Search

The clinical syndrome appears as a dysregulated host response to infection that results in life-threatening organ dysfunction known as Sepsis. Sepsis is a serious public health concern where for every five deaths in ICU there is one patient who dies with sepsis worldwide. Sepsis is featured as unbalanced inflammation and immunosuppression which is sustained and profound, increasing patient susceptibility to secondary infections and mortality. microRNAs (miRNAs) play a central role in the control of many biological processes, and the deregulation of their expression has been linked to the development of oncological, cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the role of miRNAs in sepsis pathophysiology. Overall, miRNAs are seen as promising biomarkers, and it has been proposed to develop miRNA-based diagnosis and therapies for sepsis. Yet, the picture is not so straightforward because of miRNAs' versatile and dynamic features. More research is needed to clarify the expression and role of miRNAs in sepsis and promote the use of miRNAs for sepsis management. This study provides an extensive, current, and thorough analysis of the involvement of miRNAs in sepsis. Its purpose is to encourage future research in this area, as tiny miRNAs have the potential to be used for rapid diagnosis, prognosis, and treatment of sepsis., (© 2025 Wiley Periodicals LLC.)

Background: This study aimed to explore the mechanisms underlying T-cell differentiation in asthma. Methods and Results: Flow cytometry was performed to detect Th cells. LC-MS/MS was performed to assess lipid metabolism. HE staining was performed to assess the pathological changes of the lung tissues. ELISA was performed to detect cytokine levels. The results of quantitative real-time polymerase chain reaction (qRT-PCR) and western blot showed that miR-192-5p expression was decreased, while SCD1 expression was increased in CD4 + T cells isolated from the peripheral blood of children with asthma. The dual luciferase reporter assay determined the direct interaction between miR-192-5p and SCD1. MiR-192-5p inhibitor reduced ASCL3 and PPARα, increased FASN and SREBP1c mRNA expression and protein levels in mouse spleen CD4 + T cells, and elevated Th2 and Th17 cells, but these effects were reversed by the SCD1 inhibitor. Oleic acid (OA) reduced Th1 cells and increased Th2 and Th17 cells in mouse spleen CD4 + T cells treated with an SCD1 inhibitor. Additionally, pri-miR-192-5p expression was increased in CD4 + T cells isolated from the peripheral blood of asthmatic children, and the deletion of METTL3 upregulated pri-miR-192-5p expression in an m6A-dependent manner. MiR-192-5p mimic and inhibitor both reversed miR-192-5p and SCD1 expression affected by overexpression or deletion of METTL3, both in vivo and in vitro . Furthermore, METTL3 overexpression attenuated lung inflammation, elevated Th1 cells, and reduced Th2 and Th17 cells in CD4 + T cells isolated from the peripheral blood of asthmatic mice. These effects were reversed by the miR-192-5p inhibitor. Conclusion: These results suggest that METTL3/miR-192-5p/SCD1 axis regulates lipid metabolism and affects T cell differentiation, thus affecting asthma progression. This study may provide novel insights into the pathogenesis of asthma and a new treatment strategy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 Zhengrong Chen et al. Mediators of Inflammation published by John Wiley & Sons Ltd.)

Introduction: The aim of present study was to evaluate the impact of perimenopause on insulin resistance. Specifically, insulin sensitivity was assessed in a perimenopausal mouse model treated with 4-vinylcyclohexene diepoxide (VCD), together with the changes in exosomal miRNA and hepatic mRNA expression profiles. Methods: Homeostasis model assessment of insulin resistance (HOMA-IR) was utilized to assess the status of insulin resistance, and insulin action was evaluated during menopausal transition. RNA sequencing (RNA-seq) analysis was used to identify altered expression profiles of exosomal miRNAs and hepatic mRNAs. Differentially expressed miRNA (DEM)-differentially expressed gene (DEG) network analyses were also conducted. Furthermore, altered expression levels of these exosomal miRNAs and genes were validated in plasma exosomes and liver tissue of perimenopausal mice. Results: HOMA-IR in VCD-treated mice was significantly increased, and hepatic glycogen was significantly decreased. Key exosomal miRNAs (miR-17-3p, miR-134-5p, miR-700-5p, and miR-6899-3p) and hepatic genes ( G6pdx , Ptpn2 , Lepr , Kras , and Braf ) may be associated with impaired insulin signaling during perimenopause. Conclusion: The perimenopausal period acts as a potential factor in introducing insulin resistance as evidenced by impaired insulin action and altered expression profiles of exosomal miRNAs and hepatic genes. The present study contributes to the understanding that abnormal cargos carried by plasma exosomes, such as miRNAs, may be related to altered expression of the corresponding genes in the liver and abnormal insulin response., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 Yu Yang et al. Journal of Diabetes Research published by John Wiley & Sons Ltd.)

