Exosomal microRNAs (miRNAs) have great potential in the fight against hepatocellular carcinoma (HCC), the fourth most common cause of cancer-related death worldwide. In this study, we explored the various applications of these small molecules while analyzing their complex roles in tumor development, metastasis, and changes in the tumor microenvironment. We also discussed the complex interactions that exist between exosomal miRNAs and other non-coding RNAs such as circular RNAs, and show how these interactions coordinate important biochemical pathways that propel the development of HCC. The possibility of targeting exosomal miRNAs for therapeutic intervention is paramount, even beyond their mechanistic significance. We also highlighted their growing potential as cutting-edge biomarkers that could lead to tailored treatment plans by enabling early identification, precise prognosis, and real-time treatment response monitoring. This thorough analysis revealed an intricate network of exosomal miRNAs lead to HCC progression. Finally, strategies for purification and isolation of exosomes and advanced biosensing techniques for detection of exosomal miRNAs are also discussed. Overall, this comprehensive review sheds light on the complex web of exosomal miRNAs in HCC, offering valuable insights for future advancements in diagnosis, prognosis, and ultimately, improved outcomes for patients battling this deadly disease.

Human amniotic epithelial cells (hAECs) are novel and promising therapeutic agents for patients suffering from degenerative diseases. Studies have demonstrated that the therapeutic effects of hAECs mainly depend on their paracrine components. Currently, appropriate pretreatment is a widely confirmed strategy for enhancing the repair potential of stem cells; however, the effect of proinflammatory factor pretreatment on hAECs and their secretome is still unclear. In this study, we used the well-characterized proinflammatory factors tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) to stimulate hAECs and analyzed the effect of TNF-α and IFN-γ on hAECs, including gene expression profile, paracrine proteins, and microRNAs (miRNAs) in exosomes. Results showed that TNF-α and IFN-γ pretreatment improved the viability of hAECs but inhibited the proliferation of hAECs. TNF-α and IFN-γ pretreatment altered the gene expression profile of hAECs, and upregulated differentially expressed genes were predominantly enriched in biological adhesion, antioxidant activity, and response to IFN-beta. In addition, TNF-α and IFN-γ pretreatment enhanced the paracrine secretion of cytokines by hAECs. The upregulated differentially expressed proteins were mainly enriched in tissue remodeling proteins and cytokine-cytokine receptor. Notably, the expression of miRNAs in exosomes from hAECs was also changed by TNF-α and IFN-γ pretreatment. The target genes of upregulated exosomal miRNAs substantially contributed to the response to stimulus, metabolic pathways, and PI3K-Akt signaling pathway. Our findings improve our understanding of the biological characteristics of hAECs after proinflammatory factor pretreatment and provide novel insights to strengthen and optimize the therapeutic potential of hAECs and their secretome in regenerative medicine.

Gestational Diabetes Mellitus (GDM) has been on the rise for the last two decades along with the growing incidence of obesity. The ubiquitous use of Endocrine-Disrupting Chemicals (EDCs) worldwide has been associated with this increase in GDM incidence. Epigenetic modifications such as DNA methylation, histone acetylation, and methylation have been associated with prenatal exposure to EDCs. EDC exposure can also drive a sustained disruption of the hypothalamus-pituitary-thyroid axis and various other signaling pathways such as thyroid signaling, PPARγ signaling, PI3K-AKT signaling. This disruption leads to impaired glucose metabolism, insulin resistance as well as β-cell dysfunction, which culminate into GDM. Persistent EDC exposure in pregnant women also increases adipogenesis, which results in gestational weight gain. Importantly, pregnant mothers transfer these EDCs to the fetus via the placenta, thus leading to other pregnancy-associated complications such as intrauterine growth restriction (IUGR), and large for gestational age neonates. Furthermore, this early EDC exposure of the fetus increases the susceptibility of the infant to metabolic diseases in early life. The transgenerational impact of EDCs is also associated with higher vascular tone, cognitive aberrations, and enhanced susceptibility to lifestyle disorders including reproductive health anomalies. The review focuses on the impact of environmental toxins in inducing epigenetic alterations and increasing the susceptibility to metabolic diseases during pregnancy needs to be extensively studied such that interventions can be developed to break this vicious cycle. Furthermore, the use of EDC-associated ExomiRs from the serum of patients can help in the early diagnosis of GDM, thereby leading to triaging of patients based on increasing risk factor of the clinicopathological condition.

