
Exosomal miRNAs in pancreatitis: Mechanisms and potential applications (Review)
- Authors:
- Published online on: May 23, 2025 https://doi.org/10.3892/mmr.2025.13575
- Article Number: 210
-
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Pancreatitis, characterized by inflammation of the pancreas, is a severe and often life-threatening condition that occurs in both acute and chronic forms. Acute pancreatitis (AP) is frequently associated with reversible pancreatic injury, whereas chronic pancreatitis (CP) is associated with persistent inflammation, fibrosis and loss of pancreatic function (1,2). The pathogenesis of pancreatitis involves complex interactions between the pancreas, immune system and various metabolic and environmental factors, such as alcohol consumption, gallstones and dyslipidemia (3). When left untreated, pancreatitis can progress to complications such as pancreatic necrosis, pseudocysts, or pancreatic cancer, making timely diagnosis and effective treatment critical (4). Despite substantial advancements in understanding the pathophysiology of pancreatitis, clinical management of this condition remains challenging, with a lack of reliable biomarkers for early diagnosis and limited therapeutic options to mitigate inflammation and tissue damage (5,6).
Exosomal miRNAs are small, non-coding RNA molecules packaged into extracellular vesicles (EVs), such as exosomes, which mediate intercellular communication by transferring genetic material and modulating the function of recipient cells (7,8). A number of miRNAs have been implicated in a wide range of physiological and pathological processes, including inflammation, immune modulation, cell survival and fibrosis, which are key factors in pancreatitis (9,10). Exosomal miRNAs can modulate various cellular responses in pancreatitis, by influencing the behavior of various cell types, such as pancreatic acinar cells (PACs), immune cells and pancreatic stellate cells (PSCs). For example, exosomal miR-148a and miR-551b-5p, which are upregulated in the peripheral blood of patients with AP, promote activation of the IL-6/STAT3 pathways, further amplifying autophagy impairment in PACs (11). Conversely, exosomal miR-130a-3p, a profibrotic miRNA, plays a protective role by promoting PSC activation and collagen formation via suppressing suppression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (12). Indeed, exosomal miRNA profiles evolve throughout pancreatitis progression. During the acute phase of pancreatitis, exosomal miRNAs such as miR-21 and miR-155 are upregulated and associated with inflammatory responses and immune cell activation. As pancreatitis progresses to the chronic stage, the role of exosomal miRNAs in fibrosis becomes more prominent, with miR-122 being involved in regulating collagen deposition and tissue remodeling. Furthermore, the chronic stage may also see an increased presence of exosomal miRNAs that modulate immune cell infiltration, particularly miR-146a, which is involved in controlling macrophage polarization (13). Therefore, understanding the role of exosomal miRNAs in the pathogenesis of pancreatitis is crucial for identifying novel biomarkers for early diagnosis and exploring miRNA-based therapeutic strategies.
The present review summarized the pathogenesis of pancreatitis and the biogenesis and functions of exosomal miRNAs. It also focused on the mechanisms by which exosomal miRNAs modulate cellular responses during pancreatitis, their potential as biomarkers for early diagnosis and their emerging role as therapeutic agents for the management of this disease.
Pathogenesis of pancreatitis
Pancreatitis, an inflammatory condition of the pancreas, is classified as AP and CP. AP is typically a self-limiting disease, whereas CP results from repeated episodes of inflammation that culminates in irreversible damage, fibrosis and functional impairment of the pancreas (14). The pathogenesis of pancreatitis involves a complex interplay between PACs, inflammatory cells and various molecular signaling pathways.
Pancreatitis is initiated by an insult to PACs, resulting in the intracellular activation of digestive enzymes such as trypsinogen that target the breakdown of pancreatic tissue and initiate an inflammatory an inflammatory response that contributes to both local and systemic complications (15). One of the most common causes of AP is obstruction of the common bile duct by gallstones, which leads to increased pancreatic duct pressure and premature activation of digestive enzymes within PACs. This obstruction also facilitates the reflux of bile acids into the pancreatic ducts, which can directly injure acinar cells and further enhance inflammation (16). Additionally, alcohol induces the secretion and activation of pancreatic enzymes within PACs. Alcohol metabolism in the liver produces toxic metabolites, such as acetaldehyde, which promote oxidative stress, inflammation and pancreatic tissue injury (17). Viral infections, such as mumps and coxsackievirus, as well as hematological conditions, such as hypertriglyceridemia, can also trigger pancreatitis. Elevated triglyceride levels result in the formation of lipid droplets that obstruct the pancreatic ducts and facilitate PAC injury and inflammation (18).
The activation of digestive enzymes within PACs initiates a cascade of inflammatory events. Persistent inflammation can progress to severe forms in the presence of systemic inflammation, ischemia and multi-organ failure (19). Upon injury, PACs release pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6, which amplify the inflammatory response by recruiting and activating immune cells, such as neutrophils and macrophages (20). These cytokines contribute to systemic inflammation and trigger the development of sepsis and systemic inflammatory response syndrome (21). Also, cytokine signaling promotes endothelial activation, increases vascular permeability and facilitates extravasation of immune cells into pancreatic tissue. Infiltrating inflammatory cells release additional pro-inflammatory mediators, such as reactive oxygen species (ROS), matrix metalloproteinases and cytokines, thereby propagating local tissue injury and contributing to systemic inflammation (22). As a key regulator of inflammation in pancreatitis, the pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome can be activated by cellular stressors such as ROS, calcium overload and ATP release, thus promoting the release of IL-1β and IL-18, which amplifies the inflammatory cascade and contributes to the tissue damage observed in both acute and chronic pancreatitis (23). In chronic pancreatitis, ongoing inflammation leads to the activation of PSCs, which play a central role in fibrosis. Upon activation, PSCs transform into myofibroblasts and produce excessive extracellular matrix components, such as collagen, leading to pancreatic fibrosis. This fibrotic process impairs pancreatic function and disrupts normal tissue architecture (24).
The involvement of exosomal miRNAs in pancreatic cell injury, inflammation, fibrosis and tissue remodeling processes provides an additional layer of regulation, which influences disease progression and resolution. Exosomal miRNAs are key modulators of inflammation, fibrosis, PAC death and immune cell function, making them attractive candidates for diagnostic and therapeutic applications in pancreatitis. Exosomal miRNAs function as a part of complex networks involving cytokines, chemokines and other exosome-associated RNAs (25). The interplay between exosomal miRNAs and factors such as extracellular matrix components, growth factors and immune modulators contributes to the pathogenesis of pancreatitis. Although animal models of pancreatitis, such as the cerulein-induced model, have provided valuable insights into the inflammatory and fibrotic stages of the disease, they fail to fully mimic human pancreatitis owing to species differences in disease progression and immune responses. Current models typically lack the complexity of human tissue microenvironments, limiting their ability to accurately reflect the role of exosomal miRNAs in intercellular communication (26). Thus, the development of more advanced models, such as organoid cultures and humanized mouse models, is necessary to study the interactions between exosomal miRNAs and pancreatic cells.
Overviews of exosomal miRNAs
miRNAs are small, non-coding RNA (ncRNA) molecules that play crucial roles in the regulation of gene expression at the post-transcriptional level and are involved in various physiological and pathological processes, including inflammatory responses, immune modulation and pancreatitis pathogenesis (27). Exosomes, a subset of EVs, have emerged as vital mediators of intercellular communication, transporter of various bioactive molecules including miRNAs (9). Exosomal miRNAs can transfer genetic information and modulate gene expression in recipient cells, influencing their function and behavior (10). Exosomal communication is vital for the maintenance of cellular homeostasis and coordination of complex biological responses.
Biogenesis of miRNAs
The biogenesis of miRNAs begins in the nucleus with the transcription of miRNA genes, which are often located within intergenic regions, although they can also be found within introns of protein-coding genes or within the untranslated regions (UTRs) of other ncRNA (28). Transcription of miRNA genes is tightly regulated by various factors that respond to cellular cues, including those involved in inflammation, stress and immune responses (29). In pancreatitis, inflammatory signals can influence the expression of specific miRNAs, potentially altering disease progression and resolution (30).
The biogenesis of miRNAs is an intricate, multi-step process involving both canonical and non-canonical pathways that are modulated to ensure gene expression and cellular function (Fig. 1). Initially, miRNAs are transcribed into primary miRNAs (pri-miRNAs) by RNA polymerase II, which produces a long primary transcript that is capped, polyadenylated and spliced, similar to conventional mRNAs (31). Subsequently in the nucleus, pri-miRNAs undergo crucial catalyzation by a microprocessor complex consisting of Drosha, a ribonuclease III enzyme and its cofactor DGCR8 (DiGeorge syndrome critical region 8) to generate a precursor miRNA (pre-miRNA) (32). Drosha cleaves the pri-miRNA in a sequence-dependent manner, excising a 60–70 nucleotide stem-loop structure from the primary transcript, resulting in the formation of the pre-miRNA. Subsequently, Exportin-5 recognizes the pre-miRNA's stem-loop structure and facilitates its transport across the nuclear envelope and into the cytoplasm for further processing. In the cytoplasm, pre-miRNAs undergo a second processing step facilitated by another ribonuclease III enzyme Dicer, which cleaves the pre-miRNA~22 nucleotides from the terminal loop, resulting in a double-stranded RNA duplex composed of the mature miRNA (the guide strand) and its complementary passenger strand (33). The miRNA duplexes are then loaded onto argonaute (AGO) proteins to form the RNA-induced silencing complex (RISC), wherein the guide strand retained is considered a mature miRNA and the other strand is typically degraded (34). Mature miRNAs within the RISC complex then bind to complementary sequences in the 3′UTRs of target mRNAs, promoting mRNA degradation or translational suppression, thereby post-transcriptionally regulating gene expression (35).