As functional derivatives of mesenchymal stem cells (MSCs), small extracellular vesicles (sEVs) have garnered significant attention and application in regenerative medicine. However, the technical limitations for large-scale isolation of sEVs and their heterogeneous nature have added complexity to their applications. It remains unclear if the heterogeneous sEVs represent different aspects of MSCs functions. Here, we provide a method for the large-scale production of sEVs subpopulations derived from human umbilical cord mesenchymal stem cells (HucMSCs), utilizing tangential flow filtration combined with size exclusion chromatography. The resulting subpopulations, S1-sEVs and S2-sEVs, exhibited stable variations in size, membrane-marked proteins, and carrying cargos, thereby displaying distinct functions both in vitro and in animal disease models. S1-sEVs, that highly expressed CD9, HRS and GPC1, demonstrated a greater immunomodulatory impact, while S2-sEVs with enriched expression of CD63 and FLOT1/2 possessed enhanced capacities in promoting cell proliferation and angiogenesis. These discrepancies are attributed to the specific proteins and miRNAs they contain. Further investigation revealed that the two distinct sEVs subpopulations corresponded to different biological processes: the ESCRT pathway (S1-sEVs) and the ESCRT-independent pathway represented by lipid rafts (S2-sEVs). Therefore, we propose the potential for large-scale isolation and purification of sEVs subpopulations from HucMSCs with distinct functions. This approach may provide advantages for targeted therapeutic interventions in various MSC indications., (© 2025 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Extracellular vesicles (EVs) have shown great potential for treating various diseases. Translating EVs-based therapy from bench to bedside remains challenging due to inefficient delivery of EVs to the injured area and lack of techniques to visualize the entire targeting process. Here we developed a dopamine surface functionalization platform that facilitates easy and simultaneous conjugation of targeting peptide and multi-mode imaging probes to the surface of EVs. Utilizing this platform we concurrently modified M2 microglia-derived EVs (M2-EVs) with neuronal targeting peptide rabies virus glycoprotein peptide 29 (RVG29) and multi-modal imaging tracers, resulting in the targeted delivery of M2-EVs to stroke mice brain and enabled the dynamic visualization of the targeting process from whole-body to cellular levels. We determined that intra-arterial injection achieved the highest efficiency of targeted delivery of engineered EVs to the stroke mice brain, improved therapeutic efficacy by reducing neuronal apoptosis. Mechanistically, EVs miRNA array revealed that a number of anti-apoptosis related miRNAs were significantly up-regulated, including miR-221-3p and miR-423-3p, both exerted anti-apoptotic effects through p38/ERK signalling pathways in stroke. Overall, this platform provides a facile and powerful tool for multifunctional engineering of EVs for multiscale therapeutic evaluation and enhancement of EV-based therapy, with valuable prospects for clinical translation., (© 2025 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

