Gastrointestinal(GI)cancers,which predominantly manifest in the stomach,colorectum,liver,esophagus,and pancreas,accounting for approximately 35%of global cancer-related mortality.The advent of liquid biopsy has introd...Gastrointestinal(GI)cancers,which predominantly manifest in the stomach,colorectum,liver,esophagus,and pancreas,accounting for approximately 35%of global cancer-related mortality.The advent of liquid biopsy has introduced a pivotal diagnostic modality for the early identification of premalignant GI lesions and incipient cancers.This non-invasive technique not only facilitates prompt therapeutic intervention,but also serves as a critical adjunct in prognosticating the likelihood of tumor recurrence.The wealth of circulating exosomes present in body fluids is often enriched with proteins,lipids,microRNAs,and other RNAs derived from tumor cells.These specific cargo components are reflective of processes involved in GI tumorigenesis,tumor progression,and response to treatment.As such,they represent a group of promising biomarkers for aiding in the diagnosis of GI cancer.In this review,we delivered an exhaustive overview of the composition of exosomes and the pathways for cargo sorting within these vesicles.We laid out some of the clinical evidence that supported the utilization of exosomes as diagnostic biomarkers for GI cancers and discussed their potential for clinical application.Furthermore,we addressed the challenges encountered when harnessing exosomes as diagnostic and predictive instruments in the realm of GI cancers.展开更多
To illustrate the mechanisms of exosomal microRNAs(miRNAs)in common mental disorders,and explore their potential as diagnostic biomarkers and therapeutic targets,a systematic literature review of relevant studies on e...To illustrate the mechanisms of exosomal microRNAs(miRNAs)in common mental disorders,and explore their potential as diagnostic biomarkers and therapeutic targets,a systematic literature review of relevant studies on exosomal miRNAs in mental disorders was conducted.Data from cell experiments,animal models,and clinical studies were analyzed and combined to study the mechanisms and roles of exosomal miRNAs in various mental disorders.Research has shown that exosomal miRNAs,such as miR-146a,miR-223,miR-125b,and miR-451a,affect Alzheimer’s disease(AD)formation by regulating key pathways such as toll-like receptor 4(TLR4)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt),respectively.MiR-146a-5p regulates the occurrence of schizophrenia through the Notch pathway.TLR4 regulates miR-146a and miR-155 in major depressive disorder(MDD),and miR-144-5p regulates the disease through PI3K/Akt.Exosomal miR-484,miR-652-3p,miR-142-3p,miR-21a-3p,and miR-21-5p regulate key pathways in bipolar disorder,autism spectrum disorder,and Rett syndrome(e.g.,TLR4,PI3K/Akt,and Epha4/TEK)and have an influence on mental disorders.Exosomal miRNAs are involved in the occurrence of mental disorders through TLR4,PI3K/Akt,and Epha4/TEK pathways,which provides a clearer understanding of disease cognition.Of these pathways,the TLR4 and PI3K/Akt pathways play a role in AD,MDD,and neurodevelopmental disorders,which can be used as an effective breakthrough in the study of mental disorders.Exosomal miRNAs could also serve as diagnostic biomarkers and therapeutic targets,providing new insights into precise interventions for mental disorders.展开更多
Exosomal circular RNA(circRNAs)are pivotal in cancer biology,and tumor pathophysiology.These stable,non-coding RNAs encapsulated in exosomes participated in cancer progression,tumor growth,metastasis,drug sensitivity ...Exosomal circular RNA(circRNAs)are pivotal in cancer biology,and tumor pathophysiology.These stable,non-coding RNAs encapsulated in exosomes participated in cancer progression,tumor growth,metastasis,drug sensitivity and the tumor microenvironment(TME).Their presence in bodily fluids positions them as potential non-invasive biomarkers,revealing the molecular dynamics of cancers.Research in exosomal circRNAs is reshaping our understanding of neoplastic intercellular communication.Exploiting the natural properties of exosomes for targeted drug delivery and disrupting circRNA-mediated pro-tumorigenic signaling can develop new treatment modalities.Therefore,ongoing exploration of exosomal circRNAs in cancer research is poised to revolutionize clinical management of cancer.This emerging field offers hope for significant breakthroughs in cancer care.This review underscores the critical role of exosomal circRNAs in cancer biology and drug resistance,highlighting their potential as non-invasive biomarkers and therapeutic targets that could transform the clinical management of cancer.展开更多
This article comments on the study by Zhang et al,which proposed that exosomes derived from hypoxia-injured endometrial epithelial cells promote human umbilical cord mesenchymal stem cell migration and differentiation...This article comments on the study by Zhang et al,which proposed that exosomes derived from hypoxia-injured endometrial epithelial cells promote human umbilical cord mesenchymal stem cell migration and differentiation into endo-metrial epithelial cells via exosomal miR-137-3p.The authors demonstrated that miR-137-3p targets ubiquitin protein ligase E3C and activates signal transducer and activator of transcription 3 signaling,thereby driving epithelial lineage transition.While this study expands our understanding of exosome-mediated intercellular communication in endometrial repair,several key gaps remain.Notably,microRNA(miRNA)profiling was performed in human umbilical cord mesenchymal stem cells post-exosome treatment,not in the exosomes derived from hypoxia-injured endometrial epithelial cell themselves,leaving open whether miR-137-3p is directly transferred or indirectly induced.In addition,data on exosome characterization were unavailable,and the rationale for selecting miR-137-3p over other differentially expressed miRNAs was not well justified.Future studies should include direct exosomal miRNA content analysis,in vivo validation,and deeper mechanistic exploration of the ubiquitin protein ligase E3C-signal transducer and activator of transcription 3 ubiquitination axis to establish the clinical and biological relevance of this pathway.展开更多
Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma ...Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms.Methods:Exosomes were isolated from melanoma cell lines A375 and A2058,and their effects on the proliferation,migration,and angiogenesis of human umbilical vein endothelial cells(HUVECs)were examined.The interaction between miR-424-5p and its target gene,large tumor suppressor kinase 2(LATS2),was analyzed using luciferase reporter assays and functional experiments.In vivo,tumor growth and angiogenesis were studied in a xenograft model using nude mice.Results:Melanoma cell-derived exosomes could be internalized by HUVECs,which promoted proliferation,migration,and angiogenesis.miR-424-5p was highly expressed in melanoma cells and their exosomes,and its inhibition in exosomes suppressed HUVEC proliferation,migration,and angiogenesis.LATS2 was identified as a direct target of miR-424-5p,and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions.In vivo,exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models.Conclusions:Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2,contributing to melanoma progression.Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma.展开更多
This study by Zhang et al elucidates the role of exosome miR-137-3p targeting ubiquitin protein ligase E3C to activate signal transducer and activator of transcription 3 under hypoxia conditions,thereby promoting the ...This study by Zhang et al elucidates the role of exosome miR-137-3p targeting ubiquitin protein ligase E3C to activate signal transducer and activator of transcription 3 under hypoxia conditions,thereby promoting the migration and differentiation of human umbilical cord mesenchymal stem cells to endometrial epithelial cells.It emphasizes that exosomal miR-137-3p/ubiquitin protein ligase E3C/signal transducer and activator of transcription 3 axis is a promising pathway for endometrial regeneration.This article introduced the therapeutic potential of exosomal microRNAs in regenerative medicine while underscoring the need for standardized protocols in optimizing exosome delivery and validating molecular pathways for clinical translation.展开更多
Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann c...Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann cell function may also be impaired.Recently,important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported.This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles,marking,to our knowledge,the first instance of such treatment.An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis.After initial diagnosis,the patient underwent a combination of generic riluzole,sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis,and taurursodiol.The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function.We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired(senescent)and that exposure of the patient’s Schwann cells to allogeneic Schwann cell-derived exosomal vesicles,cultured expanded from a cadaver donor improved their growth capacity in vitro.After a period of observation lasting 10 weeks,during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored,the patient received weekly consecutive infusions of 1.54×1012(×2),and then consecutive infusions of 7.5×1012(×6)allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco’s phosphate-buffered saline.None of the infusions were associated with adverse events such as infusion reactions(allergic or otherwise)or changes in vital signs.Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend.A more sensitive in-house assay suggested possible inflammasome activation during the disease course.A trend for clinical stabilization was observed during the infusion period.Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles.Initial findings suggest that this approach is safe.展开更多