Although the canonical pathway of miRNA biogenesis is well-established, several non-canonical pathways also exist. For example, mirtrons are a prominent class of Drosha-independent miRNAs that are directly spliced from introns (36). Additionally, pre-miRNAs are directly cleaved by ribonuclease 3B2, resulting in the generation of mature miRNAs without the need for Dicer (37). Another non-canonical miRNA biogenesis pathway involves alternative splicing of primary transcripts. Exon-derived miRNAs, also called exonic miRNAs, are a subset of miRNAs formed by the alternative splicing of pre-mRNA. These miRNAs are produced from exon-exon junctions of coding genes and are typically processed by Dicer without requiring the typical Drosha cleavage step (38). These alternative mechanisms enable cells to generate miRNAs through distinct enzymatic processes, bypassing key steps in the canonical pathway and providing additional layers of control over miRNA expression and function. The biogenesis of miRNAs is not only crucial for physiological processes but also participates in disease pathogenesis. Understanding the detailed mechanisms of miRNA biogenesis, including both canonical and non-canonical pathways and the regulatory networks involved and provides valuable insights into their roles in pancreatitis.
Exosomal miRNA sorting and transport
The sorting of miRNAs into exosomes is a highly selective and regulated process (Fig. 1). Exosome biogenesis begins in the multivesicular bodies (MVBs), which are formed when the early endosomes mature and invaginate, creating intraluminal vesicles (ILVs) that fuse the MVB with the plasma membrane to generate exosomes (39). The endosomal sorting complex required for transport (ESCRT) proteins, including TSG101 and Alix, are involved in the budding of intraluminal vesicles within the MVBs. The ESCRT machinery interacts with RNA-binding proteins to enrich specific miRNAs in exosomes (40). For instance, heterogeneous nuclear ribonucleoprotein A2B1 binds to miRNAs and facilitates their interaction with the exosomal membrane, while Y-box binding protein 1 acts as an adaptor to facilitate the incorporation of miRNAs into exosomes by interacting with both miRNAs and ESCRT proteins (41,42). Rab GTPases are key regulators of vesicular trafficking and several members of the Rab family, including Rab27a and Rab27b, have been implicated in the packaging of miRNAs into exosomes. These GTPases control the movement of MVBs to the plasma membrane and their subsequent fusion with the membrane to release exosomes (43,44). Once miRNA-loaded exosomes are released into the extracellular environment, they can be taken up by recipient cells through several mechanisms, including endocytosis, phagocytosis, or direct fusion with the plasma membrane (45). For instance, caveolin-mediated and clathrin-mediated endocytosis are two prominent mechanisms by which exosomes can enter target cells (46,47). Also, exosomes can fuse directly with the plasma membrane of recipient cells, releasing their cargo without internalization (48). The transport of exosomal miRNAs to distant tissues is particularly important in pancreatitis, in which inflammatory signals and cellular stress may elicit the secretion of exosomes containing miRNAs that modulate immune responses and tissue damage.
Exosomal miRNA functions
Exosomal miRNAs mediate intercellular communication under various physiological and pathological conditions. Once inside the recipient cell, exosomal miRNAs are released from the vesicles and participate in diverse cellular processes including inflammation, immune modulation, tissue repair and fibrosis (49,50). As messengers, exosomal miRNAs exert profound effects on recipient cells by regulating gene expression at the post-transcriptional level, often via translational repression or mRNA degradation (51). In addition, exosomal miRNAs exert a ligand-like function in recipient cells, where they act as direct agonists of specific receptor families by interacting with proteins, thereby affecting cellular processes and disease progression (52). Thus, exosomal miRNAs function as critical mediators of intercellular communication, orchestrating a complex network of pro-inflammatory and pro-fibrotic signals by regulating both local pancreatic cell behaviors and systemic immune responses. Understanding the biogenesis, sorting, transport and function of exosomal miRNAs is essential for elucidating their roles in pancreatitis. Furthermore, different exosome isolation techniques affect the purity and yield of exosomes, which in turn affects downstream miRNA analysis. For example, ultracentrifugation leads to contamination with protein aggregates and other vesicles, which skew miRNA profiles (53). Precipitation-based methods, such as ExoQuick, fail to isolate the purest exosomes (54). The emerging microfluidic technologies offer the advantage of high precision and minimal sample volume, but they are not yet widely available for routine clinical use (55). However, factors include variations in the source of exosomes, such as blood and pancreatic fluid, differences in isolation protocols and the presence of other biomolecules, such as proteins and lipids that may interfere with miRNA quantification. Additionally, the dynamic nature of exosomal miRNA release in response to environmental stimuli such as inflammation or oxidative stress can lead to fluctuations in miRNA levels, complicating their use as stable biomarkers.
Effects of exosomal miRNAs on various cell types during pancreatitis
Exosomal miRNAs are involved in pancreatitis by influencing various pathological processes, such as inflammation, pancreatic injury, fibrosis and external pancreatic organ injury. Various cell types are affected by exosomal miRNAs, which regulate the expression of genes related to various cellular processes and signaling pathways in pancreatitis (Table I; Fig. 2). Exosomes are produced by various cells, including PACs and immune cells and the miRNA cargo in these exosomes can vary based on their tissue of origin. For example, exosomes derived from PACs carry miRNAs that regulate digestive enzyme secretion and inflammation, such as miR-503-322 (56). By contrast, exosomes from immune cells such as macrophages and T cells carry miRNAs that modulate the immune response in pancreatitis (57). Understanding the tissue-specific profiles of exosomal miRNAs is important for developing targeted diagnostic and therapeutic approaches. It should be noticed that lncRNAs and circRNAs can act as sponges for miRNAs, thereby altering their availability and functional impact on target genes. For instance, the lncRNA MALAT1 has been shown to modulate the effects of miR-181a-5 in macrophage polarization. The collective activity of these RNAs within exosomes can influence the inflammatory response, fibrosis and immune regulation in pancreatitis, reflecting a more complex and integrated view of disease mechanisms (58).
Macrophages
Macrophage activation leads to an imbalance in cytokine networks, promoting systemic inflammation and potentially resulting in multiple organ failure in AP. Overactivated macrophages produce excessive pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β, which exacerbate the inflammatory response and contribute to pancreatic endothelial barrier dysfunction and tissue damage (59). During CP, macrophages are activated by IL-4 and IL-13, which are secreted by PSCs and drive acinar-to-ductal metaplasia through the activation of nuclear factor-κB (NF-κB) and matrix metalloproteinases, thus participating in extracellular matrix remodeling and fibrosis, which have protective effects in pancreatitis but also contribute to cancer pathogenesis (60,61).
Exosomal miRNAs derived from pancreatic cells influence the inflammatory response of macrophages in pancreatitis by modulating their activation and polarization. For instance, PACs are known to release exosomes containing miRNAs that activate macrophages and promote inflammatory responses through the tumor necrosis factor receptor-associated factor 6/NF-κB signaling cascade, with miRNA target genes primarily involved in mitogen-activated protein kinases pathways, further mediating macrophage-mediated tissue damage (62). In rats with taurocholate-induced AP, plasma exosomes are enriched with miR-155, which harbors potent pro-inflammatory activity on macrophages (63). Overexpressed miR-155 aggravates impaired autophagy in caerulein-treated PACs by inhibiting the expression of Rictor (64). Silencing of miR-155 ameliorates pancreatic and lung damage in an AP mouse model by blocking the accumulation of autophagosomes that are unable to fuse with lysosomes and alleviates pancreatic inflammation by targeting TAK1-binding protein 2 (65). Increased levels of miR-155 are associated with severe AP and its expression increases with disease progression. Further mechanistic evaluation revealed that miR-155 increases the Th17-mediated inflammatory response by targeting suppressor of cytokine signaling 1 (SOCS1) (66). These findings demonstrate the pro-inflammatory role of miR-155, which can be loaded with exosomes to facilitate macrophage activation and inflammatory damage to the pancreas. In addition, elevated miR-183-5p levels in serum EVs are related to AP severity. Mechanistically, miR-183-5p is elevated in injured PACs and transported by EVs to macrophages where miR-183-5p induces M1 macrophage polarization through the downregulation of FoxO1 and the release of inflammatory cytokines, thereby aggravating AP-related injuries (67). In activated PACs and AP pancreatic tissue, exosomal miR-125b-5p is upregulated to promote M1 macrophage polarization and inhibit M2 macrophage polarization, resulting in massive production of pro-inflammatory factors and ROS accumulation by inhibiting insulin-like growth factor 2 expression and further activating the PI3K/AKT signaling pathway, thus exacerbating AP (68). Similarly, exosomal miR-24-3p derived from cerulein-treated PACs promotes peritoneal macrophage M1 polarization and pyroptosis by inhibiting membrane-associated RING-CH-type finger 3 (MARCH3) expression and reducing NLRP3 ubiquitination, which contributes to ROS production, inflammation and apoptosis in PACs (69).
Collectively, exosomal miRNAs affect macrophage behavior and shape the inflammatory milieu that is associated with pancreatitis. Although exosomal miRNAs from pancreatic cells predominantly promote inflammatory responses in macrophages, there is potential for therapeutic intervention. For instance, targeting specific exosomal miRNAs could mitigate the inflammatory effects and offer new avenues for treating pancreatitis. Additionally, understanding the exact role of exosomal miRNA-regulated macrophages in inflammation and tissue repair could provide insights into balancing these processes to improve clinical outcomes.