B cell maturation is crucial for effective adaptive immunity. It requires a complex signalling network to mediate antibody diversification through mutagenesis. B cells also rely on queues from other cells within the germinal centre. Recently, a novel class of intercellular signals mediated by extracellular vesicles (EVs) has emerged. Studies have shown that B cell EV-mediated signalling is involved in immune response regulation and tumorigenesis. However, the mechanistic role of B cell EVs is not yet established. We herein study the biological properties and physiological function of B cell EVs during B cell maturation. We use emerging technologies to profile B cell EV surface marker signatures at the single particle level, molecular cargo and physiological roles in B cell maturation. EV ncRNA cargo, characterised by RNA-seq, identified an EV-mediated novel non-coding RNA (ncRNA) regulatory network for B cell maturation. We show that a previously uncharacterised micro-RNA (miR-5099) in combination with a set of long ncRNA are carried within B cell EVs and could contribute to antibody diversification. The physiological role of EVs in B cell maturation is investigated using EV blockade assays and complementation studies using diverse EV sources further confirmed the physiological role and mode of action of EVs in B cell maturation., (© 2025 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Background and Purpose: Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect., Experimental Approach: ProtectomiR candidates were selected after systematic analysis of miRNA expression changes in cardiac tissue samples from a closed-chest AMI model in pigs subjected to sham operation, AMI and ischaemic preconditioning, postconditioning or remote preconditioning, respectively. Cross-species orthologue protectomiR candidates were validated in simulated ischaemia-reperfusion injury (sI/R) model of isolated rat ocardiomyocytes and in human AC16 cells as well. For miR-450a, we performed target prediction and analysed the potential mechanisms of action by GO enrichment and KEGG pathway analysis., Key Results: Out of the 220 detected miRNAs, four were up-regulated and 10 were down-regulated due to all three conditionings versus AMI. MiR-450a and miR-451 mimics at 25 nM were protective in rat cardiomyocytes, and miR-450a showed protection in human cardiomyocytes as well. MiR-450a has 3987 predicted mRNA targets in pigs, 4279 in rats and 8328 in humans. Of these, 607 genes are expressed in all three species. A total of 421 common enriched GO terms were identified in all three species, whereas KEGG pathway analysis revealed 13 common pathways., Conclusion and Implications: This is the first demonstration that miR-450a is associated with cardioprotection by ischaemic conditioning in a clinically relevant porcine model and shows cardiocytoprotective effect in human cardiomyocytes, making it a promising drug candidate. The mechanism of action of miR-450a involves multiple cardioprotective pathways., Linked Articles: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Three types of highly promising small RNA therapeutics, namely, small interfering RNAs (siRNAs), microRNAs (miRNAs) and the RNA subtype of antisense oligonucleotides (ASOs), offer advantages over small-molecule drugs. These small RNAs can target any gene product, opening up new avenues of effective and safe therapeutic approaches for a wide range of diseases. In preclinical research, synthetic small RNAs play an essential role in the investigation of physiological and pathological pathways as silencers of specific genes, facilitating discovery and validation of drug targets in different conditions. Off-target effects of small RNAs, however, could make it difficult to interpret experimental results in the preclinical phase and may contribute to adverse events of small RNA therapeutics. Out of the two major types of off-target effects we focused on the hybridization-dependent, especially on the miRNA-like off-target effects. Our main aim was to discuss several approaches, including sequence design, chemical modifications and target prediction, to reduce hybridization-dependent off-target effects that should be considered even at the early development phase of small RNA therapy. Because there is no standard way of predicting hybridization-dependent off-target effects, this review provides an overview of all major state-of-the-art computational methods and proposes new approaches, such as the possible inclusion of network theory and artificial intelligence (AI) in the prediction workflows. Case studies and a concise survey of experimental methods for validating in silico predictions are also presented. These methods could contribute to interpret experimental results, to minimize off-target effects and hopefully to avoid off-target-related adverse events of small RNA therapeutics. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Sevoflurane (Sev) is a widely applied anesthetic in clinical practice; however, it could induce neurotoxicity and lead to postoperative cognitive dysfunction (POCD). This study aimed to investigate the role and underlying mechanism of circHOMER1 in Sev-induced neurotoxicity and POCD. Sev treated mouse hippocampal neuronal HT22 cells and SD rats. RT-qPCR was used to detect the levels of circHOMER1 and miR-217. ELISA was employed to measure the levels of inflammatory factors IL-6, IL-1β, and TNF-α. Commercially available kits assessed the concentration of MDA and measured the activities LDH and SOD. The CCK-8 assay assessed cell viability. Flow cytometry analyzed cell apoptosis. The Morris water maze test evaluated the learning and cognitive abilities of the rats. Dual luciferase reporter assays and RIP experiments validated the targeted binding of circHOMER1 to miR-217. Sev treatment significantly reduces cell viability, increases apoptosis, stimulates inflammatory responses and oxidative stress, and induces learning and memory impairments in SD rats. Following exposure to Sev, the expression of circHOMER1 is markedly decreased, while overexpression of circHOMER1 can alleviate Sev-induced neuroinflammation, oxidative stress, and learning and memory deficits in rats. CircHOMER1 targets miR-217, and transfection of miR-217 antagonizes the neuroprotective effects of circHOMER1. This study demonstrated that circHOMER1 negatively regulated miR-217, thereby inhibiting Sev-induced neurotoxicity and learning and memory disorders., (© 2025 Wiley Periodicals LLC.)

