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18 recordsLinked to original sources
PubMed2026

Small extracellular vesicles are the key players in ochratoxin A-induced kidney toxicity.

BACKGROUND: Despite growing evidence of ochratoxin A (OTA)-induced kidney toxicity, the underlying mechanisms remain elusive. Emerging evidence suggests that small extracellular vesicles (sEVs) act as mediators of intercellular communication to recipient cells during various physiological and pathological conditions. Given the distinctive properties of sEVs, it is hypothesized that OTA-induced sEVs might mediate the OTA-induced kidney pathogenesis. METHODS: To explore the involvement of sEVs in OTA-induced kidney toxicity, sEVs were isolated and characterized from OTA-exposed rat kidney epithelial cells (NRK52E). Later, these sEVs were used to treat NRK52E cells and Wistar rats to assess the impact of OTA-induced sEVs on kidney toxicity. Label-free proteomics was also performed on OTA-induced sEVs, and key proteins were identified and validated. The biodistribution of sEVs in rats was also assessed using live imaging. The role of validated protein/s in kidney toxicity was further confirmed via a gene silencing and overexpression study. RESULTS: OTA exposure increased sEV secretion into conditioned media of NRK52E cells and into the urine of Wistar rats. Interestingly, we found that OTA-induced sEVs cause similar kidney toxicity in vitro and in vivo systems as OTA exposure, and blocking of sEV secretion markedly alleviated OTA-mediated kidney toxicity. Proteomics analysis identified annexin A2 and fibrinogen-ɣ as common proteins detected in sEVs derived from OTA-exposed NRK52E cells or rat urine. However, immunoblotting validated that annexin A2 was the only sEV-associated protein, expressed significantly in both NRK52E and rat urine following OTA exposure. Notably, silencing of annexin A2 attenuated the ability of OTA-induced sEVs to cause kidney toxicity, whereas overexpression exacerbates it. CONCLUSIONS: Our findings identify the annexin A2-enriched sEVs as key mediators of OTA-induced kidney toxicity. Annexin A2, along with other kidney injury markers, offers a promising non-invasive translational biomarker for early detection and monitoring of OTA-induced kidney toxicity.

Ochratoxins↗
PubMed2026

Functional and Proteomic Profiles of CD3(+) Plasma-Derived Small Extracellular Vesicles Differentiate Cancer Patients From Healthy Donors.

Small extracellular vesicles (sEV) released by T cells play a key role in immune regulation. Immune capture with anti-CD3 antibodies was used to isolate and study T cell-derived CD3(+)sEV from the plasma of patients with melanoma (MPs) or healthy donors (HDs). Functional responses induced in recipient target cells by CD3(+)sEV of MPs differed from responses induced by CD3(+)sEV of HDs. Approximating functions mediated by melanoma cell-derived sEV (MTEX), CD3(+)sEV of MPs reduced metabolic activity and proliferation of T cells while promoting activity in Mel526 cell targets. Proteomics profiling confirmed functional differences between CD3(+)sEV of MPs and HDs. Of 294 sEV-specific proteins identified in CD3(+)sEV, 226 were detected in the parent T cell proteome, confirming that the CD3(+)sEV proteome mimics that of the parent T lymphocytes. Among them were 66 differentially expressed proteins (DEPs) that differentiated vesicles from MPs and HDs. These DEPs were associated with processes linked to cancer-related functions. DEPs upregulated in CD3(+)sEV of MPs were associated with RHO-GTPase, cytokine, and MAPK signaling pathways. Thus, T cells of MPs were reprogrammed by MTEX to produce CD3(+)sEV that functionally resembled MTEX, partly recapitulated features of the tumor proteome, and differed from CD3(+)sEV of HDs. In cancer, the TEX-rewired T cells produce CD3(+)sEV that potentially could serve as a liquid biopsy of patients' T cells.

Humans↗
PubMed2025

MicroRNAs signatures in small extracellular vesicles for psychological resilience in young adults using machine learning.