BACKGROUND There is currently no effective treatment for osteoarthritis(OA),which is the most common joint disorder leading to disability.Although human umbilical cord mesenchymal stem cells(hUC-MSCs)are promising OA ...BACKGROUND There is currently no effective treatment for osteoarthritis(OA),which is the most common joint disorder leading to disability.Although human umbilical cord mesenchymal stem cells(hUC-MSCs)are promising OA treatments,their use is limited by the condition itself,and understanding of the underlying mechanisms of OA is lacking.AIM To explore the specific molecular mechanism by which hUC-MSC-derived exosomal miR-199a-3p improves OA.METHODS Sodium iodoacetate was injected into rat articulations to construct an animal model of OA.Interleukin(IL)-1βwas used to induce human chondrocytes(CHON-001)to construct an OA chondrocyte model.Exosomes in hUC-MSCs were isolated using Ribo™Exosome Isolation Reagent.Real-time reverse transcriptase-polymerase chain reaction and western blotting were used to detect the expression of related genes and proteins,and damage to CHON-001 cells and rat articular cartilage tissue was evaluated by enzyme-linked immunosorbent assay,terminal deoxynucleotidyl transferase-mediated deoxyuridine tripho-sphate-nick end labelling staining and hematoxylin and eosin staining.RESULTS hUC-MSC-derived exosomes(hUC-MSC-Exos)inhibited the expression of IL-1β-induced inflammatory cytokines,namely,IL-6,IL-8 and tumor necrosis factor-α.hUC-MSC-Exos also improved the viability but inhibited the apoptosis of CHON-001 cells,improved the pathological condition of articular cartilage tissue and alleviated the development of OA in vivo.Mechanistically,hUC-MSC-Exos downregulated the expression of mitogen-activated protein kinase 4 by delivering miR-199a-3p,thereby inhibiting the activation of the nuclear factor-kappaB signaling pathway,alleviating IL-1β-induced chondrocyte inflammation and apoptosis,and ultimately improving the development of OA.CONCLUSION hUC-MSC-derived exosomal miR-199a-3p alleviates OA by inhibiting the mitogen-activated protein kinase 4/nuclear factor-kappaB signaling pathway.The present findings suggest that miR-199a-3p delivery by hUC-MSCExos may be a novel strategy for the treatment of OA.展开更多
Sepsis,a severe systemic inflammatory response to infection,remains a leading cause of morbidity and mortality worldwide.Exosomes,as mediators of intercellular communication,play a pivotal role in the pathogenesis of ...Sepsis,a severe systemic inflammatory response to infection,remains a leading cause of morbidity and mortality worldwide.Exosomes,as mediators of intercellular communication,play a pivotal role in the pathogenesis of sepsis through modulating immune responses,metabolic reprogramming,coagulopathy,and organ dysfunction.This review highlights the emerging significance of exosomes in these processes.Initially,it provides an in-depth insight into exosome biogenesis and characterization,laying the groundwork for understanding their diverse and intricate functions.Subsequently,it explores the regulatory roles of exosomes in various immune cells such as neutrophils,macrophages,dendritic cells,T cells,and B cells.This analysis elucidates how exosomes are pivotal in modulating immune responses,thus contributing to the complexity of sepsis pathophysiology.Additionally,this review delves into the role of exosomes in the regulation of metabolism and subsequent organ dysfunction in sepsis.It also establishes a connection between exosomes and the coagulation cascade,which affects endothelial integrity and promotes thrombogenesis in sepsis.Moreover,the review discusses the dual role of exosomes in the progression and resolution of sepsis,exploring their complex involvement in inflammation and healing processes.Furthermore,it underscores their potential as biomarkers and therapeutic targets.Understanding these mechanisms presents new opportunities for novel interventions to mitigate the severe outcomes of sepsis,emphasizing the therapeutic promise of exosome research in critical care settings.展开更多
The intricate interactions between immune cells and tumors exert a profound influence on cancer progression and therapeutic efficacy.Within the tumor microenvironment,exosomes have emerged as pivotal mediators of inte...The intricate interactions between immune cells and tumors exert a profound influence on cancer progression and therapeutic efficacy.Within the tumor microenvironment,exosomes have emerged as pivotal mediators of intercellular communication,with their cargo of non-coding RNAs(ncRNAs)serving as key regulatory elements.This review examines the multifaceted roles of immune cell-derived exosomal ncRNAs in tumor biology.The involvement of various immune cells,including T cells,B cells,natural killer cells,macrophages,neutrophils,and myeloid-derived suppressor cells,in utilizing exosomal ncRNAs to regulate tumor initiation and progression is explored.Additionally,the biogenesis and delivery mechanisms of these immune cell-derived exosomal ncRNAs are discussed,alongside their potential clinical applications in cancer.展开更多
BACKGROUND Exosomal microRNAs(miRNAs)have emerged as promising biomarkers for cancer diagnosis due to their stability,tumor specificity,and accessibility.How-ever,the diagnostic potential of serum exosomal miRNAs in m...BACKGROUND Exosomal microRNAs(miRNAs)have emerged as promising biomarkers for cancer diagnosis due to their stability,tumor specificity,and accessibility.How-ever,the diagnostic potential of serum exosomal miRNAs in metastatic pancreatic cancer remains underexplored.AIM To investigate the diagnostic potential of serum exosomal miRNAs in metastatic pancreatic cancer.METHODS A total of 36 patients were enrolled,comprising 8 patients in the discovery phase(4 with metastatic and 4 with non-metastatic pancreatic cancer)and 28 in the validation cohort(15 non-metastatic and 13 metastatic cases).Exosomes were isolated using the exoEasy Maxi Kit and characterized by transmission electron microscopy,nanoparticle tracking analysis,and western blotting.High-throu-ghput sequencing was conducted to identify differentially expressed serum exosomal miRNAs,which were subsequently validated using TaqMan probe-based reverse transcription-quantitative polymerase chain reaction.Bioinformatic analyses were performed to predict downstream target genes and explore their roles in metastatic progression.RESULTS Transmission electron microscopy revealed that the isolated exosomes were predominantly round or oval with well-defined membrane boundaries.Nano-particle tracking analysis showed a peak particle size of approximately 138 nm,accounting for 99.2%of total particles,consistent with the typical size range of exosomes.Western blotting confirmed the expression of exosome-specific markers CD63 and CD81.High-throughput sequencing identified 42 differentially expressed exosomal miRNAs between metastatic and non-metastatic groups.Among them,hsa-let-7f-5p was significantly upregulated in metastatic pancreatic cancer(P=0.007),as validated by reverse transcription-quantitative polymerase chain reaction.Target gene prediction indicated that hsa-let-7f-5p may be involved in metastasis through its interactions with nerve growth factor,cyclin-dependent kinase inhibitor 1A,high mobility group AT-hook 2,insulin-like growth factor 2 mRNA-binding protein 1,and insulin-like growth factor 2 mRNA-binding protein 3.CONCLUSION The elevated expression of serum exosomal hsa-let-7f-5p in metastatic pancreatic cancer suggests its potential as a non-invasive biomarker for distinguishing metastatic from non-metastatic disease.展开更多