Increasing long noncoding RNAs (lncRNAs) have been found to participate in regulating the progression of colorectal cancer (CRC), which is a common gastrointestinal malignancy. Here, the specific role and mechanisms of lncRNA LINC00294 were investigated in CRC. The expression levels of LINC00294, miR-499a-5p, and La-related protein 4B (LARP4B) in CRC cells (HCT116 and SW620) and tissues were assessed by RT-qPCR. The viability, proliferation, cell cycle, and apoptosis of HCT116 and SW620 cells were determined by CCK-8, EdU, and flow cytometry assays. Protein levels of cell cycle and cell apoptosis markers were measured by western blot analysis. FISH assay was performed to evaluate the subcellular localization of LINC00294 in CRC cells. Luciferase reporter assay, RNA pull-down assay, as well as RIP assay verified the interactions between miR-499a-5p and LINC00294 (or LARP4B). The xenograft model was established in mice to investigate the function of LINC00294 in vivo. LINC00294 presented a decreased expression level in CRC cells and tissues. LINC00294 overexpression suppressed the cell proliferative capacity, promoted cell cycle arrest, and induced cell apoptosis in CRC HCT116 and SW620 cells. LINC00294 interacted with miR-499a-5p, and miR-499a-5p targeted LARP4B. MiR-499a-5p was upregulated while LARP4B was downregulated in CRC cells. In rescue assays, LARP4B knockdown reversed the inhibition of LINC00294 overexpression on malignant phenotypes of HCT116 and SW620 cells. In the xenograft model, LINC00294 overexpression inhibited tumor growth in vivo. LINC00294 exerted an antitumor function in CRC by forming a LINC00294/miR-499a-5p/LARP4B regulatory network., (© 2024 Wiley Periodicals LLC.)

Sevoflurane (Sev) has a cardioprotective role in myocardial ischemia/reperfusion injury (MI/RI), but its mechanism has not been fully elucidated. This study aimed to investigate whether the circ_CDR1as/miR-671-5p/HMGA1 axis mediates the cardioprotective effect of Sev in MI/RI. Cardiomyocytes underwent hypoxia/reoxygenation (H/R) treatment was used to simulate MI/RI in vitro. H/R cardiomyocytes were then pretreated with Sev to explore the protective effect of Sev on H/R cells. The level of CDR1as/miR-671-5p/HMGA1 axis were detected by RT-qPCR. The proliferation and apoptosis of cardiomyocytes were detected by CCK-8 and flow cytometry. The levels of myocardial injury markers and inflammatory markers were detected by ELISA assay. Finally, the regulatory relationship between CDR1as and miR-671-5p/HMGA1 axis was verified by Dual-luciferase reporting and RNA pull-down assays. Sev Pretreatment can reduce the level of CDR1as and mitigate H/R-induced damage to cardiomyocytes. This Pretreatment lowers the levels of myocardial injury markers, oxidative stress markers, and pro-inflammatory factors in H/R-affected cardiomyocytes. However, CDR1as overexpression inhibits Sev's protective effect on H/R cardiomyocytes. At the molecular mechanism, we found that CDR1as mediates Sev's protective effect through the CDR1as/miR-671-5p/HMGA1 axis. CDR1as increases HMGA1 levels by sponging miR-671-5p, while high HMGA1 levels diminish Sev's protective effect. Sev plays a cardioprotective role in MI/RI by inhibiting the circ_CDR1as/miR-671-5p/HMGA1 axis., (© 2024 Wiley Periodicals LLC.)

Although gemcitabine (GEM) is the cornerstone of the treatment of pancreatic cancer (PC), GEM resistance frequently arises. Circular RNA (circRNA) circ_0075829 is highly expressed in PC. However, whether circ_0075829 contributes to GEM resistance of PC is largely unknown. To generate GEM-resistant PC cells (BxPC-3/GR and SW1990/GR), we exposed GEM-sensitive PC cells to GEM. Circ_0075829, microRNA (miR)-326, and glutamic-oxaloacetic transaminase 1 (GOT1) were quantified by a qRT-PCR or western blot method. Cell survival and viability were gauged by MTS assay. Cell proliferation, apoptosis, invasion, and migration were assessed by EdU, flow cytometry, transwell, and wound-healing assays, respectively. Dual-luciferase reporter assays were used to verify the relationship between miR-326 and circ_0075829 or GOT1. Mouse xenografts were performed to evaluate the role of circ_0075829 in vivo. Our data showed that circ_0075829 was upregulated in GEM-resistant PC tissues and cells. Knockdown of circ_0075829 impeded the proliferation, invasion, migration, and glutamine metabolism, and promoted cell apoptosis and GEM sensitivity of GEM-resistant PC cells. Moreover, circ_0075829 silencing suppressed the tumorigenicity of SW1990/GR cells and sensitized them to the cytotoxic effect of GME in vivo. Mechanistically, circ_0075829 bound miR-326 and exerted regulatory effects by affecting miR-326 expression. GOT1 was a direct miR-326 target and a key downstream effector of miR-326. Furthermore, circ_0075829 modulated GOT1 expression via miR-326. Our findings establish a novel regulatory network, the circ_0075829/miR-326/GOT1 competing endogenous RNA (ceRNA) crosstalk, in the regulation of GEM resistance in PC., (© 2024 Wiley Periodicals LLC.)

