Exosomes are small extracellular vesicles, ranging from 30 to 150 nm, that are essential in cell biology, mediating intercellular communication and serving as biomarkers due to their origin from cells. Exosomes as biomarkers for diagnosing various illnesses have gained significant investigation due to the high cost and invasive nature of current diagnostic procedures. Exosomes have a clear advantage in the diagnosis of diseases because they include certain signals that are indicative of the genetic and proteomic profile of the ailment. This feature gives them the potential to be useful liquid biopsies for real-time, noninvasive monitoring, enabling early cancer identification for the creation of individualized treatment plans. According to our analysis, the trend toward utilizing exosomes as diagnostic and prognostic tools has raised since 2012. In this regard, the proportion of malignant indications is higher compared with non-malignant ones. To be precise, exosomes have been used the most in gastrointestinal, thoracic, and urogenital cancers, along with cardiovascular, diabetic, breathing, infectious, and brain disorders. To the best of our knowledge, this is the first research to examine all registered clinical trials that look at exosomes as a diagnostic and prognostic biomarker.

Metabolic-Associated Fatty Liver Disease (MAFLD) is the most common chronic liver disease worldwide, associated with systemic metabolic dysregulation. It can progress from simple hepatic steatosis (MAFL) to more severe conditions like Metabolic-Associated Steatohepatitis (MASH), fibrosis, cirrhosis, and Hepatocellular Carcinoma (HCC). There is a critical lack of reliable non-invasive diagnostic methods and effective pharmaceutical treatments for MAFLD/MASH, emphasizing the need for further research. Extracellular vesicles (EVs) are nanoscale structures that play important roles in cell signaling by delivering bioactive molecules. However, there is a significant gap in literature regarding the roles of EVs from hosts, plants, and microbiota in MAFLD. This review explores the potential of EVs from various sources-host, plants, and microbiota-as biomarkers, therapeutic agents, drug carriers, and treatment targets for MAFLD. Firstly, the roles of host-derived extracellular vesicles (EVs) in MAFLD, with a focus on cell-type specific EVs and their components-proteins, miRNAs, and lipids-for disease diagnosis and monitoring were discussed. Moreover, it highlighted the therapeutic potential of mesenchymal stem cell (MSC)-derived EVs in reducing lipid accumulation and liver injury, and immune cell-derived EVs in mitigating inflammation and fibrosis. The review also discussed the use of host-derived EVs as drug carriers and therapeutic targets due to their ability to deliver bioactive molecules that impact disease mechanisms. Additionally, it summarized research on plant-derived EVs, which help reduce liver lipid accumulation, inflammation, and enhance gut barrier function in MAFLD. Also, the review explored microbial-derived EVs as novel therapeutic targets, particularly in relation to insulin resistance, liver inflammation, and dysfunction in MAFLD. Overall, by exploring the diverse roles of EVs from host, plant, and microbiota sources in MAFLD, this review offers valuable insights into their potential as non-invasive biomarkers and novel therapeutic strategies, which could pave the way for more effective diagnostic and treatment options for this increasingly prevalent liver disease. Notably, the challenges of translating EVs into clinical practice were also thoroughly discussed, aiming to provide possible directions and strategies for future research.

Non-alcoholic fatty liver disease (NAFLD) is a disease with various levels varying from fatty liver steatosis to acute steatosis which is non-alcoholic steatohepatitis (NASH), which can develop into hepatic failure, as well as in some conditions it can develop into hepatocellular carcinoma (HCC). In the NAFLD and NASH context, aberrant microRNA (miRNA) expression has a thorough contribution to the incidence and development of these liver disorders by influencing key biological actions, involving lipid metabolism, inflammation, and fibrosis. Dysregulated miRNAs can disrupt the balance between lipid accumulation and clearance, exacerbate inflammatory responses, and promote fibrogenesis, thus advancing the severeness of the disorder from simple steatosis to more complex NASH. In the current review, the latest development concerned with the activity of complex regulatory networks of miRNA in the incidence as well as the evolution of NAFLD is to be discussed, also conferring about the miRNAs' role in the onset, pathogenesis as well as diagnosis of NAFLD and NASH discussing miRNAs' role as diagnostic biomarkers and their therapeutic effects on NAFLD/NASH.