Gastric cancer (GC) is one of the most prominent malignancies that originate in the epithelial cells of the gastric mucosa and is one of the main causes of cancer-related mortality worldwide. New circulating biomarkers of exosomal RNA might have great potential for non-invasive early prognosis of GC. Sijunzi Decoction (SJZD) is a typical representative formula of the method of benefiting Qi and strengthening the spleen in Traditional Chinese Medicine (TCM). However, the effects and mechanism of SJZD in treating GC remain unclear. This study looked for biomarkers of exosomal RNA for early prognosis of GC, and explored the mechanism of SJZD in treating GC. A gastric cancer model with spleen deficiency syndrome was established in nude mice, and the curative effects of SJZD were investigated. Differentially expressed miRNAs in plasma and saliva exosomes were sequenced and analyzed. Potential target genes of these miRNAs were predicted and applied for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment annotation. Overlapping miRNAs in saliva and plasma samples were analyzed, and qRT-PCR was performed for verification. miR-151a-3p was selected, and qRT-PCR further determined that miR-151a-3p was downregulated in saliva and plasma exosomes from the SJZD group. The intersected miR-151a-3p target genes were predicted and enriched in the extrinsic apoptotic signaling pathways. SJZD significantly ameliorates gastric cancer with spleen deficiency syndrome in mouse models, and exosomal miRNAs, particularly miR-151-3p, might be modulated by SJZD in plasma and saliva. The exosomal miR-151-3p in saliva may serve as a non-invasive potential marker for gastric cancer diagnosis and prognosis.

The exosomal miRNA plays a crucial role in the intercellular communication response to environmental stress and pathogenic stimulation. In the present study, the expression of exosomal miRNAs in the Pacific oyster Crassostrea gigas after high-temperature stress or Vibrio splendidus stimulation was investigated through high-throughput sequencing. The exosomes were identified to be teardrop-like vesicles with the average size of 81.7 nm by transmission electron microscopy. There were 66 known miRNAs and 33 novel miRNAs identified, of which 10 miRNAs were differentially expressed after both high-temperature stress and Vibrio stimulation compared to the control group. A total of 1868 genes were predicted as the putative targets of miRNAs, of which threonine aspartase 1-like was targeted by the highest number of related miRNAs. The robustness and reliability of miRNA expression from the sRNA sequencing data were verified by employing eight miRNAs for qPCR. GO and KEGG clustering analyses revealed that apoptosis was significantly enriched by the target genes of differentially expressed exosomal miRNAs after high-temperature stress, and autophagy and cytokine activity were significantly enriched after Vibrio stimulation. Energy metabolism was found to be significantly shared in the target gene enrichments after both high-temperature stress and Vibrio stimulation. These findings would improve our understanding of the regulatory mechanisms of exosomal miRNAs in C. gigas after high-temperature stress or Vibrio stimulation.

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

Breast cancer is one of the top two reproductive cancers responsible for high rates of morbidity and mortality among women globally. Despite the advancements in the treatment of breast cancer, its early diagnosis remains a challenge. Recent evidence indicates that despite the adroit use of numerous strategies to facilitate rapid and precision-oriented screening of breast cancer at the community level through the use of mammograms, Fine-needle aspiration cytology (FNAC) and biomarker tracking, no strategy has been unequivocally accepted as a gold standard for facilitating rapid screening for disease. This necessitates the need to identify novel strategies for the detection and triage of breast cancer lesions at higher rates of specificity, and sensitivity, whilst taking into account the epidemiologic and social-demographic features of the patients. Recent shreds of evidence indicate that exosomes could be a robust source of biomaterial for the rapid screening of breast cancer due to their high stability and their presence in body fluids. Increasing evidence indicates that the Exosomal microRNAs- play a significant role in modifying the tumour microenvironment of breast cancers, thereby potentially aiding in the proliferation, invasion and metastasis of breast cancer. In this review, we summarize the role of ExomiRs in the tumour microenvironment in breast cancer. These ExomiRs can also be used as candidate biomarkers for facilitating rapid screening and triaging of breast cancer patients for clinical intervention.

