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Chronic infection with liver flukes (such as Clonorchis sinensis) can induce severe biliary injuries, which can cause cholangitis, biliary fibrosis, and even cholangiocarcinoma. The release of extracellular vesicles by C. sinensis (CsEVs) is of importance in the long-distance communication between the hosts and worms. However, the biological effects of EVs from liver fluke on biliary injuries and the underlying molecular mechanisms remain poorly characterized. In the present study, we found that CsEVs induced M1-like activation. In addition, the mice that were administrated with CsEVs showed severe biliary injuries associated with remarkable activation of M1-like macrophages. We further characterized the signatures of miRNAs packaged in CsEVs and identified a miRNA Csi-let-7a-5p, which was highly enriched. Further study showed that Csi-let-7a-5p facilitated the activation of M1-like macrophages by targeting Socs1 and Clec7a; however, CsEVs with silencing Csi-let-7a-5p showed a decrease in proinflammatory responses and biliary injuries, which involved in the Socs1- and Clec7a-regulated NF-κB signaling pathway. Our study demonstrates that Csi-let-7a-5p delivered by CsEVs plays a critical role in the activation of M1-like macrophages and contributes to the biliary injuries by targeting the Socs1- and Clec7a-mediated NF-κB signaling pathway, which indicates a mechanism contributing to biliary injuries caused by fluke infection. However, molecules other than Csi-let-7a-5p from CsEVs that may also promote M1-like polarization and exacerbate biliary injuries are not excluded.

Paclitaxel (PTX) is one of the widely used chemotherapy drugs in breast cancer (BC) treatment. Unfortunately, the survival rate of metastatic BC patients remains poor due to PTX resistance. Therefore, uncovering the underlying mechanism behind the PTX resistance of BC cells is crucial for BC therapy. The enrichment of circular RNA ATP binding cassette subfamily B member 10 (circ-ABCB10), let-7a-5p and dual specificity phosphatase 7 (DUSP7) was measured by quantitative real time polymerase chain reaction (qRT-PCR) in PTX-resistant and PTX-sensitive BC tissues and cells. Chemoresistance, apoptosis, invasion and autophagy of BC cells were measured by 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, transwell invasion assay and Western blot assay, respectively. The binding sites between let-7a-5p and circ-ABCB10 or DUSP7 were predicted by Starbase bioinformatic software, and the combination was confirmed by dual-luciferase reporter assay. The protein expression of DUSP7 was examined by Western blot assay. Murine xenograft model was established to confirm the role of circ-ABCB10 in vivo. Circ-ABCB10 depletion promoted the PTX sensitivity and apoptosis while suppressed the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 could bind to let-7a-5p in BC cells, and circ-ABCB10 contributed to PTX resistance of BC cells via let-7a-5p. DUSP7 is a direct target of let-7a-5p in BC cells, and the accumulation of DUSP7 reversed the promoting effects of let-7a-5p overexpression on the PTX sensitivity and apoptosis and the inhibitory impact on the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 interference suppressed the growth of BC tumors in vivo. Circ-ABCB10 mediated PTX resistance, apoptosis, invasion and autophagy of BC cells via let-7a-5p/DUSP7 axis.

Background Acute lung injury (ALI) is a life-threatening respiratory condition characterized by severe inflammation and lung tissue damage, frequently causing rapid respiratory failure and long-term complications. The microRNA let-7a-5p is involved in the progression of lung injury, inflammation, and fibrosis by regulating immune cell activation and cytokine production. This study aims to use an innovative cellular electroporation platform to generate extracellular vesicles (EVs) carring let-7a-5p (EV- let-7a-5p ) derived from transfected Wharton’s jelly-mesenchymal stem cells (WJ-MSCs) as a potential gene therapy for ALI. Methods A cellular nanoporation (CNP) method was used to induce the production and release of EV- let-7a-5p from WJ-MSCs transfected with the relevant plasmid DNA. EV- let-7a-5p in the conditioned medium were isolated using a tangential flow filtration (TFF) system. EV characterization followed the minimal consensus guidelines outlined by the International Society for Extracellular Vesicles. We conducted a thorough set of therapeutic assessments, including the antifibrotic effects using a transforming growth factor beta (TGF-β)-induced cell model, the modulation effects on macrophage polarization, and the influence of EV- let-7a-5p in a rat model of hyperoxia-induced ALI. Results The CNP platform significantly increased EV secretion from transfected WJ-MSCs, and the encapsulated let-7a-5p in engineered EVs was markedly higher than that in untreated WJ-MSCs. These EV- let-7a-5p did not influence cell proliferation and effectively mitigated the TGF-β-induced fibrotic phenotype by downregulating SMAD2/3 phosphorylation in LL29 cells. Furthermore, EV- let-7a-5p regulated M2-like macrophage activation in an inflammatory microenvironment and significantly induced interleukin (IL)-10 secretion, demonstrating their modulatory effect on inflammation. Administering EVs from untreated WJ-MSCs slightly improved lung function and increased let-7a-5p expression in plasma in the hyperoxia-induced ALI rat model. In comparison, EV- let-7a-5p significantly reduced macrophage infiltration and collagen deposition while increasing IL-10 expression, causing a substantial improvement in lung function. Conclusion This study reveals that the use of the CNP platform to stimulate and transfect WJ-MSCs could generate an abundance of let-7a-5p -enriched EVs, which underscores the therapeutic potential in countering inflammatory responses, fibrotic activation, and hyperoxia-induced lung injury. These results provide potential avenues for developing innovative therapeutic approaches for more effective interventions in ALI.