Pediatric non-alcoholic fatty liver disease (NAFLD) is emerging as a worldwide health concern with the potential to advance to cirrhosis and liver cancer. NAFLD can also directly contribute to heart problems through inflammation and insulin resistance, even in individuals without other risk factors. The pathological mechanisms of NAFLD are linked to functional differences of miRNAs in different biological environments. The miRNA in serum exosomes may reflect the pathological state of the liver and changes in systemic metabolism, while the miRNA in serum may be associated with physiological processes other than the liver. Pediatric non-alcoholic fatty liver disease (NAFLD) is emerging as a worldwide health concern with the potential to advance to cirrhosis and liver cancer. NAFLD can also directly contribute to heart problems through inflammation and insulin resistance, even in individuals without other risk factors. The pathological mechanisms of NAFLD are linked to functional differences of miRNAs in different biological environments. The miRNA in serum exosomes may reflect the pathological state of the liver and changes in systemic metabolism, while the miRNA in serum may be associated with physiological processes other than the liver. Pediatric non-alcoholic fatty liver disease (NAFLD) is emerging as a worldwide health concern with the potential to advance to cirrhosis and liver cancer. NAFLD can also directly contribute to heart problems through inflammation and insulin resistance, even in individuals without other risk factors. The pathological mechanisms of NAFLD are linked to functional differences of miRNAs in different biological environments. The miRNA in serum exosomes may reflect the pathological state of the liver and changes in systemic metabolism, while the miRNA in serum may be associated with physiological processes other than the liver. Our study identified 36 miRNAs with differential expression in the serum of NAFLD patients compared to the control group, including 21 miRNAs with significantly increased expression and 15 with decreased expression. Consistent with our previously reported data on serum-derived exosomal miRNA profiling, this study also observed a notable upregulation of serum miR-122-5p levels in NAFLD patients. PCR validation confirmed the differential expression of miR-122-5p identified through RNA sequencing. Functional analysis using GO and KEGG pathways revealed a diverse range of biological roles associated with these differentially expressed miRNAs. Notably, NAFLD significantly impacts heart health, with miR-122-5p playing a key role in regulating cardiovascular function. Furthermore, activation of the miR-122/Sirt-6/ACE2 axis may contribute to myocardial necrosis, highlighting its potential role in NAFLD-associated cardiovascular risks. Our study suggests that miR-122 plays a key role in the progression of NAFLD and its associated metabolic disturbances, which can increase the risk of cardiovascular disease. Targeting miR-122 may offer potential therapeutic benefits for improving both liver and heart health in individuals with NAFLD.

The global epidemic of metabolic diseases has led to the emergence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), which pose a significant threat to human health. Despite recent advances in research on the pathogenesis and treatment of MASLD/MASH, there is still a lack of more effective and targeted therapies. Extracellular vesicles (EVs) discovered in a wide range of tissues and body fluids encapsulate different activated biomolecules and mediate intercellular communication. Recent studies have shown that EVs derived from the liver and adipose tissue (AT) play vital roles in MASLD/MASH pathogenesis and therapeutics, depending on their sources and intervention types. Besides, adipose-derived stem cell (ADSC)-derived EVs appear to be more effective in mitigating MASLD/MASH. This review presents an overview of the definition, extraction strategies, and characterisation of EVs, with a particular focus on the biogenesis and release of exosomes. It also reviews the effects and potential molecular mechanisms of liver- and AT-derived EVs on MASLD/MASH, and emphasises the contribution and clinical therapeutic potential of ADSC-derived EVs. Furthermore, the future perspective of EV therapy in a clinical setting is discussed.