BACKGROUND Radiation resistance limits radiotherapy efficacy in esophageal squamous cell carcinoma(ESCC).The tumor microenvironment,particularly adipocytes,plays a role in promoting cancer progression.Extracellular ve...BACKGROUND Radiation resistance limits radiotherapy efficacy in esophageal squamous cell carcinoma(ESCC).The tumor microenvironment,particularly adipocytes,plays a role in promoting cancer progression.Extracellular vesicles and microRNAs(miRNAs)regulate gene expression and hold prognostic potential for esophageal carcinoma.Elucidating radioresistance mechanisms and identifying radiosensitization targets can help enhance radiotherapy efficacy for esophageal cancer.AIM To investigate the potential role of miRNAs derived from adipocyte exosomes as prognostic markers for radiotherapy efficacy in ESCC.METHODS Free adipocytes were isolated from human thoracic adipose tissue.A co-culture model of adipocytes and ESCC cells was established to observe colony formation and cell survival post-irradiation.ESCC cell apoptosis was assessed by flow cytometry.Western Blot and immunofluorescence assays were performed to evaluate DNA damage in ESCC cells post-irradiation.Adipocyte-derived exosomes were isolated by ultracentrifugation and identified by electron microscopy.A similar set of experiments was performed on ESCC cells to analyze cell survival,apoptosis,and DNA damage post-radiation exposure.Exosomes from adipose tissue and serum exosomes from ESCC patients pre-and post-radiotherapy were subjected to high-throughput miRNA-sequencing and validated using real-time quantitative polymerase chain reaction.The correlation between potential target miRNAs and the short-term prognosis of radiotherapy in ESCC was evaluated by receiver operating characteristic curve analysis.RESULTS Co-culturing adipocytes with ESCC cells enhanced radioresistance,as evidenced by increased colony formation.Adipocyte co-culture reduced ESCC cell apoptosis and DNA damage post-radiation.Adipocyte-derived exosomes similarly conferred radioresistance in ESCC cells,decreasing apoptosis and DNA damage post-irradiation.Highthroughput miRNA-sequencing identified miR-660-5p in serum and adipose tissue exosomes.Patients with high expression of serum exosome miR-660-5p showed poor prognosis after radiotherapy.CONCLUSION Adipocyte-derived exosomal miR-660-5p is a potential biomarker for evaluating radiotherapy efficacy in ESCC.展开更多
BACKGROUND Hesperetin,a flavonoid predominantly present in citrus fruits,exhibits significant intervention effects on both the initiation and progression of gastric cancer.However,the specific mechanisms underlying th...BACKGROUND Hesperetin,a flavonoid predominantly present in citrus fruits,exhibits significant intervention effects on both the initiation and progression of gastric cancer.However,the specific mechanisms underlying this effect remain unclear.AIM To investigate the interventional role of hesperetin on N-methyl-N’-nitro-Nnitrosoguanidine(MNNG)-induced exosomes in inducing gastric carcinogenesis.METHODS Bioinformatics technology was used to identify the critical molecular components underlying hesperetin-mediated inhibition of MNNG induced gastric carcinogenesis through exosomal circular RNA.Biological experiments were conducted to validate these findings.RESULTS Exosomes derived from TGES-1 cells(TGES-1-EX)significantly enhanced the proliferation,migration,invasion,epithelial-mesenchymal transition(EMT),and stemness of GES-1 cells.The oncogenic potential of TGES-1-EX was significantly diminished following hesperetin pretreatment.TGES-1-EX with overexpressed or knocked down circ0008274 was extracted and GES-1 cells were treated in combination with hesperetin or alone.Our investigation revealed that hesperetin exerted significant inhibitory effects on MNNG-induced gastric carcinogenesis by exosomal circ0008274.Bioinformatics prediction identified microRNA(miR)-526b-5p as a potential miRNA binding to circ0008274.Functional experiments demonstrated that hesperetin may mediate its intervention in MNNG-induced gastric cancer initiation by targeting miR-526b-5p through exosomal circ0008274.TGES-1-EX circ0008274 promoted the proliferation,EMT,and cancer stem cell-like characteristics in GES-1 cells through miR-526b-5p-mediated regulatory mechanisms.CONCLUSION Hesperetin exerted an interventional effect on the gastric carcinogenesis process,particularly through the modulation of exosomal circ0008274 and its interaction with miR-526b-5p.展开更多
BACKGROUND Gastric cancer(GC)is among the most common malignant tumors and remains a leading cause of cancer-related mortality worldwide.Furthermore,exosomal miRNAs are regarded as promising noninvasive biomarkers for...BACKGROUND Gastric cancer(GC)is among the most common malignant tumors and remains a leading cause of cancer-related mortality worldwide.Furthermore,exosomal miRNAs are regarded as promising noninvasive biomarkers for diagnosing malignant tumors.AIM To investigate the expression of exosomal miR-17-92 clusters and develop a potential biomarker for GC diagnosis METHODS Exosomes were isolated from serum samples obtained from 72 GC patients and 20 healthy controls.The isolated exosomes were validated using transmission electron microscopy,nanoparticle tracking analysis,and western blotting.Exosomal RNA was then extracted,and the expression profile of the miR-17-92 cluster was analyzed using qRT-PCR.Statistical methods were employed to evaluate the relationship between the serum exosomal miR-17-92 cluster expre-ssion and the clinicopathological parameters of GC patients as well as to assess the diagnostic utility of these miRNAs.RESULTS The expression of four members of the exosomal miR-17-92 cluster-miR-17,miR-18,miR-19a,and miR-92-was significantly upregulated in the serum samples of patients with GC compared with those of healthy controls.The miR-17-92 cluster panel demonstrated substantially higher clinical diagnostic value for GC than any individual component or pair.Additionally,the expression of traditional tumor biomarkers-carcinoembryonic antigen and carbohydrate antigen 19-9-was significantly elevated in the serum of patients with GC compared with that of healthy controls.Each biomarker,whether alone or in combination,effectively differentiated the patients from healthy controls.Furthermore,a combined panel of the two traditional tumor biomarkers and the four miR-17-92 cluster members exhibited the highest diagnostic accuracy for GC.Elevated miR-17-92 expression was also strongly associated with tumor size,tumor depth,lymph node metastasis,distant metastasis,and tumor-node-metastasis stage.CONCLUSION Our findings revealed that the circulating exosomal miR-17-92 cluster may be used as a potential noninvasive biomarker to improve diagnostic efficiency for GC.展开更多
Most papillary thyroid carcinoma(PTC) patients have a good prognosis. However, lymph node metastasis(LNM), the most common manifestation of disease progression, is frequently associated with a poor prognosis.Neverthel...Most papillary thyroid carcinoma(PTC) patients have a good prognosis. However, lymph node metastasis(LNM), the most common manifestation of disease progression, is frequently associated with a poor prognosis.Nevertheless, few studies have focused on the underlying mechanisms of LNM. In the current study, we aimed to investigate the potential role of exosomal circRNAs that contribute to LNM in PTC. We identified 9 000 differentially expressed exosomal circRNAs in PTC patients with LNM, including 684 upregulated and 2 193 downregulated circRNAs. Functional enrichment analysis revealed that these differentially expressed circRNAs were primarily involved in a variety of molecular and signaling pathways correlated with PTC progression and LNM. Through bioinformatics analysis, we identified 14 circRNA-miRNA-mRNA networks related to LNM-associated signaling pathways in PTC. Moreover, both circTACC2-miR-7-EGFR and circBIRC6-miR-24-3p-BCL2L11 axes were verified for their potential involvement in PTC with LNM. Additionally, we identified four upregulated circRNA-related hub genes and eight hub genes correlated with downregulated circRNAs, some of which were validated as being potentially involved in LNM in PTC. Collectively, our findings provide a novel framework for an in-depth investigation of the function of dysregulated exosomal circRNAs and their potential as biomarkers in PTC patients with LNM.展开更多
BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,...BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,over 30%of patients suffer from drug-resistant epilepsy,which can lead to severe cognitive impairments and adverse psychosocial outcomes.AIM To explore the role of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy,providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy.METHODS Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each,and the TLE model group was established by injecting kainic acid.BMSCs were isolated from the mice,and exosomes were purified using ultracentrifugation.Exosomal miR-203 was identified and characterized using highthroughput sequencing and quantitative reverse-transcription polymerase chain reaction.The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using in vitro cell culture models.RESULTS Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice.In vitro investigations demonstrated the efficient internalization of these exosomes by hippocampal neurons,resulting in downregulation of suppressor of cytokine signaling 3 expression and activation of the nuclear factor kappaB pathway,ultimately leading to enhanced secretion of pro-inflammatory cytokines.CONCLUSION Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy.The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway,thus providing a potential avenue for the development of cell-free therapeutics.展开更多