Schwann cells (SCs) have important roles in supporting and repairing peripheral neurons, and thus have great potential for nerve injury treatment. Adipose tissue-derived stem cells (ADSCs) can be reliably induced to differentiate into SCs. However, the underlying molecular mechanisms are unclear. We explored the roles of MEG3/let-7a-5p/RBPJ axis in the differentiation into SCs from ADSCs. Primary ADSCs were induced to differentiate into SCs by appropriate reagents. ELISA, immunostaining, Western blotting, and qRT-PCR were employed to examine levels of SC-markers such as S100, GFAP, SOX10, p75NTR, GAP43, MPZ, β-NGF, BDNF, and NCAM and let-7 family, MEG3, RBPJ, and Notch signaling related proteins. Dual luciferase assay and RNA immunoprecipitation were performed to validate interactions of let-7a-5p/RBPJ mRNA and MEG3/let-7a-5p. Cultured ADSCs could be induced to differentiate into functional SCs. Let-7a-5p and let-7d-5p were elevated during the differentiation while MEG3 and RBPJ/Notch-signaling were suppressed. Let-7a-5p mimics promoted ADSC differentiation into SCs and up-regulated the levels of SC-related markers including S100, GFAP, SOX10, p75NTR, GAP43, MPZ, β-NGF, and NCAM, while RBPJ or MEG3 overexpression retarded the differentiation and reduced those levels. Let-7a-5p directly targeted RBPJ and MEG3 disinhibited Notch-RBPJ signaling via sponging let-7a-5p. RBPJ overexpression reversed the acceleration of let-7a-5p mimics on SC differentiation while let-7a-5p mimics blocked MEG3-mediated suppression on SC differentiation. Let-7a-5p sponged by MEG3 promotes differentiation of ADSCs into SCs via suppressing Notch signaling by targeting RBPJ. These findings shed light on mechanisms underlying the differentiation of ADSCs to SCs and provide avenues to accelerate the process.

This study aimed to investigate the role of let‐7a‐5p in the pathogenesis of essential hypertension (EH) and its correlation with the renin‐angiotensin‐aldosterone system (RAAS) biomarkers. Ninety‐eight EH patients and 24 healthy controls (HC) enrolled in the study were assayed for the relative expression of let‐7a‐5p in plasma by quantitative real‐time polymerase chain reaction (Q‐PCR), and biomarkers of the RAAS system, including angiotensin‐converting enzyme 2 (ACE2), Ang (1‐7), MAS1, angiotensin‐converting enzyme (ACE), angiotensin II (Ang II), and angiotensin II type 1 receptor (AT1R), were determined by enzyme‐linked immunosorbent assay (ELISA) The expression levels of the biomarkers of RAAS system were determined. The results showed that the expression levels of let‐7a‐5p in the plasma of EH patients were remarkably higher than those of HC. The prediction model of combined let‐7a‐5p showed high accuracy by constructing a subject operating characteristic (ROC) curve with an area under the curve (AUC) of 0.885, and the reliability of the model was further verified by the Hosmer–Lemeshow (H–L) goodness‐of‐fit test, the Model Calibration Curve, and the Decision Curve Analysis. Spearman correlation analysis revealed that the expression of let‐7a‐5p was positively correlated with ACE (r = 0.352, p < 0.001), and mediation analysis indicated that ACE partially mediated between let‐7a‐5p and the development of hypertension. The present study concludes with the potential of let‐7a‐5p as a companion diagnostic biomarker for EH. It suggests that there may be a complex regulatory mechanism between it and specific RAAS biomarkers, which provides a new perspective on the pathogenesis and diagnosis of EH.