This study aimed to investigate the structural properties of tobacco polysaccharide (TP) and its mechanism of modulating hyperlipidemia in high-fat diet-induced mice. The structural properties of TP were characterized by FT-IR, 1HNMR, SEM, AFM and thermogravimetric analysis. And the regulatory mechanism of TP on lipid metabolism was investigated in hyperlipidemia mice. These results showed that TP had a high composition of reducing monosaccharide and the glycosidic bond type was α-glycosidic bond. The intervention by TP resulted in a significant reduction of body weight and improvement in lipid accumulation. And the modulation mechanism by which TP ameliorated the abnormalities of lipid metabolism was associated with the expression levels of lipid metabolism-related genes and serum exosomes miRNA-128-3p, as well as the modulation of structure and abundance of the gut microbiota in mice. In addition, TP treatment significantly increased the content of short-chain fatty acids (SCFAs) in mice feces. The results of molecular docking and dual-luciferase assay exhibited a good interaction between propionic acid and PPAR-α, and it was hypothesized that the interaction might further ameliorate the hyperlipidemia. Therefore, TP can regulate the expression levels of lipid metabolism-related genes through miRNAs from serum exosomes and SCFAs from gut microbiota.

The growing prevalence of NAFLD and its global health burden have provoked considerable research on possible diagnostic and therapeutic options for NAFLD. Although various pathophysiological mechanisms and genetic factors have been identified to be associated with NAFLD, its treatment remains challenging. In recent years, exosomes have attracted widespread attention for their role in metabolic dysfunctions and their efficacy as pathological biomarkers. Exosomes have also shown tremendous potential in treating a variety of disorders. With increasing evidence supporting the significant role of exosomes in NAFLD pathogenesis, their theragnostic potential has become a point of interest in NAFLD. Expectedly, exosome-based treatment strategies have shown promise in the prevention and amelioration of NAFLD in preclinical studies. However, there are still serious challenges in preparing, standardizing, and applying exosome-based therapies as a routine clinical option that should be overcome. Due to the great potential of this novel theragnostic agent in NAFLD, further investigations on their safety, clinical efficacy, and application standardization are highly recommended.

Non-alcoholic steatohepatitis (NASH) is a hepatocyte inflammation based on hepatocellular steatosis, yet there is no effective drug treatment. Atherosclerosis (AS) is caused by lipid deposition in the endothelium, which can lead to various cardiovascular diseases. NASH and AS share common risk factors, and NASH can also elevate the risk of AS, causing a higher morbidity and mortality rate for atherosclerotic heart disease. Therefore, timely detection and diagnosis of NASH and AS are particularly important. In this study, differential gene expression analysis and weighted gene co-expression network analysis were performed on the AS (GSE100927) and NASH (GSE89632) datasets to obtain common crosstalk genes, respectively. Then, candidate Hub genes were screened using four topological algorithms and externally validated in the GSE43292 and GSE63067 datasets to obtain Hub genes. Furthermore, immune infiltration analysis and gene set variation analysis were performed on the Hub genes to explore the underlying mechanisms. The DGIbd database was used to screen candidate drugs for AS and NASH. Finally, a NASH model was constructed using free fatty acid-induced human L02 cells, an AS model was constructed using lipopolysaccharide-induced HUVECs, and a co-morbidity model was constructed using L02 cells and HUVECs to verify Hub gene expression. The result showed that a total of 113 genes common to both AS and NASH were identified as crosstalk genes, and enrichment analysis indicated that these genes were mainly involved in the regulation of immune and metabolism-related pathways. 28 candidate Hub genes were screened according to four topological algorithms, and CXCL9, IL2RB, and SPP1 were identified as Hub genes after in vitro experiments and external dataset validation. The ROC curves and SVM modeling demonstrated the good diagnostic efficacy of these three Hub genes. In addition, the Hub genes are strongly associated with immune cell infiltration, especially macrophages and γ-δ T cell infiltration. Finally, five potential therapeutic drugs were identified. has-miR-185 and hsa-miR-335 were closely related to AS and NASH. This study demonstrates that CXCL9, IL2RB, and SPP1 may serve as potential biomarkers for the diagnosis of the co-morbidity patterns of AS and NASH and as potential targets for drug therapy.

