia , Animais , Masculino , Camundongos , Modelos Animais de Doenças , Exossomos/metabolismo , Gânglios Espinais/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Camundongos Endogâmicos C57BL , Microglia/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Neuralgia/metabolismo , Neuralgia/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética
11.
Clin Transl Oncol ; 26(9): 2166-2171, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38602645

RESUMO

Breast cancer is one of the most prevalent malignancies affecting women globally and poses a significant public health challenge. Early clinical detection plays a pivotal role in providing optimal treatment opportunities and favorable prognoses, crucial for reducing breast cancer mortality and enhancing patients' quality of life. Therefore, the timely identification and diagnosis of breast cancer are imperative. Conventional tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA15-3), serve as reliable methods for actively monitoring disease progression and have become a routine auxiliary diagnostic approach in clinical settings. However, these biomarkers exhibit limitations in sensitivity and specificity, particularly in the early screening and diagnosis of tumors, often yielding results inconsistent with clinical manifestations. In recent years, research has increasingly focused on exosomes released by tumor cells as potential new biomarkers for early stage breast cancer screening. Exosomes carry various components, including tumor-derived proteins, nucleic acids, and lipids. This paper delves into the specific utilization of serum exosomal microRNA-21 (miR-21) as a biomarker for early detection and diagnosis of breast cancer, evaluating its efficacy within this framework.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Detecção Precoce de Câncer , Exossomos , MicroRNAs , Humanos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Feminino , MicroRNAs/sangue , Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer/métodos
12.
Clin Transl Oncol ; 26(8): 1921-1933, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38485857

RESUMO

BACKGROUND: Studies have shown that many exosomal microRNAs (miRNAs) can be used as non-invasive biomarkers of lung cancer, but their diagnostic and prognostic values need to be further clarified. METHODS: We conducted a systematic literature search in Web of Science, PubMed, and ScienceDirect databases, obtained relevant articles and extracted data, and used statistical methods and statistical software to comprehensively evaluate the diagnostic and prognostic value of exosomal miRNAs in lung cancer. REGISTRATION NUMBER: PROSPERO CRD42023447398. RESULTS: In terms of diagnosis, two exosomal miRNAs (miR-486-5p and miR-451a) were reported with the highest frequency in lung cancer patients, both of which had good diagnostic value. Compared with the control group, the pooled sensitivities of miR-486-5p and miR-451a were 0.80 (95% CI: 0.73-0.86) and 0.76 (95% CI: 0.60-0.87), specificities: 0.93 (95% CI: 0.63-0.99) and 0.85 (95% CI: 0.72-0.92), and AUCs: 0.85 (95% CI: 0.81-0.88) and 0.88 (95% CI: 0.84-0.90), for the respective miRNAs. For prognosis, in lung cancer patients with abnormally expressed exosomal miRNAs, miR-1290 was associated with PFS outcome; miR-382, miR-1246, miR-23b-3p, miR-21-5p, and miR-10b-5p were associated with OS outcome; miR-21 and miR-4257 were associated with DFS outcome; miR-125a-3p and miR-625-5p were associated with PFS and OS outcomes; miR-216b and miR-451a were associated with OS and DFS outcomes. CONCLUSIONS: Exosomal miRNAs are valuable biomarkers in lung cancer patients. Exosomal miR-486-5p and miR-451a can be used as new diagnostic biomarkers for lung cancer. Dysregulated exosomal miRNAs could serve as indicators of survival outcomes in lung cancer patients.


Assuntos
Biomarcadores Tumorais , Exossomos , Neoplasias Pulmonares , MicroRNAs , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Exossomos/genética , Exossomos/metabolismo , Prognóstico , Biomarcadores Tumorais/genética
13.
Clin Transl Oncol ; 26(8): 1988-1997, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38502292