AIMS: Psychological resilience refers to an individual's capacity to adapt to adverse events. MicroRNAs (miRNAs) play a crucial role in regulating post-transcriptional processes, while small extracellular vesicles (sEVs) act as transport vehicles. This study aimed to employ genome-wide profiling to identify and validate differences in the expression of resilience-associated sEV-miRNAs between low resilience (LR) and high resilience (HR) in young adults. METHODS: Eighty participants were divided into LR or HR based on the Connor - Davidson Resilience Scale (CD-RISC). The expression levels of the target sEV-miRNAs in LR and HR were compared and analyzed. RESULTS: Expression analyses demonstrated significant differences in let-7b, miR-151b, miR-335, and miR-193a between LR and HR (p&#x2009;<&#x2009;0.01), with let-7b showing the highest discriminative ability. The AUC values for each sEV-miRNA ranged from 0.74 to 0.94, based on logistic regression and three machine learning models: random forest, support vector machine, and eXtreme gradient boosting. Based on leave-one-out cross-validation in different models, the combined four sEV-miRNAs demonstrated strong performance for detecting LR (AUC&#x2009;=&#x2009;0.87-0.90). Sex-specific differences were also observed, with female participants showing more pronounced resilience signatures in targeted sEV-miRNAs. CONCLUSIONS: These findings suggest that sEV-miRNAs hold potential as biomarkers for psychological resilience in young adults.

Humans↗
PubMed2024

Proteomic profiles of peritoneal fluid-derived small extracellular vesicles correlate with patient outcome in ovarian cancer.

Cancer-derived small extracellular vesicles (sEVs) are capable of modifying the tumor microenvironment and promoting tumor progression. Ovarian cancer (OvCa) is a lethal malignancy that preferentially spreads through the abdominal cavity. Thus, the secretion of such vesicles into the peritoneal fluid could be a determinant factor in the dissemination and behavior of this disease. We designed a prospective observational study to assess the impact of peritoneal fluid-derived sEVs (PFD-sEVs) in OvCa clinical outcome. For this purpose, 2 patient cohorts were enrolled: patients with OvCa who underwent a diagnostic or cytoreductive surgery and nononcological patients, who underwent abdominal surgery for benign gynecological conditions and acted as the control group. Systematic extraction of PFD-sEVs from surgical samples enabled us to observe significant quantitative and qualitative differences associated with cancer diagnosis, disease stage, and platinum chemosensitivity. Proteomic profiling of PFD-sEVs led to the identification of molecular pathways and proteins of interest and to the biological validation of S100A4 and STX5. In addition, unsupervised analysis of PFD-sEV proteomic profiles in high-grade serous ovarian carcinomas (HGSOCs) revealed 2 clusters with different outcomes in terms of overall survival. In conclusion, comprehensive characterization of PFD-sEV content provided a prognostic value with potential implications in HGSOC clinical management.

Humans↗
PubMed2026

Novel serum small extracellular vesicle miRNAs with multi-target RCA-CRISPR sensor for liver cancer detection.

BACKGROUND: Detecting liver cancer (LC) remains a significant challenge in clinical practice. Small extracellular vesicle (sEV) miRNAs show promise as non-invasive biomarkers for LC detection, yet their diagnostic potential remains largely unexplored. This study aimed to identify specific sEV miRNA signatures for LC detection and develop a novel synchronized multi-miRNA detection platform to enhance diagnostic efficiency and sensitivity. METHODS: High-throughput sequencing was conducted across four distinct cohorts: normal controls (NC), hepatitis B virus (HBV) patients, liver cirrhosis patients, and LC patients. This sequencing process identified miRNAs with differential expression, followed by RT-qPCR validation in serum sEV miRNAs from LC patients and NC. An innovative detection method, RCA-CRISPR, was introduced, combining rolling circle amplification (RCA) with CRISPR/Cas12a (RCA-CRISPR) for quick and sensitive miRNAs detection. RESULTS: Sequencing results showed a consistent elevation of hsa-miR-203b-5p, hsa-miR-4661-5p, and hsa-miR-219a-2-3p across all cohorts. RT-qPCR validations confirmed significant upregulation of these miRNAs in serum sEVs from LC patients, and the combined three-miRNA panel exhibited high diagnostic accuracy (p&#x2009;=&#x2009;0.0003; AUC&#x2009;=&#x2009;0.81). The RCA-CRISPR method demonstrated a detection limit of 3.12 pM for simultaneous multi-target miRNA detection, highlighting its exceptional sensitivity. CONCLUSIONS: Our study identifies hsa-miR-203b-5p, hsa-miR-4661-5p, and hsa-miR-219a-2-3p as promising sEV miRNA biomarkers for LC detection. The developed RCA-CRISPR sensor provides a robust tool for multi-miRNA analysis, potentially advancing non-invasive LC diagnostics. Future validation in larger, prospectively collected cohorts is essential to establish the clinical utility and performance of this biomarker panel and RCA-CRISPR sensor.

MicroRNAs↗
PubMed2026

Small extracellular vesicles reflect senescence progression in human bone marrow-derived mesenchymal stem cells during hollow fiber bioreactor culture.