MicroRNAs (miRNAs) are small noncoding RNAs approximately 22 nucleotides in length. Their main function is to regulate gene expression at the posttranscriptional level by inhibiting the translation of messenger RNAs (mRNAs). miRNAs originate in the cell nucleus from specific genes, where they can perform their function. However, they can also be found in serum, plasma, or other body fluids travelling within vesicles called exosomes and/or bound to proteins or other particles such as lipoproteins. miRNAs can form complexes outside the cell where they are synthesized, mediating paracrine and endocrine communication between different tissues. In this way, they can modulate the gene expression and function of distal cells. It is known that the expression of miRNAs can be affected by multiple factors, such as the nutritional or pathological state of the individual, or even in conditions such as obesity, insulin resistance, or after any dietary intervention. In this review, we will analyse miRNAs whose expression and circulation are affected in conditions of obesity and insulin resistance, as well as the changes generated after a dietary intervention, with the purpose of identifying new possible biomarkers of early response to nutritional treatment in these conditions.

Exosomes play a key role in cell-to-cell communication by transferring their cargo to target tissues. Little is known on the course of exosome size and number in infants and children.

Longitudinally, we assessed the size and number of circulating exosomes at birth and at ages 2 and 7 yr in 75 infants/children born appropriate-for-gestational-age (AGA; n=40) or small-for-gestational-age (SGA; n=35 with spontaneous catch-up), and related those results to concomitantly assessed measures of endocrine-metabolic health (HOMA-IR; IGF-1), body composition (by DXA at ages 0 and 2) and abdominal fat partitioning (subcutaneous, visceral and hepatic fat by MRI at age 7).

Circulating exosomes of AGAs decreased in size (on average by 4.2%) and increased in number (on average by 77%) between birth and age 7. Circulating exosomes of SGAs (as compared to those of AGAs) had a larger size at birth [146.8 vs 137.8 nm, respectively; p=0.02], and were in lower number at ages 2 [4.3x1011 vs 5.6x1011 particles/mL, respectively; p=0.01] and 7 [6.3x1011 vs 6.8x1011 particles/mL, respectively; p=0.006]. Longitudinal changes were thus more pronounced in SGAs for exosome size, and in AGAs for exosome number. At age 7, exosome size associated (P<0.0001) to liver fat in the whole study population.

Early-life changes in circulating exosomes include a minor decrease in size and a major increase in number, and these changes may be influenced by fetal growth. Exosome size may become one of the first circulating markers of liver fat in childhood.

As the pediatric obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in childhood. Pediatric NAFLD pathophysiology is tangled and still unclear, but insulin resistance (IR), genetics, epigenetics, oxidative stress, and inflammation act as key players. Due to the increased cardiometabolic risk of these patients, several biomarkers have been proposed for early NAFLD identification, but their clinical utility is poor. Recently, hepatic dysregulation of microRNAs (miRNAs) has been linked to metabolic dysfunction, which in turn implied in NAFLD development. Evidence on the intriguing role of miRNAs in NAFLD pathogenesis has emerging especially in at-risk children such as those with obesity. However, pediatric evidence supporting their potential use as early noninvasive NAFLD tools is still limited but promising.

We provided an overview on the emerging role of miRNAs in pediatric NAFLD by addressing some issues regarding their pathophysiological link with the metabolic milieu and their role as reliable NAFLD markers in children with obesity.

Strong evidence supports a potential role of miRNAs as early biomarkers of NAFLD in children with obesity. They might represent a valid diagnostic and targeted therapeutic tool due to its close pathogenic link with the metabolic milieu.

Exosomes are lipid-bound particles that carry lipids, protein, and nucleic acid and affect cellular function. This review highlights the current knowledge on the crosstalk between exosomes and lipid metabolism and their impact on cardiometabolic disease.