The underlying regulating mechanisms of miR-105-5p/PTEN in colon cancer (CC) progression are still unknown. MiR-105-5p and PTEN expressions were determined using RT-PCR. PTEN protein levels were examined by western blot. Also, the contents of inflammatory cytokines (IL-1β, TNF-α, and IL-6) were measured via ELISA. An inflammation model was constructed via LPS. NF-κB p65 expression was assessed via immunofluorescence assay. A xenograft tumor model was constructed in BALB/c nude mice. The functions of miR-105-5p were investigated by establishing a xenograft tumor model, H&E staining, TUNEL assay, immunohistochemistry assay, ELISA, RT-PCR, and western blot. In this research, We found that miR-105-5p expressions were upregulated in CC cells. MiR-105-5p depletion notably augmented PTEN expressions and enhanced immune response, while impeded EMT and distinctly declined the levels of p-IκBα and Nuc-NF-κB p65 in LoVo cells. Whereas, these effects were notably counteracted by PTEN depletion. MiR-105-5p upregulation exerted the opposite effects in CaCo2 cells. LPS markedly increased miR-105-5p expressions and suppressed PTEN expressions in LoVo cells. MiR-105-5p depletion offset LPS-triggered promoting effects on EMT and suppressing effects on the immune response. Meanwhile, in vivo assay proved that miR-105-5p depletion markedly impeded tumor growth and EMT, yet facilitated apoptosis and immune response. It also distinctly deactivated the NF-κB pathway. To sum up, these data indicated that miR-105-5p depletion might impede EMT, yet enhance the immune response in CC by elevating PTEN expressions via deactivation of the NF-κB pathway., (© 2024 Wiley Periodicals LLC.)