PACs
PACs are responsible for synthesizing and secreting digestive enzymes and the dysfunction of PACs initiates a cascade of events, including enzyme activation and inflammatory signaling, leading to inflammation and tissue damage (70). Pathological calcium overload triggers enzyme activation and cellular necrosis. It also elicits mitochondrial dysfunction and impairs ATP production, exacerbating cellular stress and injury, suggesting that calcium dysregulation is a key factor in the pathogenesis of pancreatitis (19). Hence, PAC injury and dysfunction are central to the pathogenesis of pancreatitis.
Exosomal miRNAs are considered to regulate PAC function, thus affecting the progression of pancreatitis. It has been reported that peripheral blood mononuclear cell-derived exosomal miR-148a and miR-551b-5p are highly expressed in patients with AP compared with healthy individuals. Mechanistic investigation reveals that overexpression of miR-148a in PACs decreases the secretion of IL-1β and IL-18 to mediate autophagy impairment through the IL-6/STAT3 signaling pathway (11). Moreover, miR-148a-3p deletion reduces inflammatory infiltration and protects against cell necrosis, amylase and lipase activity in AP by inducing phosphatase with tensin homology (PTEN) expression (71). These findings indicate that exosomal miR-148a functions as a detrimental factor in accelerating the progression of pancreatitis. Additionally, miR-551-5p is increased in the serum of both patients with mild and severe AP and upregulated miR-551-5p is involved in the regulation of inflammatory responses (72). Serum miR-551-5p levels can be useful for the assessment of pancreatic injury in the acute phase of AP and can also predict AP severity (73). These results imply that overexpressed miR-551-5p in the serum of patients with pancreatitis can be loaded by exosomes, which further disrupts PAC function and contributes to disease development.
Overall, exosomal miRNAs are pivotal in modulating PAC function in pancreatitis; however, their roles remain elusive. Future studies should explore the intricate network of miRNA interactions in the exosomal milieu and how these interactions influence PAC behavior. Understanding the synergistic or antagonistic effects of different miRNAs within exosomes may reveal new therapeutic avenues.
PSCs
When activated, PSCs transform from a quiescent state to a highly active phenotype that contributes to the fibrotic and inflammatory environment characteristic of pancreatitis. This transformation is influenced by various factors, including alcohol metabolites, cytokines and oxidative stress, which collectively exacerbate the disease progression (24). Activated PSCs contribute to the inflammatory milieu in pancreatitis by interacting with immune cells and producing cytokines and chemokines that recruit and activate immune cells, further amplifying inflammation (60). PSCs exhibit unique gene expression profiles associated with the progression from acute to CP, including genes involved in extracellular matrix remodeling and inflammation (74). Although PSCs are primarily associated with fibrogenesis and inflammation, they have been shown to have immunomodulatory functions, potentially preventing autoimmune pancreatitis by regulating immune cell recruitment (75). PSCs play a central role in the pathophysiology of AP, including fibrogenesis and inflammation. Understanding the regulatory roles of exosomal miRNAs in PSCs offers potential therapeutic targets for mitigating the fibrotic and inflammatory responses in pancreatitis.
Exosomal miRNAs are implicated in the modulation of PSC activation and proliferation during pancreatitis. Exosomal miR-130a-3p, derived from PACs, can promote PSC activation and collagen formation by suppressing PPAR-γ in PSCs (12). Knockdown of miR-130a-3p alleviates pancreatic fibrosis, accompanied by decreased serum levels of hyaluronic acid and β-amylase and increased C-peptide levels, suggesting improved pancreatic function (12). Likewise, let-7 miRNA, which is enriched in exosomes from intact acinar cells, has been identified as a suppressor of PSC activation. Let-7 mediates the anti-fibrotic effects of acinar cells by modulating the expression of key signaling molecules involved in PSC activation (76). Additionally, in a murine model of alcoholic CP, exosomal miR-21 derived from activated PSCs promotes the expression of connective tissue growth factor; in turn, this provokes a phenotypic and functional transition from quiescent PSC to activated myofibroblasts, thereby producing and depositing collagen at high levels (77). During AP, miR-21 is upregulated to facilitate the inflammatory response and induce pancreatitis-associated lung injury by upregulating protein inhibitor of activated Stat3 and downregulating amphoterin (HMGB1) expression (78). Following resveratrol treatment, the expression of miR-21 in activated PSCs is reduced, which attenuates ROS-induced activation, invasion, migration and glycolysis of PSCs by upregulating the PTEN protein level (79). These results indicate that exosomal miR-21 represents novel aspects in PSC activation and fibrogenic regulation during pancreatitis.
In conclusion, exosomal miRNAs modulate PSC activation and proliferation, thus affecting inflammatory responses and fibrosis during pancreatitis. Exosomal miRNAs are involved in complex networks of cellular communication that extend beyond PSCs and influence pancreatitis progression. Clarifying the broader mechanisms underlying the role of exosomal miRNAs in pancreatitis is crucial to validate their therapeutic utility. It can be hypothesized that miRNAs associated with exosomes from PSCs could have distinct functional roles compared with those derived from acinar or ductal cells. In addition, exosomal miRNAs may interact with other exosomal secretions to form regulatory networks that influence pancreatic inflammation and fibrosis.
β cells
Pancreatic β cells, primarily responsible for insulin production, are affected by inflammatory processes, oxidative stress and immune-mediated damage, leading to their dysfunction and eventual loss, which are critical factors in the progression of pancreatitis as they result in impaired insulin secretion and glucose regulation (80). These cells are involved in the inflammatory response during pancreatitis through their interaction with cytokines and the subsequent cellular stress responses. During AP, EVs derived from M1 macrophages encapsulate inflammatory mitochondria and subsequently penetrate pancreatic β cells, causing lipid peroxidation and mitochondrial disruption (81). Moreover, fragments of mitochondrial DNA are released into the cytosol, activating the STING pathway and ultimately inducing apoptosis of β cells, which aggravates inflammatory responses and pancreatitis progression (81). Notably, exosomal miRNAs have been shown to modulate β cells and affect disease development. In transforming growth factor-β1-treated PSCs, exosomal miR-140-3p and miR-143-3p are delivered into β cells, where they increase the cleaved caspase-3 levels and induce cell death via repressing the expression of B-cell lymphoma 2 (82). However, downregulated miR-140-3p has been discovered in patients with severe AP and acute lung injury (83). Consistently, overexpression of miR-143-3p in β cells reverses high glucose-induced cell apoptosis and impairments in cell viability and insulin secretion, as well as attenuates proinflammatory cytokine production (84). These findings suggest that miR-140-3p and miR-143-3p exert protective effects against pancreatitis.
In summary, the role of exosomal miRNAs is context-dependent. As key regulators of β cell differentiation and function, dysregulation of exosomal miRNAs can affect pancreatitis and various forms of diabetes mellitus. Understanding the specific roles of exosomal miRNAs in β cells can provide insights into novel therapeutic strategies for preserving β cell function and treating pancreatitis and diabetes-related complications.
Other cells
Pancreatitis triggers a systemic inflammatory response characterized by the release of pro-inflammatory cytokines and chemokines, which lead to the activation of immune cells like neutrophils and macrophages, thereby contributing to endothelial dysfunction, capillary leakage and increased pulmonary vascular permeability, pulmonary edema and tissue injury (85). Notably, miRNA transcriptomics analysis shows miR-483-5p and miR-503-5p derived from EVs of severe AP-associated lung injury patients, can promote inflammatory responses and pulmonary injury by targeting histone deacetylase-2 (HDAC2) and uncoordinated-5 homolog B (UNC5B), respectively (86). In addition, the systemic inflammatory response in pancreatitis activates the gut-associated lymphoid tissue and increases cytokine production, along with the hydrolysis of pancreatic enzymes, which contribute to intestinal mucosal injury, leading to conditions such as ileus, ischemia and microbial dysbiosis (87). miR-155-5p is enriched in circulating exosomes from severe AP rats and can be delivered into intestinal epithelial cells, where it inhibits SOCS1 to activate NLRP3 inflammasome-mediated pyroptosis, leading to intestinal barrier damage (88). In addition, blocking exosome release with GW4869 attenuates intestinal injury (88). Similarly, downregulating the expression of miR-155-5p by stellate ganglion block can lessen the production of pro-inflammatory cytokines and alleviate lung tissue damage and edema via the SOCS5/JAK2/STAT3 axis in severe AP rats (89).
In summary, exosomal miRNAs contribute to the pathogenesis of pancreatitis-related lung and gut injury by modulating inflammatory responses, gut barrier integrity, endothelial function and immune cell recruitment. Their roles as mediators of inter-organ communication suggest that targeting exosomal miRNAs may offer a novel therapeutic approach to mitigate the severity of pancreatitis. However, further research is needed to fully elucidate the precise mechanisms by which exosomal miRNAs affect the function of distant organs.