Prolonged three-dimensional culture exposes stem cells to sustain microenvironmental and mechanical stresses that can promote aging- and senescence-associated phenotypic alterations. This study examined how long-term expansion of human bone marrow-derived mesenchymal stem cells (BMSCs) in a hollow fiber bioreactor (HFB) influences cellular senescence and the molecular composition of secreted small extracellular vesicles (sEVs). During extended HFB culture, BMSCs exhibited progressive morphological flattening and cytoskeletal disorganization, accompanied by increased senescence-associated &#x3b2;-galactosidase activity and immunophenotypic remodeling characterized by reduced fluorescence intensity and spatial redistribution of canonical MSC markers, consistent with a stress-adapted, early senescence-associated cellular state. In parallel, sEVs were collected longitudinally over 40 days and characterized by nanoparticle tracking analysis, immunoblotting, and quantitative proteomics. While vesicle size, marker expression, and yield remained stable throughout culture, proteomic profiling revealed pronounced, phase-dependent remodeling of sEV cargo, including coordinated alterations in oxidative stress-related processes, lysosomal and extracellular matrix-associated pathways, and relative depletion of cytoskeletal and translational components. Notably, these vesicular signatures closely mirrored senescence-associated changes observed at the cellular level. The strong correspondence between cellular phenotypes and sEV proteomic profiles establishes vesicle analysis as a convergent and noninvasive readout of BMSC aging, enabling sensitive monitoring of senescence progression while reducing reliance on parallel, labor-intensive cellular assays. Collectively, these findings indicate that prolonged HFB culture promotes a controlled, stress-associated senescence program in BMSCs and position sEV proteomic profiling as a robust approach for assessing stem cell aging dynamics during long-term three-dimensional bioreactor culture.

Mesenchymal Stem Cells↗
PubMed2026

Urinary Small Extracellular Vesicle DNA as a Biomarker for the Non-Invasive Diagnosis of Bladder Cancer.

Existing diagnostic technologies for bladder cancer (BC) suffer from low sensitivity, low specificity, or a lack of validation. Therefore, validated, non-invasive diagnostic biomarkers with high sensitivity and specificity for early detection of BC are needed to complement and improve upon the limitations of existing diagnostic methods. We used low-pass whole genome sequencing (LP-WGS) technology to detect copy number variations (CNVs) in small extracellular vesicle (sEV) DNA isolated from urine samples of patients. Based on these results, we constructed and validated a diagnostic model to differentiate between benign and malignant bladder lesions. We conducted a receiver operating characteristic analysis and calculated the area under the curve (AUC) to evaluate the performance of the diagnostic model. The urine sEV-DNA LP-WGS data revealed CNV differences between benign and malignant samples. The diagnostic model achieved an AUC of 0.953, a sensitivity of 86.7%, and a specificity of 100% in the training cohort and an AUC of 0.985, a sensitivity of 90%, and a specificity of 100% in the validation cohort. Even at the lowest coverage depth of 0.01X, the performance of the diagnostic model remained relatively robust. Notably, the performance of this diagnostic model surpassed that of the biomarker neuron-specific enolase (sensitivity: 85.7% vs. 64.3%; specificity: 100% vs. 87.5%) and urinary cytology (sensitivity: 100% vs. 66.7%; specificity: 100% vs. 94.1%). Our study demonstrates that urine sEV-DNA exhibits high discriminatory power in distinguishing between benign and malignant bladder lesions, making it a promising tool for auxiliary diagnosis of BC.

Humans↗
PubMed2025

Effect of extracellular vesicles in remodeling the tumor microenvironment by DNMT1 downregulation for enhanced cancer immunotherapy.