BACKGROUND Colorectal cancer(CRC)is a leading cause of cancer-related morbidity and mor-tality globally.Exosomal microRNAs(miRNAs)are known to modulate tumor progression by influencing immune responses and vascular dy...BACKGROUND Colorectal cancer(CRC)is a leading cause of cancer-related morbidity and mor-tality globally.Exosomal microRNAs(miRNAs)are known to modulate tumor progression by influencing immune responses and vascular dynamics.However,the roles of specific exosomal miRNAs,such as miR-425-5p and miR-135b-3p,in CRC remain unclear.AIM To explore the specific roles and underlying mechanisms of exosomal miR-425-5p and miR-135b-3p in CRC progression.METHODS Differentially expressed miRNAs were identified through microarray analysis of exosomes isolated from CRC tissues and adjacent normal mucosa.Functional roles of miR-425-5p and miR-135b-3p were evaluated in vitro using macrophage polarization,T cell differentiation,and vascular permeability assays,as well as in vivo tumor formation and metastasis experiments in nude mice.Validation expe-riments were performed using CRC cell lines(HCT116 and SW620).RESULTS Exosomal miR-425-5p and miR-135b-3p were significantly upregulated in CRC compared to normal tissues.Functional studies revealed that miR-425-5p promo-tes macrophage M2-like polarization and suppresses T cell proinflammatory responses,while miR-135b-3p enhances vascular permeability and angiogenesis.Inhibition of these miRNAs in CRC cell-derived exosomes significantly supp-ressed tumor growth and metastasis in nude mice,reprogramming the tumor microenvironment toward reduced angiogenesis and enhanced immune acti-vation.Combined inhibition of both miRNAs resulted in the most pronounced effects.CONCLUSION Exosomal miR-425-5p and miR-135b-3p drive CRC progression by promoting immune suppression and vascular permeability.Their inhibition offers a promising strategy for modulating the tumor microenvironment and limiting CRC metastasis.展开更多
Objectives:Exosomal long noncoding RNAs(lncRNAs)might facilitate epithelial–mesenchymal transition(EMT)in liver cancer after transarterial chemoembolization(TACE),thereby enhancing tumor cell invasiveness and migrati...Objectives:Exosomal long noncoding RNAs(lncRNAs)might facilitate epithelial–mesenchymal transition(EMT)in liver cancer after transarterial chemoembolization(TACE),thereby enhancing tumor cell invasiveness and migration.This study investigated the prognostic role of plasma exosomal long noncoding RNA-plasmacytoma variant translocation 1(lncRNA-PVT1)in TACE treated hepatocellular carcinoma(HCC).Methods:Plasma exosomal lncRNA-PVT1 was evaluated via qPCR before and after TACE.Hepatoma cell behavior was investigated in different HCC cell lines.A lncRNA-PVT1 plasmid was synthesized and overexpressed,and si-lncRNA PVT1 was transfected into poorly invasive cells to reveal its influence on cell characteristics.The lncRNA-PVT1–FoxM1 interaction was elucidated using a double-luciferase reporter gene assay.The effect of miRNA-345-5p on minimally invasive hepatoma cells was assessed.Three experimental groups were established:poorly invasive cells,poorly invasive cells co-cultured with exosomes from hypoxia-induced highly invasive cells,and poorly invasive cells co-cultured with normal hepatocyte exosomes.Liver cancer cells were subcutaneously inoculated into nude mice,with subsequent observations of weight,tumor formation,and tumor size.Results:We identified two lncRNAs(lncRNA-PVT1 and GAPLINC)associated with EMT in the hypoxic microenvironment of liver cancer.Cox multivariate regression analysis was used to establish a prognostic model distinguishing high-and low-risk groups.Hypoxia-induced HepG2 exosomes significantly promoted EMT in poorly invasive HCC cells.LncRNA-PVT1 overexpression and silencing altered E-cadherin,vimentin,and FoxM1 expression,cell proliferation,invasion,migration,and apoptosis.miR-345-5p directly targeted lncRNA-PVT1 and FoxM1,affecting downstream targets.In vivo,co-culturing poorly invasive hepatoma cells with exosomes from highly invasive cells increased tumor volumes,upregulated lncRNA-PVT1,FoxM1,Ki67,and MMP9 expression,and downregulated miR-345-5p expression.Conclusions:Plasma exosomal lncRNA-PVT1 expression is upregulated in highly invasive cells post-hypoxia,potentially serving as a biomarker for evaluating liver cancer prognosis after TACE.Through a miRNA-345-5p-mediated competing endogenous RNA mechanism,it promotes EMT in poorly invasive cells,likely contributing to recurrence and metastasis post-HCC interventional embolization.展开更多
BACKGROUND Thin endometrium,leading cause of recurrent implantation failure and infertility,has been found to respond to exosomes.AIM To investigate the efficacy of exosomes in addressing the issue of thin endometrium...BACKGROUND Thin endometrium,leading cause of recurrent implantation failure and infertility,has been found to respond to exosomes.AIM To investigate the efficacy of exosomes in addressing the issue of thin endometrium.METHODS RNA sequencing and reverse transcription-quantitative polymerase chain reaction were employed to identify differentially expressed microRNAs(miRNAs)in human umbilical cord mesenchymal stem cell(hucMSC)treated with exosomes enriched with endometrial cell-derived components.Additionally,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to highlight significant enrichment in specific biological pathways,molecular functions,and cellular components.Transwell and wound healing assays were performed to assess migratory potential,and western blotting was detected protein level.RESULTS A total of 53 differentially expressed miRNAs were identified in hucMSC treated with exosomes enriched with endometrial cell-derived components,comprising 27 upregulated and 26 downregulated miRNAs,which includes miR-137-3p.Enhanced migratory potential was observed in the Transwell and wound healing assays,and western blotting confirmed the epithelial differentiation of hucMSC and the increased p-signal transducer and activator of transcription 3.These effects were attributed to the upregulation of miR-137-3p.CONCLUSION miR-137-3p in exosomes from hypoxia-affected endometrial epithelial cell stimulates the signal transducer and activator of transcription 3 signaling pathway,enhancing the migration and differentiation of hucMSC into endometrial epithelial cell.展开更多
Background:Oral cancer,a malignancy that is prevalent worldwide,is often diagnosed at an advanced stage.MicroRNAs(miRNAs)in circulating exosomes have emerged as promising cancer biomarkers.The role of miRNA let-7c-5p ...Background:Oral cancer,a malignancy that is prevalent worldwide,is often diagnosed at an advanced stage.MicroRNAs(miRNAs)in circulating exosomes have emerged as promising cancer biomarkers.The role of miRNA let-7c-5p in oral cancer remains underexplored,and its potential involvement in tumorigenesis warrants comprehensive investigation.Methods:Serum samples from 30 patients with oral cancer and 20 healthy controls were used to isolate exosomes and quantify their RNA content.Isolation of the exosomes was confirmed through transmission electron microscopy.Quantitative PCR was used to assess the miRNA profiles.The effects of let-7c-5p and TAGLN overexpression on oral cancer cell viability,migration,and invasion were analyzed via CCK-8 and Transwell assays.Moreover,we conducted mRNA sequencing of exosomal RNA from exosomes overexpressing let-7c-5p to delineate the gene expression profile and identify potential let-7c-5p target genes.Results:let-7c-5p was upregulated in serumderived exosomes of patients with oral cancer.Overexpression of let-7c-5p in the TCA8113 and CAL-27 cell lines enhanced their proliferative,migratory,and invasive capacities,and overexpression of let-7c-5p cell-derived exosomes promoted oral cancer cell invasiveness.Exosomal mRNA sequencing revealed 2,551 differentially expressed genes between control cell-derived exosomes and overexpressed let-7c-5p cell-derived exosomes.We further identified TAGLN as a direct target of let-7c-5p,which has been implicated in modulating the oncogenic potential of oral cancer cells.Overexpression of TAGLN reverses the promoting role of let-7c-5p on oral cancer cells.Conclusion:Our findings highlight the role of exosomal let-7c-5p in enhancing oral cancer cell aggressiveness by downregulating TAGLN expression,highlighting its potential as a diagnostic and therapeutic strategy.展开更多
文摘Gastrointestinal(GI)cancers,which predominantly manifest in the stomach,colorectum,liver,esophagus,and pancreas,accounting for approximately 35%of global cancer-related mortality.The advent of liquid biopsy has introduced a pivotal diagnostic modality for the early identification of premalignant GI lesions and incipient cancers.This non-invasive technique not only facilitates prompt therapeutic intervention,but also serves as a critical adjunct in prognosticating the likelihood of tumor recurrence.The wealth of circulating exosomes present in body fluids is often enriched with proteins,lipids,microRNAs,and other RNAs derived from tumor cells.These specific cargo components are reflective of processes involved in GI tumorigenesis,tumor progression,and response to treatment.As such,they represent a group of promising biomarkers for aiding in the diagnosis of GI cancer.In this review,we delivered an exhaustive overview of the composition of exosomes and the pathways for cargo sorting within these vesicles.We laid out some of the clinical evidence that supported the utilization of exosomes as diagnostic biomarkers for GI cancers and discussed their potential for clinical application.Furthermore,we addressed the challenges encountered when harnessing exosomes as diagnostic and predictive instruments in the realm of GI cancers.