Abstract Background Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome with a high mortality rate and limited therapeutic options. Macrophage efferocytosis plays an essential role in maintaining tissue homeostasis, and its dysfunction may be associated with the pathogenesis of ACLF. We previously found that mesenchymal stem cell (MSC) treatment in ACLF mice promoted macrophage M2 polarization and elevated the efferocytosis-related protein Mertk, but the underlying mechanisms remained unclear. Methods The role of efferocytosis was investigated in liver tissues from ACLF patients and an ACLF mouse model treated with MSC-derived exosomes (MSC-Exos). In vitro experiments utilizing lipopolysaccharide-induced M1 macrophages were conducted to dissect the underlying mechanism, targeting the miRNA let-7a-5p. Engineered exosomes (MSC-Exoslet-7a-5p) were developed via electroporation to validate the therapeutic potential. Results Impaired macrophage efferocytosis in liver tissues correlated with poor prognosis in ACLF patients. Treatment with MSC-Exos significantly improved histological morphology, liver function and enhanced efferocytosis in ACLF mice. Mechanistically, MSC-Exos delivered let-7a-5p to M1 macrophages, which downregulated Arid3a and upregulated Mertk expression. Furthermore, engineered MSC-Exoslet-7a-5p promoted efferocytosis more effectively than unmodified exosomes. Conclusion MSC-Exos enhance macrophage efferocytosis in ACLF via the let-7a-5p/Arid3a/Mertk axis. Engineered MSC-Exoslet-7a-5p, by boosting this pathway, provide a potential strategy for improving ACLF therapy. Graphical abstract Graphical Abstract

Background One major factor contributing to infertility in women of childbearing age is premature ovarian insufficiency (POI). Exosomes produced from human umbilical cord mesenchymal stem cells (hUMSC-Exos) have drawn a lot of attention lately as a potential treatment for ovarian dysfunction brought on by POI. However, its therapeutic mechanism is still unclear and needs further exploration. Methods POI model was established by intraperitoneal injection of cyclophosphamide (CTX) in female Wistar rats. These POI rats were treated with hUMSC-Exos for one week. In addition to in vivo experiments, in vitro POI models were also established. In vitro experiments, theca interstitial cells (TICs) treated with CTX were exposed to normal as well as let-7a-5p inhibitory hUMSC-Exos. The ovary structure, morphology, endocrine function, and reproductive ability of POI rats were observed by H&E staining and ELISA. Western blot, immunofluorescence staining (IF), and quantitative real-time polymerase chain reaction (qRT-PCR) were used to evaluate the autophagy-related indexes in ovary and TICs of POI rats in each group. Results CTX induced abnormalities of ovarian morphology, structure, endocrine, and reproductive function in rats, and accompanied by autophagy of TICs. Notably, hUMSC-Exos diminishes ovarian structural and functional damage in POI rats and TICs autophagy via targeting the AMPK/mTOR pathway. Furthermore, downregulating let-7a-5p in hUMSC-Exos weakened their ability to prevent TICs autophagy. Conclusions Overall, the findings suggested that hUMSC-Exos improves ovarian function in POI rats by inhibiting TICs autophagy via the let-7a-5p/AMPK/mTOR pathway. Our study provided further evidence that POI patients can benefit from hUMSC-Exos-mediated therapy.

Background Either chronic or acute exposure to dust particles may lead to pneumoconiosis and lung cancer, and lung cancer mortality among patients diagnosed with pneumoconiosis is increasing. Utilizing genome-wide sequencing technology, this study aimed to identify methods to decrease the number of patients with pneumoconiosis who die from lung cancer. Methods One hundred fifty-four subjects were recruited, including 54 pneumoconiosis patients and 100 healthy controls. Exosomes were isolated from the venous blood of every subject. Distinctive miRNAs were identified using high throughput sequencing technology, and bioinformatics analysis predicted target genes involved in lung cancer as well as their corresponding biological functions. Moreover, cross-cancer alterations of genes related to lung cancer were investigated, and survival analysis was performed using 2437 samples with an average follow-up period of 49 months. Results Let-7a-5p was revealed to be downregulated by 21.67% in pneumoconiosis. Out of the 683 let-7a-5p target genes identified from bioinformatics analysis, four genes related to five signaling pathways were confirmed to be involved in lung cancer development. Alterations in these four target genes were then explored in 4105 lung cancer patients, and BCL2L1 and IGF1R were demonstrated to be aberrantly expressed. Survival analysis further revealed that high expression of BCL2L1 corresponded to reduced survival of lung cancer patients (HR (95%CI) = 1.75(1.33~2.30)), while patient survival time was unaffected by expression of IGF1R (HR (95%CI) = 1.15 (0.98~1.36)). Conclusions In patients with lung adenocarcinoma, simultaneous downregulation of exosomal let-7a-5p and elevated expression of BCL2L1 are useful as predictive biomarkers for poor survival.