BACKGROUND: The efficacy of immunotherapy is often hindered by the suppression of immune responses via the tumor microenvironment (TME). The presence of cancer cells forces other proximal non-cancerous cells to support tumor growth and persistence. A clear example of this cancerous-to-non-cancerous communication is represented by the accumulation of myeloid-derived suppressor cells (MDSCs) within the TME. Several studies have convergently shown that the overexpression of DNA-methyl-transferase-1 (DNMT1) in these cells results in protection from necroptosis and enhanced accumulation in vivo. Conversely, targeting DNMT1 through hypo-methylating agents has shown promising therapeutic potential by not only reducing the levels of MDSCs but also enhancing cancer immunogenicity and the efficacy of immune checkpoint inhibitors (ICI). METHODS: Murine 4T1 (triple-negative breast cancer (TNBC)) and CT26 (colon carcinoma) cell lines were cultured under standard conditions and used to generate tumor models in BALB/c mice. An oncolytic adenovirus expressing a DNMT1-targeting short hairpin RNA (OAd.shDNMT1) was engineered and validated for DNMT1 knockdown and genome-wide methylation reduction. Small extracellular vesicles (sEVs) were isolated from virus-infected cancer cells and characterized for RNA content and uptake by MDSCs. MDSC differentiation and suppressive function were assessed in vitro using flow cytometry and co-culture assays with murine splenocytes. In vivo, tumor-bearing mice received intratumoral OAd.shDNMT1, systemic decitabine, or immune checkpoint inhibitors (anti-Programmed cell Death protein-1), and tumor growth, immune infiltration, and systemic MDSC levels were evaluated. RESULTS: In this study, we report that, by using virally infected TNBC murine cells as a source for shDNMT1-loaded sEVs, OAd.shDNMT1 successfully reduced MDSC levels in vitro and in vivo. Furthermore, the co-administration with ICI resulted in a significant tumor growth reduction in mice bearing poorly immunogenic TNBC 4T1 cells. Also, our treatment promoted antitumor immunity, prolonged survival, and complete tumor eradication in modestly immunogenic colon CT26 cancer cells. CONCLUSION: This multifaceted strategy, based on OV-mediated immune stimulation and reduction of MDSC levels via sEVs, may improve clinical outcomes and the success of immuno-based regimens for patients facing MDSC-rich and highly aggressive cancer subtypes.

Animals↗
PubMed2027

Generation of Transgene-Free Naive Human Induced Pluripotent Stem Cells from Somatic Cells Using a Modified Temperature-Sensitive Sendai Virus System.

The Sendai virus (SeV) vector system offers an efficient, nonintegrating approach to reprogram somatic cells into either naive or primed human induced pluripotent stem cells (iPSCs). Here, we describe a protocol to generate transgene-free naive iPSCs from human dermal fibroblasts (HDFs) and peripheral blood mononuclear cells (PBMCs) using a modified, temperature-sensitive SeV system. The method leverages LMYC in place of cMYC and an optional H1FOO-DD factor to enhance efficiency and uniformity, and employs a controlled temperature shift to facilitate vector clearance.

Humans↗
PubMed2025

Identification of molecular markers and exploration of the oncogenic role of exomeres in hepatocellular carcinoma.

Extracellular vesicles and particles (EVPs) serve as functional mediators delivering their cargoes to specific destinations. Exomeres (EMs) represent a newly discovered subset of nanoparticles, with limited understanding of their biophysical characteristics and functionalities. Here, we isolated and studied EMs from different normal and cancer cell lines. Proteomic analysis reveals distinctive features of EMs compared to small extracellular vesicles (sEVs) and identifies galactosamine (N-acetyl)-6-sulfatase (GALNS) and mannosidase alpha class 2B member 1 (MAN2B1) to be expressed in EMs, indicating their potential as specific EM molecular markers. Subsequent investigations into tumor-derived EMs demonstrate their oncogenic properties to support cancer growth and metastasis. Furthermore, analysis of murine hepatocellular carcinoma-derived EM reveals their ability to induce cell cycle progression and metabolic alterations. Collectively, our data highlight the distinct nature of EMs as a nanoparticle subpopulation different from sEVs, with cancer-derived EMs significantly contributing to tumor growth and dissemination.

Carcinoma, Hepatocellular↗
PubMed1976

[Changes in the morphology of the normal left ventricle during the phases of isovolumic contraction and relaxation. Consequences on the calculation of the volume and cardiac output by cineangiocardiographic methods].

It is well known that the left ventricular volume, as measured by the cineangiographic method, decreases during the phase of isometric contraction. What is more, the cardiac index and the ejection fraction measured by this method are definitely larger than those derived from dilution methods. These discrepancies can be explained by movements of the mitral valve during the phases of isometric contraction and relaxation. The systolic ejection volume (SEV) was measured by three different methods: 1. End-diastolic volume (EDV) -end-systolic volume (ESV) ; 2. EDV - pre-filling volume (PFV) ; 3. Pre-ejection volume (PEV) - ESV. It has emerged that the results given by the methods (2) and (3) correspond closely, and differ significantly from those given by method (1); they are also close to those obtained by the dilution method. This difference seems to arise from the fact that the movements of the mitral valve during the phase of isometric relaxation are diametrically opposite to those which occur during isometric contraction; thus, when the values EDV-ESV are used in the calculation of SEV, an overestimate is made because the mitral valve is not to be found in the same position within the ventricular cavity for both values.