文摘To illustrate the mechanisms of exosomal microRNAs(miRNAs)in common mental disorders,and explore their potential as diagnostic biomarkers and therapeutic targets,a systematic literature review of relevant studies on exosomal miRNAs in mental disorders was conducted.Data from cell experiments,animal models,and clinical studies were analyzed and combined to study the mechanisms and roles of exosomal miRNAs in various mental disorders.Research has shown that exosomal miRNAs,such as miR-146a,miR-223,miR-125b,and miR-451a,affect Alzheimer’s disease(AD)formation by regulating key pathways such as toll-like receptor 4(TLR4)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt),respectively.MiR-146a-5p regulates the occurrence of schizophrenia through the Notch pathway.TLR4 regulates miR-146a and miR-155 in major depressive disorder(MDD),and miR-144-5p regulates the disease through PI3K/Akt.Exosomal miR-484,miR-652-3p,miR-142-3p,miR-21a-3p,and miR-21-5p regulate key pathways in bipolar disorder,autism spectrum disorder,and Rett syndrome(e.g.,TLR4,PI3K/Akt,and Epha4/TEK)and have an influence on mental disorders.Exosomal miRNAs are involved in the occurrence of mental disorders through TLR4,PI3K/Akt,and Epha4/TEK pathways,which provides a clearer understanding of disease cognition.Of these pathways,the TLR4 and PI3K/Akt pathways play a role in AD,MDD,and neurodevelopmental disorders,which can be used as an effective breakthrough in the study of mental disorders.Exosomal miRNAs could also serve as diagnostic biomarkers and therapeutic targets,providing new insights into precise interventions for mental disorders.
基金supported by the National Natural Science Foundation of China(Grant No.:81702242).
文摘Exosomal circular RNA(circRNAs)are pivotal in cancer biology,and tumor pathophysiology.These stable,non-coding RNAs encapsulated in exosomes participated in cancer progression,tumor growth,metastasis,drug sensitivity and the tumor microenvironment(TME).Their presence in bodily fluids positions them as potential non-invasive biomarkers,revealing the molecular dynamics of cancers.Research in exosomal circRNAs is reshaping our understanding of neoplastic intercellular communication.Exploiting the natural properties of exosomes for targeted drug delivery and disrupting circRNA-mediated pro-tumorigenic signaling can develop new treatment modalities.Therefore,ongoing exploration of exosomal circRNAs in cancer research is poised to revolutionize clinical management of cancer.This emerging field offers hope for significant breakthroughs in cancer care.This review underscores the critical role of exosomal circRNAs in cancer biology and drug resistance,highlighting their potential as non-invasive biomarkers and therapeutic targets that could transform the clinical management of cancer.
基金Supported by the General Program of the Natural Science Foundation of Guangdong Province,No.2025A1515011163.
文摘This article comments on the study by Zhang et al,which proposed that exosomes derived from hypoxia-injured endometrial epithelial cells promote human umbilical cord mesenchymal stem cell migration and differentiation into endo-metrial epithelial cells via exosomal miR-137-3p.The authors demonstrated that miR-137-3p targets ubiquitin protein ligase E3C and activates signal transducer and activator of transcription 3 signaling,thereby driving epithelial lineage transition.While this study expands our understanding of exosome-mediated intercellular communication in endometrial repair,several key gaps remain.Notably,microRNA(miRNA)profiling was performed in human umbilical cord mesenchymal stem cells post-exosome treatment,not in the exosomes derived from hypoxia-injured endometrial epithelial cell themselves,leaving open whether miR-137-3p is directly transferred or indirectly induced.In addition,data on exosome characterization were unavailable,and the rationale for selecting miR-137-3p over other differentially expressed miRNAs was not well justified.Future studies should include direct exosomal miRNA content analysis,in vivo validation,and deeper mechanistic exploration of the ubiquitin protein ligase E3C-signal transducer and activator of transcription 3 ubiquitination axis to establish the clinical and biological relevance of this pathway.
基金Natural Science Foundation of Xinjiang Uygur Autonomous Region(2022D01C803).
文摘Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms.Methods:Exosomes were isolated from melanoma cell lines A375 and A2058,and their effects on the proliferation,migration,and angiogenesis of human umbilical vein endothelial cells(HUVECs)were examined.The interaction between miR-424-5p and its target gene,large tumor suppressor kinase 2(LATS2),was analyzed using luciferase reporter assays and functional experiments.In vivo,tumor growth and angiogenesis were studied in a xenograft model using nude mice.Results:Melanoma cell-derived exosomes could be internalized by HUVECs,which promoted proliferation,migration,and angiogenesis.miR-424-5p was highly expressed in melanoma cells and their exosomes,and its inhibition in exosomes suppressed HUVEC proliferation,migration,and angiogenesis.LATS2 was identified as a direct target of miR-424-5p,and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions.In vivo,exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models.Conclusions:Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2,contributing to melanoma progression.Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma.
文摘This study by Zhang et al elucidates the role of exosome miR-137-3p targeting ubiquitin protein ligase E3C to activate signal transducer and activator of transcription 3 under hypoxia conditions,thereby promoting the migration and differentiation of human umbilical cord mesenchymal stem cells to endometrial epithelial cells.It emphasizes that exosomal miR-137-3p/ubiquitin protein ligase E3C/signal transducer and activator of transcription 3 axis is a promising pathway for endometrial regeneration.This article introduced the therapeutic potential of exosomal microRNAs in regenerative medicine while underscoring the need for standardized protocols in optimizing exosome delivery and validating molecular pathways for clinical translation.
基金support from the Miami Project to Cure Paralysis,the Buoniconti Fund,and the Interdisciplinary Stem Cell Institute(to AK,WDD,JDG,and ADL)the unconditional support of Dean Henri Ford of the Leonard M.Miller School of Medicine at the University of Miami.
文摘Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann cell function may also be impaired.Recently,important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported.This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles,marking,to our knowledge,the first instance of such treatment.An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis.After initial diagnosis,the patient underwent a combination of generic riluzole,sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis,and taurursodiol.The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function.We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired(senescent)and that exposure of the patient’s Schwann cells to allogeneic Schwann cell-derived exosomal vesicles,cultured expanded from a cadaver donor improved their growth capacity in vitro.After a period of observation lasting 10 weeks,during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored,the patient received weekly consecutive infusions of 1.54×1012(×2),and then consecutive infusions of 7.5×1012(×6)allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco’s phosphate-buffered saline.None of the infusions were associated with adverse events such as infusion reactions(allergic or otherwise)or changes in vital signs.Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend.A more sensitive in-house assay suggested possible inflammasome activation during the disease course.A trend for clinical stabilization was observed during the infusion period.Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles.Initial findings suggest that this approach is safe.