RESUMO

BACKGROUND: tRF-RNA-a representative of non-coding RNA (ncRNA)-is a precursor or fragment of mature tRNA and plays a crucial regulatory role in the occurrence and development of cancer. There is currently little research on tRF-RNA as a diagnostic marker in cancer, especially for NSCLC from serum exosomes. METHOD: Serum exosomes were successfully extracted from serum; their physical morphology was captured by transmission electron microscopy (TEM); appropriate particle size detection was performed using qNano; surface labeling was verified through western blotting. Serum exosomes i-tRF-AspGTC and tRF-1-SerCGA were selected through gene microarray, and qPCR was used to validate their significance in 242 patients and 201 healthy individuals. The area under the curve (AUC) was used to evaluate the diagnostic indicators of non-small cell lung cancer (NSCLC). RESULT: Compared with 201 healthy individuals, i-tRF-AspGTC and tRF-1-SerCGA were significantly downregulated in 242 NSCLC patients and 95 early-stage patients. For tRF-AspGTC and tRF-1-SerCGA, the predictive diagnostic efficiency rates of AUC were 0.690 and 0.680, respectively, whereas the early diagnostic efficiency rates were 0.656 and 0.688, respectively. The result of combined diagnosis with CEA and CYFRA21-1 was 0.928, and the early diagnostic efficiency was 0.843, which is a very high biological predictive factor for NSCLC. CONCLUSION: The expression of serum exosomes i-tRF-AspGTC and tRF-1-SerCGA was significantly downregulated in NSCLC patients. These exosomes could be used as predictive indicators for diagnosis or early diagnosis of NSCLC.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Exossomos , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Exossomos/metabolismo , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Idoso , Adulto , Prognóstico
14.
Biosens Bioelectron ; 255: 116211, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38537428

RESUMO

Exosomes are nanovesicles present in all the biological fluids, making them attractive as non-invasive biomarkers for diseases like cancer, among many others. However, exosomes are complex to separate and detect, requiring comprehensive molecular characterization for their routine use in diagnostics. This study explores the use of peptides as cost-effective and stable alternatives to antibodies for exosome binding. To achieve that, phage display technology was employed to select peptides with high specificity for target molecules in exosomes. Specifically, a selected peptide was evaluated for its ability to selectively bind breast cancer-derived exosomes. Proteomic analysis identified 38 protein candidates targeted by the peptide on exosome membranes. The binding of the peptide to breast cancer-derived exosomes was successfully demonstrated by flow cytometry and magneto-actuated immunoassays. Furthermore, an electrochemical biosensor was also tested for breast cancer-derived exosome detection and quantification. The peptide demonstrated effective binding to exosomes from aggressive cancer cell lines, offering promising results in terms of specificity and recovery. This research shows potential for developing rapid, accessible diagnostic tools for breast cancer, especially in low-resource healthcare settings.


Assuntos
Técnicas Biossensoriais , Neoplasias da Mama , Exossomos , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Exossomos/química , Biomarcadores Tumorais/análise , Proteômica , Peptídeos/metabolismo
15.
Geroscience ; 46(6): 5891-5909, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38499957

RESUMO

The decline in the ovarian reserve leads to menopause and reduced serum estrogens. MicroRNAs are small non-coding RNAs, which can regulate gene expression and be secreted by cells and trafficked in serum via exosomes. Serum miRNAs regulate tissue function and disease development. Therefore, the aim of this study was to identify miRNA profiles in serum exosomes of mice induced to estropause and treated with 17ß-estradiol (E2). Female mice were divided into three groups including control (CTL), injected with 4-Vinylcyclohexene diepoxide (VCD), and injected with VCD plus E2 (VCD + E2). Estropause was confirmed by acyclicity and a significant reduction in the number of ovarian follicles (p < 0.05). Body mass gain during estropause was higher in VCD and VCD + E2 compared to CTL females (p = 0.02). Sequencing of miRNAs was performed from exosomes extracted from serum, and 402 miRNAs were detected. Eight miRNAs were differentially regulated between CTL and VCD groups, seven miRNAs regulated between CTL and VCD + E2 groups, and ten miRNAs regulated between VCD and VCD + E2 groups. Only miR-200a-3p and miR-200b-3p were up-regulated in both serum exosomes and ovarian tissue in both VCD groups, suggesting that these exosomal miRNAs could be associated with ovarian activity. In the hepatic tissue, only miR-370-3p (p = 0.02) was up-regulated in the VCD + E2 group, as observed in serum. Our results suggest that VCD-induced estropause and E2 replacement have an impact on the profile of serum exosomal miRNAs. The miR-200 family was increased in serum exosomes and ovarian tissue and may be a candidate biomarker of ovarian function.