Exosomal miRNAs as biomarkers for pancreatitis
Exosomal miRNAs have emerged as promising biomarkers in the diagnosis and prognosis of various diseases, due to their stability and presence in body fluids, which makes them accessible for non-invasive testing (90–92). The potential of exosomal miRNAs as diagnostic and prognostic tools to offer insights into disease mechanisms and progression has been increasingly recognized. These miRNAs serve as potential biomarkers for the diagnosis of pancreatitis. They exhibit distinct expression patterns in pancreatitis patients compared with healthy individuals and their levels are related to disease severity. For instance, three previously unreported exosomal miRNAs from plasma of patients with severe AP are named as Novel1, Novel2 and Novel3, which are remarkably different from healthy participants, providing classification of patients with severe AP from healthy populations; moreover, animal experiments reveal that complement component 3 is a target gene of Novel3 and may serve as early diagnostic biomarker of severe AP (93). In addition, seven candidate signature exosomal miRNAs derived from blood of severe AP are identified as diagnostic biomarkers, which including miR-603, miR-548ad-5p, miR-122-5p, miR-4477a, miR-192-5p, miR-215-5p and miR-583 (94). Compared with healthy individuals, miR-579-3p was decreased in EVs from patients with CP and CP narcotic users, but is enriched within EV in pre-diabetic CP patients compared with non-diabetic patients with CP. These findings suggest that plasma EV miR-579-3p serve as basis for assessing pancreatic health (95). In addition, exosomal miRNA profiles can help differentiate various disease phenotypes, allowing for more tailored treatment approaches. For example, in type 1 autoimmune pancreatitis, circulating EVs show altered miRNA expression patterns with elevated miR-21-5p when compared with those in healthy controls and CP. Further studies unveiled that miR-21-5p is highly expressed in pancreatic inflammatory cells, suggesting that EV miR-21-5p derived from inflammatory cells might be involved in the progression of type 1 autoimmune pancreatitis (96). In addition, the diagnostic potential of exosomal miRNAs extends beyond pancreatitis to other complications, such as patients with AP, where exosomal miR-4265, miR-1208, miR-3127-5p are verified to have the early predictive value for persistent organ failure. Increased levels of these exosomal miRNAs indicate urgent need for prolonged hospitalization, elevated mortality rate and thus unfavorable prognosis (97).
It can be inferred that exosomal miRNAs possess the potential to function as biomarkers for the early diagnosis, phenotypic characterization and prognostic assessment of pancreatitis (Table II). Consequently, it is imperative that ongoing investigations are directed towards the validation of the diagnostic efficacy of exosomal miRNAs in more extensive and heterogeneous patient populations. Furthermore, efforts should be made to standardize method for exosome isolation and miRNA analysis, thereby ensuring consistency and precision within clinical environments. Advances in technology, exemplified by high-throughput sequencing and digital PCR, are being used to enhance the sensitivity and specificity of exosomal miRNA detection. Moreover, the integration of exosomal miRNA profiling with other omics technologies, such as proteomics and metabolomics, has the potential to yield a more comprehensive understanding of the pathogenesis of pancreatitis and to identify novel biomarkers. In addition, the development of point-of-care diagnostic instruments for the rapid detection of exosomal miRNAs could transform the management of pancreatitis by facilitating real-time monitoring and enabling personalized therapeutic adjustments. Exosomal miRNAs exhibit good performance in the early diagnosis of pancreatitis. Serum levels of amylase and lipase, the most common markers for AP, typically increase only after significant pancreatic damage has occurred (98). By contrast, exosomal miRNAs reflect subtle changes in the cellular environment, including inflammation and stress responses, even before clinical symptoms or conventional biomarkers become detectable. For example, miR-503-322 is upregulated in the early stages of pancreatitis, providing a high sensitivity for disease detection than enzyme-based assays (56). While exosomal miRNAs, such as miR-579-3p and miR-21-5p, have shown high specificity for pancreatitis, their sensitivity may be limited, especially in the early stages of the disease when miRNA levels can be low. To improve both sensitivity and specificity, several studies have employed panels of miRNAs rather than focusing on a single biomarker. For instance, combining miR-4265 with miR-1208 and miR-3127-5p has been shown to improve their performance in the early diagnosis of pancreatitis (97). In addition, exosomal miRNAs have significant potential for prognostication in pancreatitis. For example, the elevation of miR-216a has been associated with the severity of AP and subsequent complications, such as pancreatic necrosis and acute lung injury. Elevated levels of miR-216a in exosomes reflect the degree of inflammation and tissue injury, offering an early indicator of disease severity (99). Traditional techniques such as RT-qPCR are highly sensitive but are limited by their inability to capture a broad spectrum of miRNAs. Newer technologies, such as next-generation sequencing, allow for high-throughput analysis and the identification of novel miRNAs, but they face challenges related to cost, complexity and bioinformatics analysis. Recent developments in digital PCR and microfluidic-based technologies, however, show promise for achieving higher sensitivity and specificity with minimal sample volume. For instance, advancements in liquid biopsy technology, such as the development of exosomal miRNA detection using surface acoustic wave sensor, have improved the detection sensitivity in clinical settings (100). These cutting-edge technologies enable the detection of low-abundance miRNAs and improve the reproducibility of miRNA profiling.
Exosomal miRNA-based potential therapies in pancreatitis
Mesenchymal stem cells (MSCs) are inhabit nearly all post-natal organs and tissues, including, but not limited to, bone marrow, adipose tissue, umbilical cord and placenta (101,102). Under suitable conditions, MSCs can differentiate into osteoblasts, adipocytes and chondroblasts, rendering them as promising candidates for therapeutic applications due to their remarkable plasticity (103,104). Exosomes derived from MSCs play a pivotal role in mediating the therapeutic efficacy of MSCs. These exosomes facilitate tissue repair and regeneration by transferring growth factors and microRNAs that promote cellular proliferation and differentiation (105,106). In AP, bone marrow MSC-derived exosomal miR-181a-5p can inhibit PSC cell apoptosis and promoting M2 macrophage polarization by downregulating the expression of zinc finger E-box binding homeobox 2 and further increasing receptor for activated C-kinase 1 expression, alleviating AP injury (107). Moreover, in sodium taurocholate and caerulein-induced severe AP rat models, miR-181a-5p derived from bone marrow MSCs mitigates severe AP and reduces inflammatory responses and PSC cell apoptosis by inhibiting the PTEN/AKT/TGF-β1 signaling pathway (108). Also, miR-29a-3p within MSC-derived EVs can be transferred into cardiomyocytes, where it reduces the production of inflammatory cytokines and attenuates severe AP-induced myocardial injury by inhibiting the expression of HMGB1 to downregulate TLR4 expression and further inactivating the AKT signaling pathway (109).
A number of drugs exert the therapeutic effect in pancreatitis via regulate exosomal miRNAs. For example, melatonin prevents M1 macrophage polarization and thus reduces the secretion of inflammatory EV miRNAs and thereby decreasing inflammatory EV-mediated β cell failure and apoptosis (57). Further mechanistic studies unveiled that melatonin downregulates the transcription of specific miRNAs and reduces miRNA transport into EVs by inactivating the NF-κB pathway (57). In addition, emodin, an anthraquinone derivative with anti-inflammatory, antioxidant, anti-fibrotic properties, is abundantly present in Chinese herbal medicines such as Polygoni cuspidati rhizoma et radix and Polygoni multiflori root (110). Intriguingly, in rats with severe AP, emodin treatment ameliorates pancreatic and lung injury and inflammation by elevating the expression of exosomal miR-29a-3p derived from bronchoalveolar lavage fluid (111).
However, as yet, no clinical trial has estimated exosomal miRNA-based therapeutic strategies in pancreatitis. The exploration of exosomal miRNAs as therapeutic targets in pancreatitis has unveiled a wealth of promising avenues for research and clinical application. Continued research into the biological roles of exosomal miRNAs, their clinical applications and the development of targeted therapies holds promise for transforming the landscape of pancreatitis treatment. In addition, an interdisciplinary approach that bridges fundamental research with clinical application will be crucial in unlocking the full potential of exosome-derived miRNAs in the fight against pancreatitis. A key challenge lies in the standardization of exosome isolation protocols, as current techniques, such as ultracentrifugation and immunoaffinity capture, can yield variable results, affecting the reproducibility of findings. To address this issue, regulatory bodies like the US FDA have initiated efforts to establish standardized guidelines for exosome-based diagnostics and therapeutics. Moreover, rigorous validation of miRNA biomarkers in large, multi-center clinical trials is essential to ensure their clinical utility. Additionally, the integration of exosomal miRNA-based therapies into clinical practice must navigate regulatory approval pathways that involve safety and efficacy trials. One promising approach involves the use of engineered exosomes as vehicles for miRNA delivery, which could improve tissue-specific targeting and reduce off-target effects. Exosome-based therapeutics could be designed to carry miRNAs that either inhibit pro-inflammatory pathways or promote tissue repair during pancreatitis.
Future directions
Exosomal miRNAs are increasingly recognized as critical mediators of intercellular communication that influence inflammation, fibrosis and tissue repair during pancreatitis. They have been implicated in several critical processes, including PAC functional modulation, macrophage activation and PSC-mediated fibrotic response (11,12,62). Dysregulation of exosomal miRNA profiles correlates with the severity and progression of both acute and CP, providing strong evidence for their utility as diagnostic and prognostic biomarkers. Some exosomal miRNAs, such as miR-24-3p and miR-130a-3p, are implicated in promoting inflammation and fibrosis in pancreatitis, while others like miR-503-5p play a protective role in tissue repair and resolution of inflammation (12,69,86). These discrepancies may stem from differences in study design, such as the timing of exosomal miRNA analysis during disease progression, or the use of distinct animal models. Thus, these conflicting findings highlight the complications in targeting miRNAs for therapeutic purposes. Indeed, exosomal miRNAs are known to regulate multiple target genes and cellular processes and their effects can vary based on several factors, including the timing of expression, the cellular context and the presence of other molecular players (77,82,88). These factors complicate the development of exosomal miRNA-based therapies, as the therapeutic targeting of miRNAs could have unintended consequences depending on the disease stage and the specific cellular environment. One of the primary challenges is the potential for off-target effects, which underscore the need for precise delivery systems and methods to control miRNA activity in vivo. Another significant challenge is the effective delivery of exosomal miRNAs. The ability to selectively target pancreas, while avoiding systemic distribution, is critical to minimizing side effects and achieving therapeutic efficacy. Furthermore, the differential expression of specific exosomal miRNAs across different stages of pancreatitis could lead to the identification of novel biomarkers that are not only specific to pancreatitis but also sensitive enough to detect early disease onset, which is often clinically challenging. In addition, exosomal miRNAs have been demonstrated to modulate inflammation and fibrosis, both of which are central to the pathogenesis of pancreatitis. By either inhibiting pro-inflammatory miRNAs or restoring the levels of anti-inflammatory miRNAs, researchers may reduce the extent of tissue damage and promote healing in the pancreas.
