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
BACKGROUNDMultiple exosomal microRNAs were reported to have a significant role incolorectal cancer (CRC) cells. The function and mechanism of exosomal miR-191in CRC have not been clearly elucidated.AIMTo explore the r...BACKGROUNDMultiple exosomal microRNAs were reported to have a significant role incolorectal cancer (CRC) cells. The function and mechanism of exosomal miR-191in CRC have not been clearly elucidated.AIMTo explore the roles of miR-191 in CRC.METHODSSupernatant exosomes from CRC cells were extracted and identified. After coculture,macrophage polarization was determined using flow cytometry for themarkers cluster of differentiation (CD) 68 and CD163, enzyme-linked immunosorbentassay for the cytokines interleukin (IL)-4 and IL-10, western blotting forchitinase-like protein 3 and arginase-1 expression, and immunofluorescentstaining for 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine perchlorate.Reactive oxygen species (ROS) level, ferroptosis-related proteins (SLC7A11 andGPX4), and apoptosis were determined with flow cytometry, western blotting,and TUNEL staining. We performed in vivo experiments to determine the functionof exosomal miR-191 and M2 macrophage polarization.RESULTSWe successfully isolated exosomes from CRC cells. Inhibition of miR-191 in CRCcells suppressed M2 polarization of macrophages. After coculture of macrophages,inhibition of miR-191 induced ROS production, ferroptosis, and apoptosisof CRC cells. Silencing of exosomal miR-191 from CRC cells prevented M2polarization of macrophages, and weakened CRC development by inducingferroptosis. Exosomal miR-191 accelerated cancer progression in CRC nude miceby promoting M2 polarization of macrophages. CONCLUSIONInhibition of exosomal miR-191 attenuated CRC progression by inducing ferroptosis in macrophages. This studyrevealed a novel mechanism by which exosomal miR-191 modulates the tumor microenvironment.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
BACKGROUND Glucotoxic pancreaticβcells impair glycogenesis of hepatocytes,with exosomes serving as novel mediators.miR-375-3p is the most abundant miRNA in the pancreas and critical forβ-cell function,but whether it...BACKGROUND Glucotoxic pancreaticβcells impair glycogenesis of hepatocytes,with exosomes serving as novel mediators.miR-375-3p is the most abundant miRNA in the pancreas and critical forβ-cell function,but whether it plays a role in pancreasliver crosstalk remains unclear.AIM To investigate the role of miR-375-3p,a key regulator of pancreaticβcells,in remotely regulating hepatocyte glycogenesis via exosomes.METHODS Mice fed a high-fat diet(HFD)served as animal models,and mouse primary pancreatic islet cells and theβ-cell line MIN-6 were used as cellular models.miR-375-3p expression in pancreatic cells,hepatocytes and exosomes was detected in both animal and cellular models.Transwell assays,exosome treatment,and exosome-depleted supernatant culture were used to investigate the role of exosomal miR-375-3p in pancreatic-hepatocyte crosstalk.The AKT/GSK signaling pathway and hepatic glycogen content were used as indicators to evaluate hepatocyte glycogenesis.Luciferase reporter assays were used to evaluate the downstream targets of miR-375-3p.RESULTS Increased levels of miR-375-3p were observed in both the pancreas and liver of HFD-fed mice.In contrast to the in vivo results,high-glucose treatment exclusively increased the expression of miR-375-3p in pancreatic cells but had no effect on hepatocytes.Furthermore,hepatocytes treated with the supernatant and exosomes from glucotoxic pancreatic cells presented elevated expression of miR-375-3p.Additionally,exosomal transfer of miR-375-3p from pancreatic cells to hepatocytes suppressed the AKT/GSK signaling pathway,thereby reducing the hepatic glycogen content.Luciferase analysis indicated that the recombination signal binding protein for the immunoglobulin kappa J region(Rbpj)is a target gene of miR-375-3p.Rbpj inhibition impaired hepatic glycogenesis,and Rbpj overexpression reversed the effect on glycogenesis induced by miR-375-3p.CONCLUSION Pancreatic cell-derived miR-375-3p can be delivered to hepatocytes via exosomes and inhibits hepatocyte glycogenesis by targeting Rbpj.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