Recent studies revealed that lipids and lipid metabolizing enzymes are important for exosome biogenesis and internalization and conversely how exosomes affect lipid metabolism, secretion, and degradation. The interplay between exosomes and lipid metabolism affects disease pathophysiology. More importantly, exosomes and lipids might function as biomarkers for diagnosis and prognosis or possibly therapies.

Recent advances in our understanding of exosomes and lipid metabolism have implications for our understanding of normal cellular and physiological functions as well as disease pathogenesis. Exosome and lipid metabolism have implications in novel diagnostic tests and treatments of cardiometabolic disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. However, biomarkers for NAFLD diagnosis and liver-specific drugs for treatment are lacking. This article reviews the possibility of circulating miRNAs in the diagnosis and treatment of NAFLD diseases and focuses on several well-studied miRNAs to provide preclinical data for subsequent related studies.

Related articles were identified through searches of the PubMed database for literature published from 2010 to December 2022. Search terms included NAFLD, microRNA, biomarker, diagnosis, and therapy.

Current research data indicate that some key circulating miRNAs may be used as diagnostic biomarkers of NAFLD and the combination of several miRNAs improves diagnostic performance. In addition, some preclinical trials using cell and mouse models provide a basis for some miRNAs as potential therapeutic targets.

Current evidence suggests that circulating miRNAs are potential noninvasive biomarkers for clinical diagnosis of NAFLD, which needs to be validated in more heterogeneous and larger cohorts. In addition, several miRNAs regulate multiple downstream pathways related to the pathophysiology of NAFLD in a cell- and tissue-specific manner, making them attractive drug therapeutic targets for NAFLD. However, more preclinical and clinical trials are needed for these miRNAs to become therapeutic targets of NAFLD.

MicroRNAs (miRNAs) are secreted from cells as either protein-bound or enclosed in extracellular vesicles. Circulating liver-derived miRNAs are modifiable by weight-loss or insulin-sensitizing treatments, indicating that they could be important biomarker candidates for diagnosis, monitoring, and prognosis in nonalcoholic liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Unfortunately, the noninvasive diagnosis of NASH and fibrosis remains a key challenge, which limits case finding. Current diagnostic guidelines, therefore, recommend liver biopsies, with risks of pain and bleeding for the patient and substantial healthcare costs. Here, we summarize mechanisms of RNA secretion and review circulating RNAs associated with NAFLD and NASH for their biomarker potential. Few circulating miRNAs are consistently associated with NAFLD/NASH: miR-122, miR-21, miR-34a, miR-192, miR-193, and the miR-17-92 miRNA-cluster. The hepatocyte-enriched miRNA-122 is consistently increased in NAFLD and NASH but decreased in liver cirrhosis. Circulating miR-34a, part of an existing diagnostic algorithm for NAFLD, and miR-21 are consistently increased in NAFLD and NASH. MiR-192 appears to be prominently upregulated in NASH compared with NAFDL, whereas miR-193 was reported to distinguish NASH from fibrosis. Various members of miRNA cluster miR-17-92 are reported to be associated with NAFLD and NASH, although with less consistency. Several other circulating miRNAs have been reported to be associated with fatty liver in a few studies, indicating the existence of more circulating miRNAs with relevant as diagnostic markers for NAFLD or NASH. Thus, circulating miRNAs show potential as biomarkers of fatty liver disease, but more information about phenotype specificity and longitudinal regulation is needed.

Chronic hepatitis C virus (HCV) infection is the principal etiology of cirrhosis and, ultimately, hepatocellular carcinoma (HCC). At present, approximately 71 million people are chronically infected with HCV, and 10%-20% of these are expected to develop severe liver complications throughout their lifetime. Scientific evidence has clearly shown the causal association between miRNAs, HCV infection and HCC. Although it is not completely clear whether miRNA dysregulation in HCC is the cause or the consequence of its development, variations in miRNA patterns have been described in different liver diseases, including HCC. Many studies have analyzed the importance of circulating miRNAs and their effect on cell proliferation and apoptosis. In this Review, we aim to summarize current knowledge on the association between miRNA, HCV and HCC from a diagnostic point of view, and also the potential implications for therapeutic approaches.