Despite promising findings, challenges remain to fully harness the potential of exosomal miRNAs for clinical application. One of the primary obstacles is the efficient and standardized isolation of exosomes from biofluids, particularly from complex samples such as blood, urine and pancreatic juice. The heterogeneous nature of exosomes, derived from various cell types, complicates the identification of disease-specific miRNA signatures (56–58). Current advanced isolation techniques have limitations in terms of purity, yield and reproducibility (53–55). Therefore, the development of more reliable and scalable methods for isolating and characterizing exosomes will be crucial for the clinical implementation of exosomal miRNA-based diagnostics. Another critical issue pertains to the efficient delivery of exosomal miRNAs for therapeutic purposes. While exosomes can naturally transport miRNAs across cell membranes, their use as therapeutic agents requires further refinement (10,13,102). Ensuring that miRNA mimics or inhibitors are delivered to the appropriate tissues in sufficient concentrations, without off-target effects, is a significant hurdle. Moreover, the immunogenicity and potential toxicity of exosomal preparations must be carefully evaluated before clinical applications. Progress in engineering exosomes for specific targeting, improving the stability of miRNAs during circulation and overcoming cellular barriers to miRNA uptake will be essential to fully realize their therapeutic potential (50,91,106). There is also great potential in utilizing exosomal miRNAs as part of a broader multi-omics approach to studying pancreatitis. Incorporating transcriptomic, proteomic and metabolomic data with exosomal miRNA profiles could lead to the identification of novel molecular pathways involved in disease progression. Such integrated approaches will be crucial for identifying therapeutic targets, as well as for improving diagnostic accuracy and patient stratification. One promising avenue is investigating the role of exosomal miRNAs in the regulation of pancreatic cell fate, such as apoptosis and autophagy. Using single-cell RNA sequencing technologies to profile the exosomal miRNA cargo at a high resolution, can link miRNA expression to specific cell types involved in pancreatitis. Additionally, integrating spatial transcriptomics with exosomal miRNA analysis could provide insights into the tissue-specific functions of these miRNAs during pancreatitis (10–13).
Furthermore, methods such as ultracentrifugation remain the gold standard for exosome isolation but are time-consuming and costly, limiting their use in routine clinical practice. Newer techniques such as size-exclusion chromatography and microfluidic devices have shown promise for improving cost-effectiveness and scalability (54,55). Additionally, for miRNA detection, technologies like RT-qPCR and next-generation sequencing are highly sensitive but may not be cost-effective for large-scale clinical use (53). A key point is the need for integrated platforms that combine exosome isolation and miRNA profiling, reducing the overall cost and improving throughput. Variations in exosome isolation methods, sample preparation protocols and miRNA detection techniques can lead to discrepancies in results. It is proposed that future researches should focus on developing consensus guidelines for exosome-based research, similar to those in other fields like genomics and proteomics, to improve the consistency of results across studies (102,106). In addition, researchers should take interdisciplinary research opportunities for integrating exosomal miRNA research with emerging technologies. For example, artificial intelligence and machine learning revolutionize the analysis of miRNA profiles by identifying hidden patterns in large datasets and predicting miRNA interactions with their targets (10). Single-cell RNA sequencing could be used in tandem with exosomal miRNA profiling to investigate how individual cells within the pancreas respond to specific miRNAs during disease progression (13). Spatial transcriptomics also offer a way to map the localization of exosomal miRNAs within tissue architecture, providing key insights into how these miRNAs influence cellular communication in the pancreatic microenvironment (50).
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
LW wrote the manuscript and designed the figures. JZ, ZH, XK, CL, YX and MY revised the manuscript. KW conceived the topic and revised the manuscript. All authors read and approved the final manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
AP |
acute pancreatitis |
AGO |
argonaute |
CP |
chronic pancreatitis |
CCN2 |
connective tissue growth factor |
DGCR8 |
DiGeorge syndrome critical region 8 |
ESCRT |
endosomal sorting complex required for transport |
EVs |
extracellular vesicles |
HDAC2 |
histone deacetylase-2 |
HMGB1 |
amphoterin |
IGF2 |
insulin-like growth factor 2 |
ILVs |
intraluminal vesicles |
miRNAs |
microRNAs |
MSCs |
mesenchymal stem cells |
MVBs |
multivesicular bodies |
NLRP3 |
pyrin domain (PYD)-containing protein 3 |
PACs |
pancreatic acinar cells |
PSCs |
pancreatic stellate cells |
PPAR-γ |
peroxisome proliferator-activated receptor gamma |
ROS |
reactive oxygen species |
RISC |
RNA-induced silencing complex |
SOCS1 |
suppressor of cytokine signaling 1 |
UNC5B |
uncoordinated-5 homolog B |
UTRs |
untranslated regions |
References
Trikudanathan G, Yazici C, Evans Phillips A and Forsmark CE: Diagnosis and management of acute pancreatitis. Gastroenterology. 167:673–688. 2024. View Article : Google Scholar : PubMed/NCBI | |
Hines OJ and Pandol SJ: Management of chronic pancreatitis. BMJ. 384:e0709202024. View Article : Google Scholar : PubMed/NCBI | |
Saluja A, Dudeja V, Dawra R and Sah RP: Early Intra-acinar events in pathogenesis of pancreatitis. Gastroenterology. 156:1979–1993. 2019. View Article : Google Scholar : PubMed/NCBI | |
Capurso G, Tacelli M, Vanella G, Ponz de Leon Pisani R, Dell'Anna G, Abati M, Mele R, Lauri G, Panaitescu A, Nunziata R, et al: Managing complications of chronic pancreatitis: A guide for the gastroenterologist. Expert Rev Gastroenterol Hepatol. 17:1267–1283. 2023. View Article : Google Scholar : PubMed/NCBI | |
Szatmary P, Grammatikopoulos T, Cai W, Huang W, Mukherjee R, Halloran C, Beyer G and Sutton R: Acute pancreatitis: Diagnosis and treatment. Drugs. 82:1251–1276. 2022. View Article : Google Scholar : PubMed/NCBI | |
Barreto SG, Habtezion A, Gukovskaya A, Lugea A, Jeon C, Yadav D, Hegyi P, Venglovecz V, Sutton R and Pandol SJ: Critical thresholds: Key to unlocking the door to the prevention and specific treatments for acute pancreatitis. Gut. 70:194–203. 2021. View Article : Google Scholar : PubMed/NCBI | |
Li Y, Sui S and Goel A: Extracellular vesicles associated microRNAs: Their biology and clinical significance as biomarkers in gastrointestinal cancers. Semin Cancer Biol. 99:5–23. 2024. View Article : Google Scholar : PubMed/NCBI | |
Bayat M and Sadri Nahand J: Exosomal miRNAs: The tumor's trojan horse in selective metastasis. Mol Cancer. 23:1672024. View Article : Google Scholar : PubMed/NCBI | |
Ghafouri-Fard S, Shoorei H, Dong P, Poornajaf Y, Hussen BM, Taheri M and Akbari Dilmaghani N: Emerging functions and clinical applications of exosomal microRNAs in diseases. Noncoding RNA Res. 8:350–362. 2023. View Article : Google Scholar : PubMed/NCBI | |
Li S, Lv D, Yang H, Lu Y and Jia Y: A review on the current literature regarding the value of exosome miRNAs in various diseases. Ann Med. 55:22329932023. View Article : Google Scholar : PubMed/NCBI | |
Wei H, Zhao H, Cheng D, Zhu Z, Xia Z, Lu D, Yu J, Dong R and Yue J: miR-148a and miR-551b-5p regulate inflammatory responses via regulating autophagy in acute pancreatitis. Int Immunopharmacol. 127:1114382024. View Article : Google Scholar : PubMed/NCBI | |
Wang Q, Wang H, Jing Q, Yang Y, Xue D, Hao C and Zhang W: Regulation of pancreatic fibrosis by acinar Cell-derived exosomal miR-130a-3p via targeting of stellate cell PPAR-γ. J Inflamm Res. 14:461–477. 2021. View Article : Google Scholar : PubMed/NCBI | |