基金Supported by Basic Research Plan of Yunnan Province,No.202201AT070059National Natural Science Foundation of China,No.81760407Science and Technology Talent and Platform Plan of Yunnan Provincial Department of Science and Technology,No.202205AC160066.
文摘BACKGROUND There is currently no effective treatment for osteoarthritis(OA),which is the most common joint disorder leading to disability.Although human umbilical cord mesenchymal stem cells(hUC-MSCs)are promising OA treatments,their use is limited by the condition itself,and understanding of the underlying mechanisms of OA is lacking.AIM To explore the specific molecular mechanism by which hUC-MSC-derived exosomal miR-199a-3p improves OA.METHODS Sodium iodoacetate was injected into rat articulations to construct an animal model of OA.Interleukin(IL)-1βwas used to induce human chondrocytes(CHON-001)to construct an OA chondrocyte model.Exosomes in hUC-MSCs were isolated using Ribo™Exosome Isolation Reagent.Real-time reverse transcriptase-polymerase chain reaction and western blotting were used to detect the expression of related genes and proteins,and damage to CHON-001 cells and rat articular cartilage tissue was evaluated by enzyme-linked immunosorbent assay,terminal deoxynucleotidyl transferase-mediated deoxyuridine tripho-sphate-nick end labelling staining and hematoxylin and eosin staining.RESULTS hUC-MSC-derived exosomes(hUC-MSC-Exos)inhibited the expression of IL-1β-induced inflammatory cytokines,namely,IL-6,IL-8 and tumor necrosis factor-α.hUC-MSC-Exos also improved the viability but inhibited the apoptosis of CHON-001 cells,improved the pathological condition of articular cartilage tissue and alleviated the development of OA in vivo.Mechanistically,hUC-MSC-Exos downregulated the expression of mitogen-activated protein kinase 4 by delivering miR-199a-3p,thereby inhibiting the activation of the nuclear factor-kappaB signaling pathway,alleviating IL-1β-induced chondrocyte inflammation and apoptosis,and ultimately improving the development of OA.CONCLUSION hUC-MSC-derived exosomal miR-199a-3p alleviates OA by inhibiting the mitogen-activated protein kinase 4/nuclear factor-kappaB signaling pathway.The present findings suggest that miR-199a-3p delivery by hUC-MSCExos may be a novel strategy for the treatment of OA.
基金USA National Institutes of Health Grant(R01-HL-139547,to JF)USA VA Grants(1I01BX004838 and IK6BX004211,to JF)+1 种基金National Natural Science Foundation of China(82002087,to TG)Shenzhen Science and Technology Program(JCYJ20210324134602008,to TG)。
文摘Sepsis,a severe systemic inflammatory response to infection,remains a leading cause of morbidity and mortality worldwide.Exosomes,as mediators of intercellular communication,play a pivotal role in the pathogenesis of sepsis through modulating immune responses,metabolic reprogramming,coagulopathy,and organ dysfunction.This review highlights the emerging significance of exosomes in these processes.Initially,it provides an in-depth insight into exosome biogenesis and characterization,laying the groundwork for understanding their diverse and intricate functions.Subsequently,it explores the regulatory roles of exosomes in various immune cells such as neutrophils,macrophages,dendritic cells,T cells,and B cells.This analysis elucidates how exosomes are pivotal in modulating immune responses,thus contributing to the complexity of sepsis pathophysiology.Additionally,this review delves into the role of exosomes in the regulation of metabolism and subsequent organ dysfunction in sepsis.It also establishes a connection between exosomes and the coagulation cascade,which affects endothelial integrity and promotes thrombogenesis in sepsis.Moreover,the review discusses the dual role of exosomes in the progression and resolution of sepsis,exploring their complex involvement in inflammation and healing processes.Furthermore,it underscores their potential as biomarkers and therapeutic targets.Understanding these mechanisms presents new opportunities for novel interventions to mitigate the severe outcomes of sepsis,emphasizing the therapeutic promise of exosome research in critical care settings.
基金supported by the National Natural Science Foundation of China(No.82203056)the Natural Science Foundation of Liaoning Province(No.2023-BS-167)+1 种基金the Science and Technology Talent Innovation Support Plan of Dalian(NO.2022RQ091)the“1+X”program for Clinical Competency enhancement-Clinical Research Incubation Project of the Second Hospital of Dalian Medical University(No.2022LCYJYB01)。
文摘The intricate interactions between immune cells and tumors exert a profound influence on cancer progression and therapeutic efficacy.Within the tumor microenvironment,exosomes have emerged as pivotal mediators of intercellular communication,with their cargo of non-coding RNAs(ncRNAs)serving as key regulatory elements.This review examines the multifaceted roles of immune cell-derived exosomal ncRNAs in tumor biology.The involvement of various immune cells,including T cells,B cells,natural killer cells,macrophages,neutrophils,and myeloid-derived suppressor cells,in utilizing exosomal ncRNAs to regulate tumor initiation and progression is explored.Additionally,the biogenesis and delivery mechanisms of these immune cell-derived exosomal ncRNAs are discussed,alongside their potential clinical applications in cancer.
文摘BACKGROUND Exosomal microRNAs(miRNAs)have emerged as promising biomarkers for cancer diagnosis due to their stability,tumor specificity,and accessibility.How-ever,the diagnostic potential of serum exosomal miRNAs in metastatic pancreatic cancer remains underexplored.AIM To investigate the diagnostic potential of serum exosomal miRNAs in metastatic pancreatic cancer.METHODS A total of 36 patients were enrolled,comprising 8 patients in the discovery phase(4 with metastatic and 4 with non-metastatic pancreatic cancer)and 28 in the validation cohort(15 non-metastatic and 13 metastatic cases).Exosomes were isolated using the exoEasy Maxi Kit and characterized by transmission electron microscopy,nanoparticle tracking analysis,and western blotting.High-throu-ghput sequencing was conducted to identify differentially expressed serum exosomal miRNAs,which were subsequently validated using TaqMan probe-based reverse transcription-quantitative polymerase chain reaction.Bioinformatic analyses were performed to predict downstream target genes and explore their roles in metastatic progression.RESULTS Transmission electron microscopy revealed that the isolated exosomes were predominantly round or oval with well-defined membrane boundaries.Nano-particle tracking analysis showed a peak particle size of approximately 138 nm,accounting for 99.2%of total particles,consistent with the typical size range of exosomes.Western blotting confirmed the expression of exosome-specific markers CD63 and CD81.High-throughput sequencing identified 42 differentially expressed exosomal miRNAs between metastatic and non-metastatic groups.Among them,hsa-let-7f-5p was significantly upregulated in metastatic pancreatic cancer(P=0.007),as validated by reverse transcription-quantitative polymerase chain reaction.Target gene prediction indicated that hsa-let-7f-5p may be involved in metastasis through its interactions with nerve growth factor,cyclin-dependent kinase inhibitor 1A,high mobility group AT-hook 2,insulin-like growth factor 2 mRNA-binding protein 1,and insulin-like growth factor 2 mRNA-binding protein 3.CONCLUSION The elevated expression of serum exosomal hsa-let-7f-5p in metastatic pancreatic cancer suggests its potential as a non-invasive biomarker for distinguishing metastatic from non-metastatic disease.
基金Supported by the National Natural Science Foundation of China,No.81602792 and No.12205215and Science and Technology Program of Nantong,No.JC12022103.