Mesenchymal stem cells(MSCs)are known for their ability to differentiate into various cell lineages,including osteoblasts(bone-forming cells),and for their significant paracrine effects.Among their secreted products,e...Mesenchymal stem cells(MSCs)are known for their ability to differentiate into various cell lineages,including osteoblasts(bone-forming cells),and for their significant paracrine effects.Among their secreted products,exosomes have gained considerable attention as nanoscale carriers of bioactive molecules such as non-coding RNAs(ncRNAs).These ncRNAs,including microRNAs,long ncRNAs,and circular ncRNAs,are critical regulators of gene expression and cellular functions.Moreover,MSC-derived exosomes not only offer advantages such as targeted delivery,reduced immunogenicity,and protection of cargo material,but also carry ncRNAs that have therapeutic and diagnostic potential in bone-related disorders.Emerging evidence has highlighted the role of MSC-derived exosomal ncRNAs in osteogenesis,bone remodeling,and intercellular signaling in the bone microenvironment.This review consolidates recent research on the role of MSC-derived exosomal ncRNAs in maintaining bone homeostasis and bone-related disorders via various signaling pathways and epigenetic modifications.Furthermore,we explore the therapeutic potential of MSC-derived exosomal ncRNAs as biomarkers and therapeutic targets.This comprehensive review offers key insights into the regulatory roles of MSC-derived exosomal ncRNAs in bone biology and their clinical significance in bone-related diseases.展开更多
GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte ...GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte function,and preserving the extracellular matrix both in vitro and in vivo.Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagyrelated gene that is downregulated in OA.Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production,reduced lipid peroxidation and reactive oxygen species,increased mitophagy markers(PINK1,Parkin,LC3-II/I),decreased p62 levels,and alleviated cartilage degeneration in a rat destabilization model.A causal role for mitophagy is supported by coimmunoprecipitation experiments confirming a GRPEL1-PINK1 interaction,and by PINK1 knockdown,which diminishes the protective effects of GRPEL1.These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.展开更多
BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and ...BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.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.
文摘BACKGROUNDMultiple exosomal microRNAs were reported to have a significant role incolorectal cancer (CRC) cells. The function and mechanism of exosomal miR-191in CRC have not been clearly elucidated.AIMTo explore the roles of miR-191 in CRC.METHODSSupernatant exosomes from CRC cells were extracted and identified. After coculture,macrophage polarization was determined using flow cytometry for themarkers cluster of differentiation (CD) 68 and CD163, enzyme-linked immunosorbentassay for the cytokines interleukin (IL)-4 and IL-10, western blotting forchitinase-like protein 3 and arginase-1 expression, and immunofluorescentstaining for 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine perchlorate.Reactive oxygen species (ROS) level, ferroptosis-related proteins (SLC7A11 andGPX4), and apoptosis were determined with flow cytometry, western blotting,and TUNEL staining. We performed in vivo experiments to determine the functionof exosomal miR-191 and M2 macrophage polarization.RESULTSWe successfully isolated exosomes from CRC cells. Inhibition of miR-191 in CRCcells suppressed M2 polarization of macrophages. After coculture of macrophages,inhibition of miR-191 induced ROS production, ferroptosis, and apoptosisof CRC cells. Silencing of exosomal miR-191 from CRC cells prevented M2polarization of macrophages, and weakened CRC development by inducingferroptosis. Exosomal miR-191 accelerated cancer progression in CRC nude miceby promoting M2 polarization of macrophages. CONCLUSIONInhibition of exosomal miR-191 attenuated CRC progression by inducing ferroptosis in macrophages. This studyrevealed a novel mechanism by which exosomal miR-191 modulates the tumor microenvironment.
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Supported by Beijing Natural Science Foundation,No.7252124National High Level Hospital Clinical Research Funding,No.BJ-2024-219,No.BJ-2025-125 and No.BJ-2023-236+1 种基金National Natural Science Foundation of China,No.82370584,No.82470395 and No.81600618National Key R&D Program of China,No.2021YFE0114200.