Jia YC, Ding YX, Mei WT, Wang YT, Zheng Z, Qu YX, Liang K, Li J, Cao F and Li F: Extracellular vesicles and pancreatitis: Mechanisms, status and perspectives. Int J Biol Sci. 17:549–561. 2021. View Article : Google Scholar : PubMed/NCBI | |
Mihoc T, Latcu SC, Secasan CC, Dema V, Cumpanas AA, Selaru M, Pirvu CA, Valceanu AP, Zara F, Dumitru CS, et al: Pancreatic morphology, immunology, and the pathogenesis of acute pancreatitis. Biomedicines. 12:26272024. View Article : Google Scholar : PubMed/NCBI | |
Zaman S and Gorelick F: Acute pancreatitis: Pathogenesis and emerging therapies. J Pancreatol. 7:10–20. 2024. View Article : Google Scholar : PubMed/NCBI | |
Mederos MA, Reber HA and Girgis MD: Acute pancreatitis: A review. JAMA. 325:382–390. 2021. View Article : Google Scholar : PubMed/NCBI | |
Wang S, Ni HM, Chao X, Ma X, Kolodecik T, De Lisle R, Ballabio A, Pacher P and Ding WX: Critical role of TFEB-mediated lysosomal biogenesis in Alcohol-induced pancreatitis in mice and humans. Cell Mol Gastroenterol Hepatol. 10:59–81. 2020. View Article : Google Scholar : PubMed/NCBI | |
Qiu M, Zhou X, Zippi M, Goyal H, Basharat Z, Jagielski M and Hong W: Comprehensive review on the pathogenesis of Hypertriglyceridaemia-associated acute pancreatitis. Ann Med. 55:22659392023. View Article : Google Scholar : PubMed/NCBI | |
Wang H, Gao J, Wen L, Huang K, Liu H, Zeng L, Zeng Z, Liu Y and Mo Z: Ion channels in acinar cells in acute pancreatitis: Crosstalk of calcium, iron, and copper signals. Front Immunol. 15:14442722024. View Article : Google Scholar : PubMed/NCBI | |
An J, Jiang T, Qi L and Xie K: Acinar cells and the development of pancreatic fibrosis. Cytokine Growth Factor Rev. 71-72:40–53. 2023. View Article : Google Scholar : PubMed/NCBI | |
Ge P, Luo Y, Okoye CS and Chen H, Liu J, Zhang G, Xu C and Chen H: Intestinal barrier damage, systemic inflammatory response syndrome, and acute lung injury: A troublesome trio for acute pancreatitis. Biomed Pharmacother. 132:1107702020. View Article : Google Scholar : PubMed/NCBI | |
Kang H, Yang Y, Zhu L, Zhao X, Li J, Tang W and Wan M: Role of neutrophil extracellular traps in inflammatory evolution in severe acute pancreatitis. Chin Med J (Engl). 135:2773–2784. 2022.PubMed/NCBI | |
Papantoniou K, Aggeletopoulou I, Michailides C, Pastras P and Triantos C: Understanding the role of NLRP3 inflammasome in acute pancreatitis. Biology (Basel). 13:9452024.PubMed/NCBI | |
Kong F, Pan Y and Wu D: Activation and regulation of pancreatic stellate cells in chronic pancreatic fibrosis: A potential therapeutic approach for chronic pancreatitis. Biomedicines. 12:1082024. View Article : Google Scholar : PubMed/NCBI | |
Nail HM, Chiu CC, Leung CH, Ahmed MMM and Wang HD: Exosomal miRNA-mediated intercellular communications and immunomodulatory effects in tumor microenvironments. J Biomed Sci. 30:692023. View Article : Google Scholar : PubMed/NCBI | |
Melzer MK and Kleger A: Acute pancreatitis: Murine model systems unravel disease-modifying genes with potential implications for diagnostics and patient stratification. United European Gastroenterol J. 10:618–619. 2022. View Article : Google Scholar : PubMed/NCBI | |
Patel HR, Diaz Almanzar VM, LaComb JF, Ju J and Bialkowska AB: The role of MicroRNAs in pancreatitis development and progression. Int J Mol Sci. 24:10572023. View Article : Google Scholar : PubMed/NCBI | |
Kim H, Lee YY and Kim VN: The biogenesis and regulation of animal microRNAs. Nat Rev Mol Cell Biol. 26:276–296. 2024. View Article : Google Scholar : PubMed/NCBI | |
Shang R, Lee S, Senavirathne G and Lai EC: microRNAs in action: Biogenesis, function and regulation. Nat Rev Genet. 24:816–833. 2023. View Article : Google Scholar : PubMed/NCBI | |
Yang Y, Huang Q, Luo C, Wen Y, Liu R, Sun H and Tang L: MicroRNAs in acute pancreatitis: From pathogenesis to novel diagnosis and therapy. J Cell Physiol. 235:1948–1961. 2020. View Article : Google Scholar : PubMed/NCBI | |
Correia de Sousa M, Gjorgjieva M, Dolicka D, Sobolewski C and Foti M: Deciphering miRNAs' Action through miRNA Editing. Int J Mol Sci. 20:62492019. View Article : Google Scholar : PubMed/NCBI | |
Treiber T, Treiber N and Meister G: Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat Rev Mol Cell Biol. 20:5–20. 2019. View Article : Google Scholar : PubMed/NCBI | |
Wu K, He J, Pu W and Peng Y: The role of Exportin-5 in MicroRNA biogenesis and cancer. Genomics Proteomics Bioinformatics. 16:120–126. 2018. View Article : Google Scholar : PubMed/NCBI | |
Hynes C and Kakumani PK: Regulatory role of RNA-binding proteins in microRNA biogenesis. Front Mol Biosci. 11:13748432024. View Article : Google Scholar : PubMed/NCBI | |
Rani V and Sengar RS: Biogenesis and mechanisms of microRNA-mediated gene regulation. Biotechnol Bioeng. 119:685–692. 2022. View Article : Google Scholar : PubMed/NCBI | |
Komatsu S, Kitai H and Suzuki HI: Network regulation of microRNA biogenesis and target interaction. Cells. 12:3062023. View Article : Google Scholar : PubMed/NCBI | |
Cánovas-Márquez JT, Falk S, Nicolás FE, Padmanabhan S, Zapata-Pérez R, Sánchez-Ferrer Á, Navarro E and Garre V: A ribonuclease III involved in virulence of Mucorales fungi has evolved to cut exclusively single-stranded RNA. Nucleic Acids Res. 49:5294–5307. 2021. View Article : Google Scholar : PubMed/NCBI | |
Slezak-Prochazka I, Kluiver J, de Jong D, Kortman G, Halsema N, Poppema S, Kroesen BJ and van den Berg A: Cellular localization and processing of primary transcripts of exonic microRNAs. PLoS One. 8:e766472013. View Article : Google Scholar : PubMed/NCBI | |
Arya SB, Collie SP and Parent CA: The ins-and-outs of exosome biogenesis, secretion, and internalization. Trends Cell Biol. 34:90–108. 2024. View Article : Google Scholar : PubMed/NCBI | |
Wozniak AL, Adams A, King KE, Dunn W, Christenson LK, Hung WT and Weinman SA: The RNA binding protein FMR1 controls selective exosomal miRNA cargo loading during inflammation. J Cell Biol. 219:e2019120742020. View Article : Google Scholar : PubMed/NCBI | |
Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J, Martin-Cofreces N, Martinez-Herrera DJ, Pascual-Montano A, Mittelbrunn M and Sánchez-Madrid F: Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 4:29802013. View Article : Google Scholar : PubMed/NCBI | |
Sonoda Y, Kano F and Murata M: Applications of cell resealing to reconstitute microRNA loading to extracellular vesicles. Sci Rep. 11:29002021. View Article : Google Scholar : PubMed/NCBI | |
Jaé N, McEwan DG, Manavski Y, Boon RA and Dimmeler S: Rab7a and Rab27b control secretion of endothelial microRNA through extracellular vesicles. FEBS Lett. 589:3182–3188. 2015. View Article : Google Scholar : PubMed/NCBI | |
Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, et al: Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 12:19–30. 2010. View Article : Google Scholar : PubMed/NCBI | |
Payandeh Z, Tangruksa B, Synnergren J, Heydarkhan-Hagvall S, Nordin JZ, Andaloussi SE, Borén J, Wiseman J, Bohlooly YM, Lindfors L and Valadi H: Extracellular vesicles transport RNA between cells: Unraveling their dual role in diagnostics and therapeutics. Mol Aspects Med. 99:1013022024. View Article : Google Scholar : PubMed/NCBI | |
Robinson H, Ruelcke JE, Lewis A, Bond CS, Fox AH, Bharti V, Wani S, Cloonan N, Lai A, Margolin D, et al: Caveolin-1-driven membrane remodelling regulates hnRNPK-mediated exosomal microRNA sorting in cancer. Clin Transl Med. 11:e3812021. View Article : Google Scholar : PubMed/NCBI | |
Sun H, Bhandari K, Burrola S, Wu J and Ding WQ: Pancreatic ductal Cell-derived extracellular vesicles are effective drug carriers to enhance Paclitaxel's efficacy in pancreatic cancer cells through Clathrin-mediated endocytosis. Int J Mol Sci. 23:47732022. View Article : Google Scholar : PubMed/NCBI | |
Groot M and Lee H: Sorting mechanisms for MicroRNAs into extracellular vesicles and their associated diseases. Cells. 9:10442020. View Article : Google Scholar : PubMed/NCBI | |
Minhua Q, Bingzheng F, Zhiran X, Yingying Z, Yuwei Y, Ting Z, Jibing C and Hongjun G: Exosomal-microRNAs improve islet cell survival and function in islet transplantation. Curr Stem Cell Res Ther. 19:669–677. 2024. View Article : Google Scholar : PubMed/NCBI | |
Park EJ, Shimaoka M and Kiyono H: Functional flexibility of exosomes and micrornas of intestinal epithelial cells in affecting inflammation. Front Mol Biosci. 9:8544872022. View Article : Google Scholar : PubMed/NCBI | |