文摘BACKGROUND Radiation resistance limits radiotherapy efficacy in esophageal squamous cell carcinoma(ESCC).The tumor microenvironment,particularly adipocytes,plays a role in promoting cancer progression.Extracellular vesicles and microRNAs(miRNAs)regulate gene expression and hold prognostic potential for esophageal carcinoma.Elucidating radioresistance mechanisms and identifying radiosensitization targets can help enhance radiotherapy efficacy for esophageal cancer.AIM To investigate the potential role of miRNAs derived from adipocyte exosomes as prognostic markers for radiotherapy efficacy in ESCC.METHODS Free adipocytes were isolated from human thoracic adipose tissue.A co-culture model of adipocytes and ESCC cells was established to observe colony formation and cell survival post-irradiation.ESCC cell apoptosis was assessed by flow cytometry.Western Blot and immunofluorescence assays were performed to evaluate DNA damage in ESCC cells post-irradiation.Adipocyte-derived exosomes were isolated by ultracentrifugation and identified by electron microscopy.A similar set of experiments was performed on ESCC cells to analyze cell survival,apoptosis,and DNA damage post-radiation exposure.Exosomes from adipose tissue and serum exosomes from ESCC patients pre-and post-radiotherapy were subjected to high-throughput miRNA-sequencing and validated using real-time quantitative polymerase chain reaction.The correlation between potential target miRNAs and the short-term prognosis of radiotherapy in ESCC was evaluated by receiver operating characteristic curve analysis.RESULTS Co-culturing adipocytes with ESCC cells enhanced radioresistance,as evidenced by increased colony formation.Adipocyte co-culture reduced ESCC cell apoptosis and DNA damage post-radiation.Adipocyte-derived exosomes similarly conferred radioresistance in ESCC cells,decreasing apoptosis and DNA damage post-irradiation.Highthroughput miRNA-sequencing identified miR-660-5p in serum and adipose tissue exosomes.Patients with high expression of serum exosome miR-660-5p showed poor prognosis after radiotherapy.CONCLUSION Adipocyte-derived exosomal miR-660-5p is a potential biomarker for evaluating radiotherapy efficacy in ESCC.
基金Supported by the National Natural Science Foundation of China,No.81602883Technology Development Project of Jiangsu University,No.20220516Postgraduate Research and Practice Innovation Program of Jiangsu Province,No.KYCX233765.
文摘BACKGROUND Hesperetin,a flavonoid predominantly present in citrus fruits,exhibits significant intervention effects on both the initiation and progression of gastric cancer.However,the specific mechanisms underlying this effect remain unclear.AIM To investigate the interventional role of hesperetin on N-methyl-N’-nitro-Nnitrosoguanidine(MNNG)-induced exosomes in inducing gastric carcinogenesis.METHODS Bioinformatics technology was used to identify the critical molecular components underlying hesperetin-mediated inhibition of MNNG induced gastric carcinogenesis through exosomal circular RNA.Biological experiments were conducted to validate these findings.RESULTS Exosomes derived from TGES-1 cells(TGES-1-EX)significantly enhanced the proliferation,migration,invasion,epithelial-mesenchymal transition(EMT),and stemness of GES-1 cells.The oncogenic potential of TGES-1-EX was significantly diminished following hesperetin pretreatment.TGES-1-EX with overexpressed or knocked down circ0008274 was extracted and GES-1 cells were treated in combination with hesperetin or alone.Our investigation revealed that hesperetin exerted significant inhibitory effects on MNNG-induced gastric carcinogenesis by exosomal circ0008274.Bioinformatics prediction identified microRNA(miR)-526b-5p as a potential miRNA binding to circ0008274.Functional experiments demonstrated that hesperetin may mediate its intervention in MNNG-induced gastric cancer initiation by targeting miR-526b-5p through exosomal circ0008274.TGES-1-EX circ0008274 promoted the proliferation,EMT,and cancer stem cell-like characteristics in GES-1 cells through miR-526b-5p-mediated regulatory mechanisms.CONCLUSION Hesperetin exerted an interventional effect on the gastric carcinogenesis process,particularly through the modulation of exosomal circ0008274 and its interaction with miR-526b-5p.
基金Supported by National Natural Science Foundation of China,No.81902805Jiangsu Provincial Natural Science Foundation,No.BK20190174+1 种基金Suzhou Gusu Health Talent Research Project,No.GSWS2023039Suzhou Medical Youth Talents Project,No.Qngg2024004.
文摘BACKGROUND Gastric cancer(GC)is among the most common malignant tumors and remains a leading cause of cancer-related mortality worldwide.Furthermore,exosomal miRNAs are regarded as promising noninvasive biomarkers for diagnosing malignant tumors.AIM To investigate the expression of exosomal miR-17-92 clusters and develop a potential biomarker for GC diagnosis METHODS Exosomes were isolated from serum samples obtained from 72 GC patients and 20 healthy controls.The isolated exosomes were validated using transmission electron microscopy,nanoparticle tracking analysis,and western blotting.Exosomal RNA was then extracted,and the expression profile of the miR-17-92 cluster was analyzed using qRT-PCR.Statistical methods were employed to evaluate the relationship between the serum exosomal miR-17-92 cluster expre-ssion and the clinicopathological parameters of GC patients as well as to assess the diagnostic utility of these miRNAs.RESULTS The expression of four members of the exosomal miR-17-92 cluster-miR-17,miR-18,miR-19a,and miR-92-was significantly upregulated in the serum samples of patients with GC compared with those of healthy controls.The miR-17-92 cluster panel demonstrated substantially higher clinical diagnostic value for GC than any individual component or pair.Additionally,the expression of traditional tumor biomarkers-carcinoembryonic antigen and carbohydrate antigen 19-9-was significantly elevated in the serum of patients with GC compared with that of healthy controls.Each biomarker,whether alone or in combination,effectively differentiated the patients from healthy controls.Furthermore,a combined panel of the two traditional tumor biomarkers and the four miR-17-92 cluster members exhibited the highest diagnostic accuracy for GC.Elevated miR-17-92 expression was also strongly associated with tumor size,tumor depth,lymph node metastasis,distant metastasis,and tumor-node-metastasis stage.CONCLUSION Our findings revealed that the circulating exosomal miR-17-92 cluster may be used as a potential noninvasive biomarker to improve diagnostic efficiency for GC.
基金National Natural Science Foundation of China (Grant No. 81800698)Jiangsu Provincial Medical Key Discipline Cultivation Unit (Grant No. JSDW202241)+1 种基金Research Project of Jiangsu Commission of Health (Grant No. H2023053)Zhenjiang Science and the Technology Planning Project (Grant Nos. SH2023006and SH2023008)。
文摘Most papillary thyroid carcinoma(PTC) patients have a good prognosis. However, lymph node metastasis(LNM), the most common manifestation of disease progression, is frequently associated with a poor prognosis.Nevertheless, few studies have focused on the underlying mechanisms of LNM. In the current study, we aimed to investigate the potential role of exosomal circRNAs that contribute to LNM in PTC. We identified 9 000 differentially expressed exosomal circRNAs in PTC patients with LNM, including 684 upregulated and 2 193 downregulated circRNAs. Functional enrichment analysis revealed that these differentially expressed circRNAs were primarily involved in a variety of molecular and signaling pathways correlated with PTC progression and LNM. Through bioinformatics analysis, we identified 14 circRNA-miRNA-mRNA networks related to LNM-associated signaling pathways in PTC. Moreover, both circTACC2-miR-7-EGFR and circBIRC6-miR-24-3p-BCL2L11 axes were verified for their potential involvement in PTC with LNM. Additionally, we identified four upregulated circRNA-related hub genes and eight hub genes correlated with downregulated circRNAs, some of which were validated as being potentially involved in LNM in PTC. Collectively, our findings provide a novel framework for an in-depth investigation of the function of dysregulated exosomal circRNAs and their potential as biomarkers in PTC patients with LNM.
文摘BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,over 30%of patients suffer from drug-resistant epilepsy,which can lead to severe cognitive impairments and adverse psychosocial outcomes.AIM To explore the role of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy,providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy.METHODS Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each,and the TLE model group was established by injecting kainic acid.BMSCs were isolated from the mice,and exosomes were purified using ultracentrifugation.Exosomal miR-203 was identified and characterized using highthroughput sequencing and quantitative reverse-transcription polymerase chain reaction.The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using in vitro cell culture models.RESULTS Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice.In vitro investigations demonstrated the efficient internalization of these exosomes by hippocampal neurons,resulting in downregulation of suppressor of cytokine signaling 3 expression and activation of the nuclear factor kappaB pathway,ultimately leading to enhanced secretion of pro-inflammatory cytokines.CONCLUSION Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy.The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway,thus providing a potential avenue for the development of cell-free therapeutics.