Parkinson\'s Disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of midbrain dopaminergic neurons in the substantia nigra part of the brain. Pathology spread to numerous brain regions and cell types suggests that intercellular communication is essential to PD progression. Exosomes mediate intercellular communication between neurons, glia, and other cell types throughout PD-relevant brain regions. However, the mechanism remains unclear, and its implication in PD pathology, is not well understood. In the current study, we explored the role of exosomes in modulating the response to PD-relevant toxicants. In cellular models of PD, neuronal cell-derived exosomes are readily internalized by recipient neuronal cells as intact vesicles. Internalized exosomes in bystander neuronal cells localize to mitochondria and dysregulate mitochondrial functions, leading to cell death under PD stress conditions. NGS analysis of exosomes released by neuronal cells subjected to PD stress conditions showed that levels of specific miRNAs were altered in exosomes under PD stress conditions. Bioinformatic analysis of the miRNA targets revealed enriched pathways related to neuronal processes and morphogenesis, apoptosis and ageing. Levels of two miRNAs, hsa-miR-30a-5p and hsa-miR-181c-5p, were downregulated in exosomes under PD stress conditions. Expression of the identified miRNAs in neuronal cells led to their enrichment in exosomes, and exosome uptake in neuronal cells ameliorated mitochondrial dysfunction induced by PD stress conditions and rescued cell death. In conclusion, loss of enrichment of specific miRNAs, including miR-30a-5p and miR-181c-5p, under PD stress conditions causes mitochondrial dysfunction and neuronal death, and hence may lead to progression of PD.

Breast cancer accounts for the highest cancer cases globally, with 12% of occurrences progressing to metastatic breast cancer with a low survival rate and limited effective early intervention strategies augmented by late diagnosis. Moreover, a low concentration of prognostic and predictive markers hinders disease monitoring. Circulating and exosomal microRNAs (miRNAs) have recently shown a considerable interplay in breast cancer, standing out as effective diagnostic and prognostic markers. The primary functions are as gene regulatory agents at the genetic and epigenetic levels. An array of dysregulated miRNAs stimulates cancer-promoting mechanisms, activating oncogenes and controlling tumor-suppressing genes and mechanisms. Exosomes are vastly studied extracellular vesicles, carrying, and transporting cargo, including noncoding RNAs with premier roles in oncogenesis. Translocation of miRNAs from the circulation to exosomes, with RNA-binding proteins in stress-induced conditions, has shown significant cooperation in function to promote breast cancer. This review examines cellular and exosomal miRNA biogenesis and loading, the clinical implications of their dysregulation, their function in diagnosis, prognosis, and prediction of breast cancer, and in regulating cancer signaling pathways. The influence of cellular and exosomal miRNAs presents clinical significance on breast cancer diagnosis, subtyping, staging, prediction, and disease monitoring during treatment, hence a potent marker for breast cancer.

BACKGROUND: Distant metastases are the primary cause of therapy failure and mortality in patients with papillary thyroid carcinomas (PTCs). However, the underlying mechanism responsible for the initiation of tumor cell dissemination and metastasis in PTCs has rarely been investigated.
OBJECTIVE: The aim of this study was to investigate effects and underlying molecular mechanisms of circulating exosomal microRNAs (miRNAs) in distant metastatic PTCs.
METHODS: The most relevant circulating exosomal miRNA to distant metastatic PTCs were verified between distant metastatic PTCs and nondistant metastatic PTCs by miRNA microarray, quantitative real-time polymerase chain reaction (qRT-PCR) assays and receiver operating characteristic (ROC) curves. The parental and recipient cells of that circulating exosomal miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of circulating exosomal miRNAs that contribute to the development of distant metastases.
RESULTS: We determined that PTC-derived exosomal miR-519e-5p was significantly upregulated in the circulatory system in distant metastatic PTCs. Further tests demonstrated that PTC cells can acquire a more malignant phenotype via hnRNPA2B1-mediated sorting of tumor suppressor miR-519e-5p into exosomes to activate Wnt signaling pathway via upregulating PLAGL2. Furthermore, miR-519e-5p included in PTC-derived exosomes can be transferred to recipient CD8+ T cells and aid in tumor immune escape in distant organs through inhibiting Notch signaling pathway by downregulating NOTCH2.
CONCLUSIONS: Our findings highlight the dual role of PTC-derived exosomal miR-519e-5p in distant metastasis, which may improve our understanding of exosome-mediated distant metastatic mechanisms.