文摘BACKGROUND Glucotoxic pancreaticβcells impair glycogenesis of hepatocytes,with exosomes serving as novel mediators.miR-375-3p is the most abundant miRNA in the pancreas and critical forβ-cell function,but whether it plays a role in pancreasliver crosstalk remains unclear.AIM To investigate the role of miR-375-3p,a key regulator of pancreaticβcells,in remotely regulating hepatocyte glycogenesis via exosomes.METHODS Mice fed a high-fat diet(HFD)served as animal models,and mouse primary pancreatic islet cells and theβ-cell line MIN-6 were used as cellular models.miR-375-3p expression in pancreatic cells,hepatocytes and exosomes was detected in both animal and cellular models.Transwell assays,exosome treatment,and exosome-depleted supernatant culture were used to investigate the role of exosomal miR-375-3p in pancreatic-hepatocyte crosstalk.The AKT/GSK signaling pathway and hepatic glycogen content were used as indicators to evaluate hepatocyte glycogenesis.Luciferase reporter assays were used to evaluate the downstream targets of miR-375-3p.RESULTS Increased levels of miR-375-3p were observed in both the pancreas and liver of HFD-fed mice.In contrast to the in vivo results,high-glucose treatment exclusively increased the expression of miR-375-3p in pancreatic cells but had no effect on hepatocytes.Furthermore,hepatocytes treated with the supernatant and exosomes from glucotoxic pancreatic cells presented elevated expression of miR-375-3p.Additionally,exosomal transfer of miR-375-3p from pancreatic cells to hepatocytes suppressed the AKT/GSK signaling pathway,thereby reducing the hepatic glycogen content.Luciferase analysis indicated that the recombination signal binding protein for the immunoglobulin kappa J region(Rbpj)is a target gene of miR-375-3p.Rbpj inhibition impaired hepatic glycogenesis,and Rbpj overexpression reversed the effect on glycogenesis induced by miR-375-3p.CONCLUSION Pancreatic cell-derived miR-375-3p can be delivered to hepatocytes via exosomes and inhibits hepatocyte glycogenesis by targeting Rbpj.
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.
基金Supported by Anusandhan National Research Foundation,No.CRG/2023/000212.
文摘Mesenchymal stem cells(MSCs)are known for their ability to differentiate into various cell lineages,including osteoblasts(bone-forming cells),and for their significant paracrine effects.Among their secreted products,exosomes have gained considerable attention as nanoscale carriers of bioactive molecules such as non-coding RNAs(ncRNAs).These ncRNAs,including microRNAs,long ncRNAs,and circular ncRNAs,are critical regulators of gene expression and cellular functions.Moreover,MSC-derived exosomes not only offer advantages such as targeted delivery,reduced immunogenicity,and protection of cargo material,but also carry ncRNAs that have therapeutic and diagnostic potential in bone-related disorders.Emerging evidence has highlighted the role of MSC-derived exosomal ncRNAs in osteogenesis,bone remodeling,and intercellular signaling in the bone microenvironment.This review consolidates recent research on the role of MSC-derived exosomal ncRNAs in maintaining bone homeostasis and bone-related disorders via various signaling pathways and epigenetic modifications.Furthermore,we explore the therapeutic potential of MSC-derived exosomal ncRNAs as biomarkers and therapeutic targets.This comprehensive review offers key insights into the regulatory roles of MSC-derived exosomal ncRNAs in bone biology and their clinical significance in bone-related diseases.
基金Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education,No.NRF-2022R1I1A1A01068652.
文摘GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte function,and preserving the extracellular matrix both in vitro and in vivo.Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagyrelated gene that is downregulated in OA.Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production,reduced lipid peroxidation and reactive oxygen species,increased mitophagy markers(PINK1,Parkin,LC3-II/I),decreased p62 levels,and alleviated cartilage degeneration in a rat destabilization model.A causal role for mitophagy is supported by coimmunoprecipitation experiments confirming a GRPEL1-PINK1 interaction,and by PINK1 knockdown,which diminishes the protective effects of GRPEL1.These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.
文摘BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.