文摘BACKGROUND Colorectal cancer(CRC)is a leading cause of cancer-related morbidity and mor-tality globally.Exosomal microRNAs(miRNAs)are known to modulate tumor progression by influencing immune responses and vascular dynamics.However,the roles of specific exosomal miRNAs,such as miR-425-5p and miR-135b-3p,in CRC remain unclear.AIM To explore the specific roles and underlying mechanisms of exosomal miR-425-5p and miR-135b-3p in CRC progression.METHODS Differentially expressed miRNAs were identified through microarray analysis of exosomes isolated from CRC tissues and adjacent normal mucosa.Functional roles of miR-425-5p and miR-135b-3p were evaluated in vitro using macrophage polarization,T cell differentiation,and vascular permeability assays,as well as in vivo tumor formation and metastasis experiments in nude mice.Validation expe-riments were performed using CRC cell lines(HCT116 and SW620).RESULTS Exosomal miR-425-5p and miR-135b-3p were significantly upregulated in CRC compared to normal tissues.Functional studies revealed that miR-425-5p promo-tes macrophage M2-like polarization and suppresses T cell proinflammatory responses,while miR-135b-3p enhances vascular permeability and angiogenesis.Inhibition of these miRNAs in CRC cell-derived exosomes significantly supp-ressed tumor growth and metastasis in nude mice,reprogramming the tumor microenvironment toward reduced angiogenesis and enhanced immune acti-vation.Combined inhibition of both miRNAs resulted in the most pronounced effects.CONCLUSION Exosomal miR-425-5p and miR-135b-3p drive CRC progression by promoting immune suppression and vascular permeability.Their inhibition offers a promising strategy for modulating the tumor microenvironment and limiting CRC metastasis.
基金the Ethics Committee of the West China Hospital,Sichuan University(No.2018256)the Animal Ethical and Welfare Committee of Sichuan University in China(No.20211218A).
文摘Objectives:Exosomal long noncoding RNAs(lncRNAs)might facilitate epithelial–mesenchymal transition(EMT)in liver cancer after transarterial chemoembolization(TACE),thereby enhancing tumor cell invasiveness and migration.This study investigated the prognostic role of plasma exosomal long noncoding RNA-plasmacytoma variant translocation 1(lncRNA-PVT1)in TACE treated hepatocellular carcinoma(HCC).Methods:Plasma exosomal lncRNA-PVT1 was evaluated via qPCR before and after TACE.Hepatoma cell behavior was investigated in different HCC cell lines.A lncRNA-PVT1 plasmid was synthesized and overexpressed,and si-lncRNA PVT1 was transfected into poorly invasive cells to reveal its influence on cell characteristics.The lncRNA-PVT1–FoxM1 interaction was elucidated using a double-luciferase reporter gene assay.The effect of miRNA-345-5p on minimally invasive hepatoma cells was assessed.Three experimental groups were established:poorly invasive cells,poorly invasive cells co-cultured with exosomes from hypoxia-induced highly invasive cells,and poorly invasive cells co-cultured with normal hepatocyte exosomes.Liver cancer cells were subcutaneously inoculated into nude mice,with subsequent observations of weight,tumor formation,and tumor size.Results:We identified two lncRNAs(lncRNA-PVT1 and GAPLINC)associated with EMT in the hypoxic microenvironment of liver cancer.Cox multivariate regression analysis was used to establish a prognostic model distinguishing high-and low-risk groups.Hypoxia-induced HepG2 exosomes significantly promoted EMT in poorly invasive HCC cells.LncRNA-PVT1 overexpression and silencing altered E-cadherin,vimentin,and FoxM1 expression,cell proliferation,invasion,migration,and apoptosis.miR-345-5p directly targeted lncRNA-PVT1 and FoxM1,affecting downstream targets.In vivo,co-culturing poorly invasive hepatoma cells with exosomes from highly invasive cells increased tumor volumes,upregulated lncRNA-PVT1,FoxM1,Ki67,and MMP9 expression,and downregulated miR-345-5p expression.Conclusions:Plasma exosomal lncRNA-PVT1 expression is upregulated in highly invasive cells post-hypoxia,potentially serving as a biomarker for evaluating liver cancer prognosis after TACE.Through a miRNA-345-5p-mediated competing endogenous RNA mechanism,it promotes EMT in poorly invasive cells,likely contributing to recurrence and metastasis post-HCC interventional embolization.
基金Supported by the National High Level Hospital Clinical Research Funding,No.2022-PUMCH-B-080 and No.2022-PUMCH-C-064.
文摘BACKGROUND Thin endometrium,leading cause of recurrent implantation failure and infertility,has been found to respond to exosomes.AIM To investigate the efficacy of exosomes in addressing the issue of thin endometrium.METHODS RNA sequencing and reverse transcription-quantitative polymerase chain reaction were employed to identify differentially expressed microRNAs(miRNAs)in human umbilical cord mesenchymal stem cell(hucMSC)treated with exosomes enriched with endometrial cell-derived components.Additionally,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to highlight significant enrichment in specific biological pathways,molecular functions,and cellular components.Transwell and wound healing assays were performed to assess migratory potential,and western blotting was detected protein level.RESULTS A total of 53 differentially expressed miRNAs were identified in hucMSC treated with exosomes enriched with endometrial cell-derived components,comprising 27 upregulated and 26 downregulated miRNAs,which includes miR-137-3p.Enhanced migratory potential was observed in the Transwell and wound healing assays,and western blotting confirmed the epithelial differentiation of hucMSC and the increased p-signal transducer and activator of transcription 3.These effects were attributed to the upregulation of miR-137-3p.CONCLUSION miR-137-3p in exosomes from hypoxia-affected endometrial epithelial cell stimulates the signal transducer and activator of transcription 3 signaling pathway,enhancing the migration and differentiation of hucMSC into endometrial epithelial cell.
文摘Background:Oral cancer,a malignancy that is prevalent worldwide,is often diagnosed at an advanced stage.MicroRNAs(miRNAs)in circulating exosomes have emerged as promising cancer biomarkers.The role of miRNA let-7c-5p in oral cancer remains underexplored,and its potential involvement in tumorigenesis warrants comprehensive investigation.Methods:Serum samples from 30 patients with oral cancer and 20 healthy controls were used to isolate exosomes and quantify their RNA content.Isolation of the exosomes was confirmed through transmission electron microscopy.Quantitative PCR was used to assess the miRNA profiles.The effects of let-7c-5p and TAGLN overexpression on oral cancer cell viability,migration,and invasion were analyzed via CCK-8 and Transwell assays.Moreover,we conducted mRNA sequencing of exosomal RNA from exosomes overexpressing let-7c-5p to delineate the gene expression profile and identify potential let-7c-5p target genes.Results:let-7c-5p was upregulated in serumderived exosomes of patients with oral cancer.Overexpression of let-7c-5p in the TCA8113 and CAL-27 cell lines enhanced their proliferative,migratory,and invasive capacities,and overexpression of let-7c-5p cell-derived exosomes promoted oral cancer cell invasiveness.Exosomal mRNA sequencing revealed 2,551 differentially expressed genes between control cell-derived exosomes and overexpressed let-7c-5p cell-derived exosomes.We further identified TAGLN as a direct target of let-7c-5p,which has been implicated in modulating the oncogenic potential of oral cancer cells.Overexpression of TAGLN reverses the promoting role of let-7c-5p on oral cancer cells.Conclusion:Our findings highlight the role of exosomal let-7c-5p in enhancing oral cancer cell aggressiveness by downregulating TAGLN expression,highlighting its potential as a diagnostic and therapeutic strategy.