Adolescent↗
PubMed2026

Protocol for the isolation and characterization of extracellular vesicles and particles from human and murine cell lines.

Cells produce a heterogeneous population of extracellular vesicles and particles (EVPs). Small extracellular vesicles (sEVs or exosomes) are lipid membrane-enclosed vesicles with sizes ranging from 30 to 150 nm. Here, we present a protocol to isolate and characterize EVPs from the conditioned medium of cell lines. We describe steps for cell culture, conditioned media collection, differential ultracentrifugation, and EVP characterization. We then detail procedures for proteomic and biodistribution analyses. For complete details on the use and execution of this protocol, please refer to Yeung et al.1.

Animals↗
PubMed1975

A new mucolipidosis with psychomotor retardation, corneal clouding, and retinal degeneration.

A man now 22 years of age had slow psychomotor development about 6 months after birth and developed intermittent corneal clouding at about 18 months. He developed truncal ataxia, hypotonia of the limbs combined with spasticity, and active deep reflexes. These have not progressed. His skeleton and facies are normal. Between his first and thriteenth year he developed sev ere optic atrophy, absence of retinal blood vessels, and an extinguished electroretinogram. Biochemical analysis of cultured fibroblasts indicated no lysosomal hydrolase deficiency; cellular metachromasia was absent and there was no mucopolysaccharidoses. Ultrastructural studies indicated single membrane vacuoles containing lamellated membranes and a polymorphous substance in tissue cultured cells and conjunctiva.

Adult↗
PubMed1979

Cerebral metabolic and hemodynamic activities of l-eburnamonine in the anesthetized dog. A comparison with vincamine.

1. The cerebral metabolic and hemodynamic activities of l-eburnamonine (l-E) were investigated in anesthetized dogs and compared with those of vincamine (Vi). 2. The injection of l-E (2 mg/kg i.v.) increased vertebral, carotid and femoral blood flows (VBF, CBF, FBF) while corresponding resistances decreased. aortic blood flow (A0 BF) and systolic ejection volume (SEV) increased. Cerebral O2 and glucose consumption (CMRO2, CMRG) increased as did the O2 extraction coefficient and the O2 supply. This last increase was due to the simultaneous increase of VBF, hemoglobin (Hb) and arterial pO2.

Animals↗
PubMed1978

[Changes in the subvalvular apparatus and left ventricular function in pure mitral stenosis].

Disordered left ventricular function and changes in the sub-valvular apparatus appear to be associated in patients with isolated mitral stenosis (MS). Left ventricular cine-angiography has demonstrated two groups of patients, according to the presence (group II) or absence (group I) of changes in the sub-valvular apparatus. There was no significant difference between the two groups in terms of age, heart rate, left ventricular end diastolic pressure, surface area of the mitral valve, or ventricular ejection time. However, group II patients had a lowered ejection fraction (EF), systolic ejection volume (SEB), speed of shortening of circular fibres (VCF), and systolic work index (SWI) compared with group I cases (respectively 0.49 +/- 0.06 and 0.58 +/- 0.04 for the EF, 36 +/- 7 ml.m-2 and 41 +/- 7 ml.m-2 for the SEV, 0.85 +/- 0.12 circ.s-1 and 1.09 +/- 0.16 circ.s-1 for the VCF, 45 +/- 11 gm.m-2 and 57 +/- 11 gm.m-2 for the SWI. Nevertheless, it appears that changes in the sub-valvular apparatus indicate rather than cause dysfunction of the left ventricle, which occurs in a certain number of patients who have a normal sub-valvular apparatus.

Adult↗
PubMed2025

A comprehensive analysis of supermere, exomere, and extracellular vesicle isolation and cargo in colorectal cancer.

Biofluids contain a heterogeneous mixture of extracellular vesicles and non-vesicular nanoparticles (including exomeres and supermeres) that transport a diverse array of proteins, RNA, and lipids. Our previous efforts to characterize the contents of these carriers in colorectal cancer relied on 2D culture systems requiring large-scale setups and time-consuming ultracentrifugation-based isolation. To streamline this process, we have combined 3D hollow-fiber bioreactor production and fast-protein liquid chromatography-based size-exclusion chromatography. Here, we compare the impact of culture methods and purification strategies on small extracellular vesicle, exomere, and supermere cargo. Proteomic analyses show consistently distinct profiles for extracellular vesicles, exomeres, and supermeres regardless of culture conditions or isolation method. In contrast, these two variables influence small RNAs, their base modifications, and lipidomic profiles. We present an online tool to query these and future secretome datasets (https://superomics.shinyapps.io/browse).

Humans↗