He K, Yang T, Yu J, Zang X, Jiang S, Xu S, Liu J, Xu Z, Wang W and Hong S: Dermatophagoides farinae microRNAs released to external environments via exosomes regulate inflammation-related gene expression in human bronchial epithelial cells. Front Immunol. 14:13032652023. View Article : Google Scholar : PubMed/NCBI | |
Isaac R, Reis FCG, Ying W and Olefsky JM: Exosomes as mediators of intercellular crosstalk in metabolism. Cell Metab. 33:1744–1762. 2021. View Article : Google Scholar : PubMed/NCBI | |
Otahal A, Kuten-Pella O, Kramer K, Neubauer M, Lacza Z, Nehrer S and De Luna A: Functional repertoire of EV-associated miRNA profiles after lipoprotein depletion via ultracentrifugation and size exclusion chromatography from autologous blood products. Sci Rep. 11:58232021. View Article : Google Scholar : PubMed/NCBI | |
Gemoll T, Rozanova S, Roder C, Hartwig S, Kalthoff H, Lehr S, ElSharawy A and Habermann JK: Protein profiling of serum extracellular vesicles reveals qualitative and quantitative differences after differential ultracentrifugation and exoquickTM isolation. J Clin Med. 9:14292020. View Article : Google Scholar : PubMed/NCBI | |
Rekker K, Saare M, Roost AM, Kubo AL, Zarovni N, Chiesi A, Salumets A and Peters M: Comparison of serum exosome isolation methods for microRNA profiling. Clin Biochem. 47:135–138. 2014. View Article : Google Scholar : PubMed/NCBI | |
Liu K, Lv T, He L, Tang W, Zhang Y, Xiao X, Li Y, Chang X, Wang S, Pandol SJ, et al: Endocrine-exocrine miR-503-322 drives aging-associated pancreatitis via targeting MKNK1 in acinar cells. Nat Commun. 16:26132025. View Article : Google Scholar : PubMed/NCBI | |
Shao Y, Wu W, Fan F, Liu H, Ming Y, Liao W, Bai C and Gao Y: Extracellular vesicle content changes induced by melatonin promote functional recovery of pancreatic beta cells in acute pancreatitis. J Inflamm Res. 16:6397–6413. 2023. View Article : Google Scholar : PubMed/NCBI | |
Liu J, Niu Z, Zhang R, Peng Z, Wang L, Liu Z, Gao Y, Pei H and Pan L: MALAT1 shuttled by extracellular vesicles promotes M1 polarization of macrophages to induce acute pancreatitis via miR-181a-5p/HMGB1 axis. J Cell Mol Med. 25:9241–9254. 2021. View Article : Google Scholar : PubMed/NCBI | |
Ryu S and Lee EK: The pivotal role of macrophages in the pathogenesis of pancreatic diseases. Int J Mol Sci. 25:57652024. View Article : Google Scholar : PubMed/NCBI | |
Iyer S, Enman M, Sahay P and Dudeja V: Novel therapeutics to treat chronic pancreatitis: Targeting pancreatic stellate cells and macrophages. Expert Rev Gastroenterol Hepatol. 18:171–183. 2024. View Article : Google Scholar : PubMed/NCBI | |
Xiang H, Yu H, Zhou Q, Wu Y, Ren J, Zhao Z, Tao X and Dong D: Macrophages: A rising star in immunotherapy for chronic pancreatitis. Pharmacol Res. 185:1065082022. View Article : Google Scholar : PubMed/NCBI | |
Zhao Y, Wang H, Lu M, Qiao X, Sun B, Zhang W and Xue D: Pancreatic acinar cells employ miRNAs as mediators of intercellular communication to participate in the regulation of Pancreatitis-associated macrophage activation. Mediators Inflamm. 2016:63404572016. View Article : Google Scholar : PubMed/NCBI | |
Jimenez-Alesanco A, Marcuello M, Pastor-Jimenez M, Lopez-Puerto L, Bonjoch L, Gironella M, Carrascal M, Abian J, de-Madaria E and Closa D: Acute pancreatitis promotes the generation of two different exosome populations. Sci Rep. 9:198872019. View Article : Google Scholar : PubMed/NCBI | |
Zhang X, Chu J, Sun H, Zhao D, Ma B, Xue D, Zhang W and Li Z: MiR-155 aggravates impaired autophagy of pancreatic acinar cells through targeting Rictor. Acta Biochim Biophys Sin (Shanghai). 52:192–199. 2020. View Article : Google Scholar : PubMed/NCBI | |
Wan J, Yang X, Ren Y, Li X, Zhu Y, Haddock AN, Ji B, Xia L and Lu N: Inhibition of mir-155 reduces impaired autophagy and improves prognosis in an experimental pancreatitis mouse model. Cell Death Dis. 10:3032019. View Article : Google Scholar : PubMed/NCBI | |
Wang D, Tang M, Zong P, Liu H, Zhang T, Liu Y and Zhao Y: MiRNA-155 regulates the Th17/Treg ratio by targeting SOCS1 in severe acute pancreatitis. Front Physiol. 9:6862018. View Article : Google Scholar : PubMed/NCBI | |
Tang DS, Cao F, Yan CS, Cui JT, Guo XY, Cheng L, Li L, Li YL, Ma JM, Fang K, et al: Acinar Cell-derived extracellular vesicle MiRNA-183-5p aggravates acute pancreatitis by promoting M1 macrophage polarization through downregulation of FoxO1. Front Immunol. 13:8692072022. View Article : Google Scholar : PubMed/NCBI | |
Zheng Z, Cao F, Ding YX, Lu JD, Fu YQ, Liu L, Guo YL, Liu S, Sun HC, Cui YQ and Li F: Acinous cell AR42J-derived exosome miR125b-5p promotes acute pancreatitis exacerbation by inhibiting M2 macrophage polarization via PI3K/AKT signaling pathway. World J Gastrointest Surg. 15:600–620. 2023. View Article : Google Scholar : PubMed/NCBI | |
Su XJ, Chen Y, Zhang QC, Peng XB, Liu YP, Wang L and Du YQ: Exosomes derived from cerulein-stimulated pancreatic acinar cells mediate peritoneal macrophage M1 polarization and pyroptosis via an miR-24-3p/MARCH3/NLRP3 axis in acute pancreatitis. Pancreas. 53:e641–e651. 2024. View Article : Google Scholar : PubMed/NCBI | |
Chen F, Xu K, Han Y, Ding J, Ren J, Wang Y, Ma Z and Cao F: Mitochondrial dysfunction in pancreatic acinar cells: Mechanisms and therapeutic strategies in acute pancreatitis. Front Immunol. 15:15030872024. View Article : Google Scholar : PubMed/NCBI | |
Cai SW, Han Y and Wang GP: miR-148a-3p exhaustion inhibits necrosis by regulating PTEN in acute pancreatitis. Int J Clin Exp Pathol. 11:5647–5657. 2018.PubMed/NCBI | |
Zhang Y, Yan L and Han W: Elevated level of miR-551b-5p is associated with inflammation and disease progression in patients with severe acute pancreatitis. Ther Apher Dial. 22:649–655. 2018. View Article : Google Scholar : PubMed/NCBI | |
Kusnierz-Cabala B, Nowak E, Sporek M, Kowalik A, Kuzniewski M, Enguita FJ and Stepien E: Serum levels of unique miR-551-5p and endothelial-specific miR-126a-5p allow discrimination of patients in the early phase of acute pancreatitis. Pancreatology. 15:344–351. 2015. View Article : Google Scholar : PubMed/NCBI | |
Hu C, Yin L, Chen Z, Waldron RT, Lugea A, Lin Y, Zhai X, Wen L, Han YP, Pandol SJ, et al: The unique pancreatic stellate cell gene expression signatures are associated with the progression from acute to chronic pancreatitis. Comput Struct Biotechnol J. 19:6375–6385. 2021. View Article : Google Scholar : PubMed/NCBI | |
Chan LK, Tsesmelis M, Gerstenlauer M, Leithäuser F, Kleger A, Frick LD, Maier HJ and Wirth T: Functional IKK/NF-κB signaling in pancreatic stellate cells is essential to prevent autoimmune pancreatitis. Commun Biol. 5:5092022. View Article : Google Scholar : PubMed/NCBI | |
Zhao Y, Feng Y, Sun F, Li L, Chen J, Song Y, Zhu W, Hu X, Li Z, Kong F, et al: Optimized rAAV8 targeting acinar KLF4 ameliorates fibrosis in chronic pancreatitis via exosomes-enriched let-7s suppressing pancreatic stellate cells activation. Mol Ther. 32:2624–2640. 2024. View Article : Google Scholar : PubMed/NCBI | |
Charrier A, Chen R, Chen L, Kemper S, Hattori T, Takigawa M and Brigstock DR: Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes. J Cell Commun Signal. 8:147–156. 2014. View Article : Google Scholar : PubMed/NCBI | |
Li X, Lin Z, Wang L, Liu Q, Cao Z, Huang Z, Zhong M, Peng S, Zhang Y, Li Y and Ma X: RNA-Seq analyses of the role of miR-21 in acute pancreatitis. Cell Physiol Biochem. 51:2198–2211. 2018. View Article : Google Scholar : PubMed/NCBI | |
Yan B, Cheng L, Jiang Z, Chen K, Zhou C, Sun L, Cao J, Qian W, Li J, Shan T, et al: Resveratrol inhibits ROS-Promoted activation and glycolysis of pancreatic stellate cells via suppression of miR-21. Oxid Med Cell Longev. 2018:13469582018. View Article : Google Scholar : PubMed/NCBI | |
Ciccarelli G, Di Giuseppe G, Soldovieri L, Quero G, Nista EC, Brunetti M, Cinti F, Moffa S, Capece U, Tondolo V, et al: Beta-cell function and glucose metabolism in patients with chronic pancreatitis. Eur J Intern Med. 128:112–118. 2024. View Article : Google Scholar : PubMed/NCBI | |