Assuntos
Estradiol , Exossomos , MicroRNAs , Animais , Feminino , Exossomos/metabolismo , Exossomos/genética , MicroRNAs/sangue , MicroRNAs/genética , Camundongos , Estradiol/farmacologia , Estradiol/sangue , Cicloexenos/farmacologia , Compostos de Vinila , Menopausa , Reserva Ovariana/efeitos dos fármacos , Estrogênios/farmacologia , Terapia de Reposição de Estrogênios
16.
Adv Exp Med Biol ; 1443: 257-267, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38409426

RESUMO

Protein aggregation is a common mechanism in multiple neurodegenerative and heart diseases and the accumulation of proteins in aggregates is toxic to cells, causing injury and death. The degree of protein aggregation directly correlates with the severity of the disease. Misfolded proteins present thermodynamic barriers that culminate in the loss of structure and function and the exposure of hydrophobic residues. The exposure of hydrophobic residues is the driving force behind protein aggregation, as it reduces surface free energy and increases the propensity for the formation of large insoluble aggregates. Exploring the protein content of aggregates is fundamental to understanding their formation mechanism and pathophysiological effects. We demonstrate here a method for isolating aggregated protein content in human plasma and mouse brain samples. The samples were characterized by mass spectrometry analysis, transmission electron microscopy, and western blotting. We report the identification of proteins associated with neurodegenerative diseases in the isolated pellets. The western blotting analyses of the isolated pellet showed the positivity for CD89 and CD63, consolidated markers of exosomes, confirming the presence of exosomes within the pellet but not in the supernatant in human plasma. Notably, the concomitant isolation of exosomes together with the protein aggregates was feasible starting from 200 µL of human plasma. Moreover, the presented methodology separated albumin from the aggregated pellet, allowing identification of larger diversity of proteins through mass spectrometry analysis.


Assuntos
Exossomos , Doenças Neurodegenerativas , Camundongos , Animais , Humanos , Agregados Proteicos , Proteínas/metabolismo , Doenças Neurodegenerativas/metabolismo , Microscopia Eletrônica de Transmissão , Exossomos/metabolismo , Espectrometria de Massas
17.
Biol Res ; 57(1): 3, 2024 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-38217055

RESUMO

BACKGROUND: Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. RESULTS: Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. CONCLUSIONS: In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.


Assuntos
Exossomos , Neomicina , Neomicina/toxicidade , Neomicina/metabolismo , Exossomos/metabolismo , Células Ciliadas Auditivas , Autofagia/fisiologia
18.
Clin Transl Oncol ; 26(6): 1497-1507, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38227115

RESUMO

BACKGROUND: In view of discordance consisting in different reports, a meta-analysis was conducted to comprehensively evaluate the diagnostic efficacy of exosomal noncoding RNAs (ncRNAs) in blood and urine in the detection of bladder cancer. METHODS: Eligible studies were acquired by systematic retrieval through PubMed, Cochrane Library, and Embase. The pooled diagnostic efficacy was appraised by reckoning the area under the summary receiver operating characteristic (SROC) curve. The latent sources of heterogeneity were probed by subgroup analyses and meta-regression. STATA 12.0, Meta-DiSc 1.4, and RevMan 5.3 were applied to carry out all statistical analyses and plots. RESULTS: A total of 46 studies from 15 articles comprising 2622 controls and 3015 bladder cancer patients were included in our meta-analysis. Exosomal ncRNAs in blood and urine represented relatively satisfactory diagnostic efficacy in detecting bladder cancer, with a pooled sensitivity of 0.75, a specificity of 0.79, and an area under the SROC curve (AUC) of 0.84. Exosomal microRNAs (miRNAs) exhibited better diagnostic value with a pooled AUC of 0.91 than that of exosomal long noncoding RNAs (lncRNAs). To some extent, the heterogeneity among studies was induced by exosomal ncRNA types (miRNA or lncRNA), exosomal ncRNA profiling (single- or multiple-ncRNA), sample size, specimen types, and ethnicity. CONCLUSION: Exosomal ncRNAs in blood and urine may play a vital role in diagnosing bladder cancer as prospective noninvasive biomarkers; nonetheless, their clinical performance needs to be confirmed by further massive proactive researches.