Background Let-7a-5p is demonstrated to be a tumor inhibitor in nasopharyngeal carcinoma. However, the role of let-7a-5p in chronic rhinosinusitis with nasal polyps (CRSwNP) has not been reported. This study is designed to determine the pattern of expression and role of let-7a-5p in CRSwNP. Methods The expression level of let-7a-5p, TNF-α, IL-1β, and IL-6 in CRSwNP tissues and cells were detected by RT-qPCR. Western blot assay was carried out to measure the protein expression of the Ras-MAPK pathway. Dual luciferase reporter assay and RNA pull-down assay were used to explore the relationship between let-7a-5p and IL-6. Results Let-7a-5p was significantly downregulated in CRSwNP tissues and cells. Moreover, the mRNA expression of TNF-α, IL-1β and IL-6 was increased in CRSwNP tissues, while let-7a-5p mimic inhibited the expression of TNF-α, IL-1β and IL-6. Besides that, let-7a-5p was negatively correlated with TNF-α, IL-1β and IL-6 in CRSwNP tissues. In our study, IL-6 was found to be a target gene of let-7a-5p. Additionally, let-7-5p mimic obviously reduced the protein levels of Ras, p-Raf1, p-MEK1 and p-ERK1/2, while IL-6 overexpression destroyed the inhibitory effect of let-7a-5p on the Ras-MAPK pathway in CRSwNP. Conclusion We demonstrated that let-7a-5p/IL-6 interaction regulated the inflammatory response through the Ras-MAPK pathway in CRSwNP.

Background Osteoarthritis (OA) is a prevalent degenerative joint disorder affecting over 240 million people worldwide, yet no disease-modifying therapies currently exist, with clinical management limited to symptomatic relief or joint replacement. Exosomes (Exos) from bone marrow mesenchymal stem cells (Exo BMSC ) play positive role in the treatment of cartilage damage. Parathyroid hormone (PTH) (1–34) can enhance cartilage repair. Here, We found Exos from Exo BMSC reduces cartilage damage during treatment. Meanwhile, the Exos of PTH(1–34)-preconditioned BMSCs (Exo PTH ) can alleviate OA better than Exo BMSC . Through MicroRNA (miRNA) sequencing analysis, this study aims to reveal the effects and potential mechanism of miRNA (let-7a-5p) in Exo PTH to repair OA cartilage. Methods Differential centrifugation was used for isolating Exo BMSC and Exo PTH . Extract bone marrow mesenchymal stem cells from rats and utilize the C28/I2 chondrocytes line, the OA model was established using lipopolysaccharide (LPS; 1 µg/mL) in vitro. OA was induced in rats with intra-articular injection with collagenase-2. By performing a miRNA array, RNA-seq, in addition to bioinformatic analysis, the miRNA and the potential regulatory mechanism were detected. We compared in vitro let-7a-5p effects on the ability of OA chondrocytes to proliferate, migrate, apoptosis, and form the extracellular matrix (ECM). Histological and immunohistochemical assessments were used for evaluating cartilage pathology in vivo. Results We extracted Exo BMSC and Exo PTH and established the OA model in vitro. Compared with Exo BMSC group, Exo PTH group has a stronger effect on promoting the proliferation and migration of chondrocytes. Exo BMSC and Exo PTH can inhibit the apoptosis of chondrocytes, but there was no significant difference between the two groups. The two most significant differences in groups Exo BMSC and Exo PTH are let-7a-5p. Let-7a-5p promotes OA chondrocytes proliferation and migration by inhibiting the expression of IL-6 in vitro experiments. For in vivo experiments, let-7a-5p delays the progression of OA. Conclusion Our study shows that Exo PTH may improve the regulatory inflammatory responses to delays the progression of OA by shuttling let-7a-5p. Let-7a-5p promoted chondrocytes migration and proliferation to suppress OA pathology by inhibiting IL-6/STAT3 pathway.