Gao Y, Mi N, Wu W, Zhao Y, Fan F, Liao W, Ming Y, Guan W and Bai C: Transfer of inflammatory mitochondria via extracellular vesicles from M1 macrophages induces ferroptosis of pancreatic beta cells in acute pancreatitis. J Extracell Vesicles. 13:e124102024. View Article : Google Scholar : PubMed/NCBI | |
Zhu X, Liu D, Li G, Zhi M, Sun J, Qi L, Li J, Pandol SJ and Li L: Exosomal miR-140-3p and miR-143-3p from TGF-β1-treated pancreatic stellate cells target BCL2 mRNA to increase β-cell apoptosis. Mol Cell Endocrinol. 551:1116532022. View Article : Google Scholar : PubMed/NCBI | |
Lu XG, Kang X, Zhan LB, Kang LM, Fan ZW and Bai LZ: Circulating miRNAs as biomarkers for severe acute pancreatitis associated with acute lung injury. World J Gastroenterol. 23:7440–7449. 2017. View Article : Google Scholar : PubMed/NCBI | |
Liu C, Feng H, Zhang L, Guo Y, Ma J and Yang L: MicroRNA-143-3p levels are reduced in the peripheral blood of patients with gestational diabetes mellitus and influences pancreatic β-cell function and viability. Exp Ther Med. 25:812023. View Article : Google Scholar : PubMed/NCBI | |
Liu Q, Zhu X and Guo S: From pancreas to lungs: The role of immune cells in severe acute pancreatitis and acute lung injury. Immun Inflamm Dis. 12:e13512024. View Article : Google Scholar : PubMed/NCBI | |
Xiong Y, Chen X, Yang X, Zhang H, Li X, Wang Z, Feng S, Wen W and Xiong X: miRNA transcriptomics analysis shows miR-483-5p and miR-503-5p targeted miRNA in extracellular vesicles from severe acute pancreatitis-associated lung injury patients. Int Immunopharmacol. 125:1110752023. View Article : Google Scholar : PubMed/NCBI | |
Li F, Wang Z, Cao Y, Pei B, Luo X, Liu J, Ge P, Luo Y, Ma S and Chen H: Intestinal mucosal immune barrier: A powerful firewall against severe acute pancreatitis-associated acute lung injury via the Gut-lung axis. J Inflamm Res. 17:2173–2193. 2024. View Article : Google Scholar : PubMed/NCBI | |
Shao Y, Li Y, Jiang Y, Li H, Wang J and Zhang D: Circulating exosomal miR-155-5p contributes to severe acute pancreatitis-associated intestinal barrier injury by targeting SOCS1 to activate NLRP3 inflammasome-mediated pyroptosis. FASEB J. 37:e230032023. View Article : Google Scholar : PubMed/NCBI | |
Wang L, Yuan N, Li Y, Ma Q, Zhou Y, Qiao Z, Li S, Liu C, Zhang L, Yuan M and Sun J: Stellate ganglion block relieves acute lung injury induced by severe acute pancreatitis via the miR-155-5p/SOCS5/JAK2/STAT3 axis. Eur J Med Res. 27:2312022. View Article : Google Scholar : PubMed/NCBI | |
Balaraman AK, Moglad E, Afzal M, Babu MA, Goyal K, Roopashree R, Kaur I, Kumar S, Kumar M, Chauhan AS, et al: Liquid biopsies and exosomal ncRNA: Transforming pancreatic cancer diagnostics and therapeutics. Clin Chim Acta. 567:1201052025. View Article : Google Scholar : PubMed/NCBI | |
Xu C, Jiang C, Li Z, Gao H, Xian J, Guo W, He D, Peng X, Zhou D and Li D: Exosome nanovesicles: Biomarkers and new strategies for treatment of human diseases. MedComm (2020). 5:e6602024. View Article : Google Scholar : PubMed/NCBI | |
Preethi KA, Selvakumar SC, Ross K, Jayaraman S, Tusubira D and Sekar D: Liquid biopsy: Exosomal microRNAs as novel diagnostic and prognostic biomarkers in cancer. Mol Cancer. 21:542022. View Article : Google Scholar : PubMed/NCBI | |
Xu Y, Sun Y, Yin R, Dong T, Song K, Fang Y, Liu G, Shen B and Li H: Differential expression of plasma exosomal microRNA in severe acute pancreatitis. Front Pharmacol. 13:9809302022. View Article : Google Scholar : PubMed/NCBI | |
Qu Y, Ding Y, Lu J, Jia Y, Bian C, Guo Y, Zheng Z, Mei W, Cao F and Li F: Identification of key microRNAs in exosomes derived from patients with the severe acute pancreatitis. Asian J Surg. 46:337–347. 2023. View Article : Google Scholar : PubMed/NCBI | |
Desai CS, Khan A, Bellio MA, Willis ML, Mahung C, Ma X, Baldwin X, Williams BM, Baron TH, Coleman LG, et al: Characterization of extracellular vesicle miRNA identified in peripheral blood of chronic pancreatitis patients. Mol Cell Biochem. 476:4331–4341. 2021. View Article : Google Scholar : PubMed/NCBI | |
Nakamaru K, Tomiyama T, Kobayashi S, Ikemune M, Tsukuda S, Ito T, Tanaka T, Yamaguchi T, Ando Y, Ikeura T, et al: Extracellular vesicles microRNA analysis in type 1 autoimmune pancreatitis: Increased expression of microRNA-21. Pancreatology. 20:318–324. 2020. View Article : Google Scholar : PubMed/NCBI | |
Li L, Zhang Q, Feng Y, Kong F, Sun F, Xie P, Zhao J, Yu H, Zhou J, Wu S, et al: A novel serum exosomal miRNA signature in the early prediction of persistent organ failure in patients with acute pancreatitis. Ann Surg. Feb 7–2024.(Epub ahead of print) doi: 10.1097/SLA.0000000000006229. View Article : Google Scholar | |
Zerem E, Kurtcehajic A, Kunosic S, Zerem Malkocevic D and Zerem O: Current trends in acute pancreatitis: Diagnostic and therapeutic challenges. World J Gastroenterol. 29:2747–2763. 2023. View Article : Google Scholar : PubMed/NCBI | |
Zhu H, Zhou X, Sun X, Fu C, Li G, Dong X, Kong X, Su X and Du Y: Serum exosomal miR-216a contributes to acute pancreatitis-associated acute lung injury by enhancing endothelial cell vascular permeability via downregulating LAMC1. Pancreas. Feb 13–2025.(Epub ahead of print). doi: 10.1097/MPA.0000000000002467. View Article : Google Scholar | |
Han SB and Lee SS: Simultaneous detection of exosomal microRNAs isolated from cancer cells using surface acoustic wave sensor array with high sensitivity and reproducibility. Micromachines (Basel). 15:2492024. View Article : Google Scholar : PubMed/NCBI | |
Trigo CM, Rodrigues JS, Camoes SP, Sola S and Miranda JP: Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? J Adv Res. 70:103–124. 2025. View Article : Google Scholar : PubMed/NCBI | |
Rahimian S, Mirkazemi K, Nejad AK and Doroudian M: Exosome-based advances in pancreatic cancer: The potential of mesenchymal stem cells. Crit Rev Oncol Hematol. 207:1045942025. View Article : Google Scholar : PubMed/NCBI | |
Galgaro BC, Beckenkamp LR, van den MNM, Korb VG, Naasani LIS, Roszek K and Wink MR: The adenosinergic pathway in mesenchymal stem cell fate and functions. Med Res Rev. 41:2316–2349. 2021. View Article : Google Scholar : PubMed/NCBI | |
Xie Q, Liu R, Jiang J, Peng J, Yang C, Zhang W, Wang S and Song J: What is the impact of human umbilical cord mesenchymal stem cell transplantation on clinical treatment? Stem Cell Res Ther. 11:5192020. View Article : Google Scholar : PubMed/NCBI | |
Pang K, Kong F and Wu D: Prospect of mesenchymal Stem-cell-conditioned medium in the treatment of acute pancreatitis: A systematic review. Biomedicines. 11:23432023. View Article : Google Scholar : PubMed/NCBI | |
Oveili E, Vafaei S, Bazavar H, Eslami Y, Mamaghanizadeh E, Yasamineh S and Gholizadeh O: The potential use of mesenchymal stem cells-derived exosomes as microRNAs delivery systems in different diseases. Cell Commun Signal. 21:202023. View Article : Google Scholar : PubMed/NCBI | |
Li H, Du R, Xiang A, Liu Y, Guan M and He H: Bone marrow mesenchymal stem cell-derived exosomal miR-181a-5p promotes M2 macrophage polarization to alleviate acute pancreatitis through ZEB2-mediated RACK1 ubiquitination. FASEB J. 38:e700422024. View Article : Google Scholar : PubMed/NCBI | |
Li HY, He HC, Song JF, Du YF, Guan M and Wu CY: Bone marrow-derived mesenchymal stem cells repair severe acute pancreatitis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling. Cell Signal. 66:1094362020. View Article : Google Scholar : PubMed/NCBI | |
Ren S, Pan L, Yang L, Niu Z, Wang L, Feng H and Yuan M: miR-29a-3p transferred by mesenchymal stem cells-derived extracellular vesicles protects against myocardial injury after severe acute pancreatitis. Life Sci. 272:1191892021. View Article : Google Scholar : PubMed/NCBI | |
Sharifi-Rad J, Herrera-Bravo J, Kamiloglu S, Petroni K, Mishra AP, Monserrat-Mesquida M, Sureda A, Martorell M, Aidarbekovna DS, Yessimsiitova Z, et al: Recent advances in the therapeutic potential of emodin for human health. Biomed Pharmacother. 154:1135552022. View Article : Google Scholar : PubMed/NCBI | |
Yang Q, Luo Y, Ge P, Lan B, Liu J, Wen H, Cao Y, Sun Z, Zhang G, Yuan H, et al: Emodin ameliorates severe acute Pancreatitis-associated acute lung injury in rats by modulating Exosome-specific miRNA expression profiles. Int J Nanomedicine. 18:6743–6761. 2023. View Article : Google Scholar : PubMed/NCBI |