Assuntos
Biomarcadores Tumorais , Exossomos , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/urina , Humanos , Exossomos/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/urina , RNA Longo não Codificante/genética , RNA Longo não Codificante/urina , RNA Longo não Codificante/sangue , RNA não Traduzido/genética , RNA não Traduzido/sangue , RNA não Traduzido/urina , MicroRNAs/urina , MicroRNAs/sangue , MicroRNAs/genética , Curva ROC
19.
Mol Microbiol ; 122(5): 613-629, 2024 11.
Artigo em Inglês | MEDLINE | ID: mdl-37758682

RESUMO

The study of host-pathogen interactions has increased considerably in recent decades. This intercellular communication has been mediated by extracellular vesicles (EVs) that play an important role during the interaction. EVs are particles of lipid bilayer and described in different types of cells, eukaryotic or prokaryotic. Depending on their biogenesis they are described as exosomes (derived from multivesicular bodies) and microvesicles (derived from the plasma membrane). The EVs carry biomolecules, including nucleic acids, lipids, and proteins that can be released or internalized by other cells in different pathways (endocytosis, macropinocytosis, phagocytosis, or membrane fusion) in the process described as uptake. The balance between biogenesis and uptake of EVs could modify physiological and pathophysiological processes of the cell. This review is focusing on the dynamic roles of release and capture of EVs during host-pathogen interaction. We also do a critical analysis of methodologies for obtaining and analyzing EVs. Finally, we draw attention to critical points to be considered in EV biogenesis and uptake studies.


Assuntos
Vesículas Extracelulares , Interações Hospedeiro-Patógeno , Vesículas Extracelulares/metabolismo , Humanos , Animais , Exossomos/metabolismo , Endocitose , Comunicação Celular , Transporte Biológico , Fagocitose
20.
Braz J Otorhinolaryngol ; 90(1): 101343, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37925811

RESUMO

OBJECTIVES: Nasopharyngeal Carcinoma (NPC) is a common malignant tumor of nasopharyngeal mucosal epithelium in clinical practice. Radiotherapy and chemotherapy are the main treatment methods at present, but the therapeutic effect is still unsatisfactory. Studies have shown that exosomes and microRNAs (miRNAs) play an important role in the development of cancer. Therefore, this study aimed to investigate the effects of NPC derived exosomes on NPC and their molecular mechanisms. METHODS: Serum was collected from healthy subjects, Epstein-Barr Virus (EBV) infected patients and NPC patients (n = 9 group) and exosomes were extracted separately. High-throughput sequencing of exosomes was performed to screen differentially expressed miRNAs. The function of the screened miRNA was identified by treating NPC cells with exosomes. The target gene of miRNA was identified using the dual-luciferase assay. Real-Time quantitative Polymerase Chain Reaction (RT-qPCR) was used to determine the levels of miR-99a-5p and Bromodomain Adjacent Tozinc finger domain protein 2A (BAZ2A). Cell Counting Kit-8 assay, flow cytometry, and wound healing assay were utilized to detect cell viability, cell cycle and apoptosis, and migration ability. The protein levels were evaluated by Western blot. RESULTS: MiR-99a-5p was identified as the most significant differentially expressed miRNA in exosomes (p < 0.05). The proliferation and migration of NPC cells were extremely facilitated by exosomes, accompanied by the suppressed apoptosis, upregulated BAZ2A, Monocyte Chemotactic Protein-1 (MCP1), and Vascular Endothelial Growth Factor A (VEGFA), and downregulation of Interleukin (IL)-1ß and Nuclear Transcription Factor-κB (NF-κB) (p < 0.05). BAZ2A was a target gene of miR-99a-5p. Furthermore, the regulatory effect of exosomes on the proliferation, migration, and apoptosis was significantly abolished by overexpression of miR-99a-5p or downregulation of BAZ2A (p < 0.05). CONCLUSION: NPC derived exosomes facilitated the proliferation and migration of NPC through regulating the miR-99a-5p/BAZ2A axis.


Assuntos
Infecções por Vírus Epstein-Barr , Exossomos , MicroRNAs , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Infecções por Vírus Epstein-Barr/genética , Linhagem Celular Tumoral , Proliferação de Células , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas que Contêm Bromodomínio , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo
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