Atherosclerosis is a chronic proinflammatory disease of the vascular wall resulting in narrowing of arteries due to plaque formation, thereby causing reduced blood supply that is the leading cause for diverse end-organ damage with high mortality rates. Monocytes/macrophages, activated by elevated circulating lipoproteins, are significantly involved in the formation and development of atherosclerotic plaques. The imbalance between proinflammatory and anti-inflammatory macrophages, arising from dysregulated macrophage polarization, appears to be a driving force in this process. Proatherosclerotic processes acting on monocytes/macrophages include accumulation of cholesterol in macrophages leading to foam cell formation, as well as dysfunctional efferocytosis, all of which contribute to the formation of unstable plaques. In recent years, microRNAs (miRs) were identified as factors that could modulate monocyte/macrophage function and may therefore interfere with the atherosclerotic process. In this review, we present effects of monocyte/macrophage-derived miRs on atherosclerotic processes in order to reveal new treatment options using miRmimics or antagomiRs. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background and Purpose: MicroRNA (miRNA) therapy is a promising approach to induce cardioprotection. We have previously identified cardiac microRNA-125b* (microRNA-125b-2-3p; miR-125b*) as a potential cardioprotective miRNA, termed ProtectomiR. We aimed to characterize the pharmacokinetics and pharmacodynamics, and the effect of miR-125b* mimic on infarct size using an in vivo mouse model., Experimental Approach: To characterize the pharmacokinetics properties of miR-125b* mimic, a single injection of 10-μg miR-125b* mimic or its scramble miRNA control, or vehicle i.v. was given to C57BL/6 mice. MiR-125b* expression was measured from plasma, heart, kidney and liver samples. Effect of miR-125b* on area at risk and infarct size was assessed after 45-min coronary occlusion, followed by 24-h reperfusion; 10-μg miR-125b* mimic or 10-μg non-targeting miRNA mimic control or vehicle were administered via the right jugular vein at 10th mins of coronary occlusion. To assess molecular mechanism involved in cardioprotection, expression of mRNA targets of miR-125b* were measured from ventricular myocardium at 1, 2, 4, 8 or 24 h post-treatment using quantitative real time polymerase chain reaction., Key Results: MiR-125b* expression was markedly increased in plasma and myocardium 1 h, and in the liver 2h after treatment. Infarct size was significantly reduced after miR-125b* mimic treatment when compared to the vehicle. The expression of Ccna2, Eef2k and Cacnb2 target mRNAs was significantly reduced 8 h after injection of miR-125b* mimic., Conclusion and Implications: This is the first demonstration of pharmacokinetic and molecular pharmacodynamic properties as well as the cardioprotective effect of miR-125b* mimic in vivo., Linked Articles: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background and Purpose: MicroRNA (miR)-210 function in endothelial cells and its role in diabetes-associated endothelial dysfunction are not fully understood. We aimed to characterize the miR-210 function in endothelial cells and study its therapeutic potential in diabetes., Experimental Approach: Two different diabetic mouse models (db/db and Western diet-induced), miR-210 knockout and transgenic mice, isolated vessels and human endothelial cells were used., Key Results: miR-210 levels were lower in aortas isolated from db/db than in control mice. Endothelium-dependent relaxation (EDR) was impaired in aortas from miR-210 knockout mice, and this was restored by inhibiting miR-210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR-210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR-210. However, plasma miR-210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR-210 transgenic mice and pharmacological overexpression using miR-210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR-210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR-210 mimic restored decreased nitric oxide production by high glucose in endothelial cells., Conclusion and Implications: This study unravels the mechanisms by which down-regulated miR-210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR-210 serves as a novel therapeutic target., Linked Articles: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The main pathogenesis of the frozen shoulder is thought to be the inflammation of the intra-articular synovium and subsequent fibrosis of the shoulder joint capsule. However, the molecular pathogenesis of the frozen shoulder is still unknown. A class of noncoding RNAs, microRNAs contribute to various diseases including musculoskeletal diseases. MicroRNA-26a (miR-26a) has been reported to be associated with fibrosis in several organs. This study aims to reveal the role of miR-26a on fibrosis in the shoulder capsule using a frozen shoulder model in miR-26a deficient (miR-26a KO) mice. MiR-26a KO and wild-type (WT) mice were investigated using a frozen shoulder model. The range of motion (ROM) of the shoulder, histopathological changes such as synovitis, and fibrosis-related gene expression in the model mice were evaluated to determine the role of miR-26a. In WT mice, both inflammatory cell infiltration and thickening of the inferior shoulder joint capsule were observed after 1 week of immobilization, and this thickening further progressed over the subsequent 6 weeks. However, the immobilized shoulder in miR-26a KO mice consistently exhibited significantly better ROM compared with WT mice at 1 and 6 weeks, and histological changes were significantly less severe. The expression of inflammation- and fibrosis-related genes was decreased in the miR-26a KO mice compared with WT mice at 1 and 6 weeks. Together, miR-26a deficiency attenuated the severity of frozen shoulder in the immobilization model mouse. The present study suggests that miR-26a has the potential to be a target miRNA for therapeutic approach to frozen shoulder., (© 2024 Orthopaedic Research Society.)

Emerging evidence has discovered that circular RNAs play important regulators of nonsmall cell lung cancer (NSCLC), but the role and potential molecular mechanism of hsa_circ_100549 (circ_0004630) involved in NSCLC is poorly defined. In this study, circ_0004630, microRNA-1208 (miR-1208), and leucine-rich repeat kinase 2 (LRRK2) expression were detected using real-time quantitative polymerase chain reaction. Cell proliferation, colony formation, apoptosis, and invasion were assessed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine, colony formation, flow cytometry, and transwell assays. Protein levels of glucose transporter 1, Hexokinase 2, and LRRK2 were detected using western blot assay. Glucose consumption, lactate production, and adenosine triphosphate content were assessed using the corresponding kits. After predicting via bioinformatics software Circinteractome and Targetscan, the binding between miR-1208 and circ_0004630 or LRRK2 was verified by a dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assay. The xenograft tumor model analyzed the biological role circ_000460 on tumor growth in vivo. It was found that circ_0004630 and LRRK2 were increased, and miR-1208 was low expression in NSCLC tissues and cells. Functionally, the downregulation of circ_0004630 inhibited NSCLC cell proliferation, invasion, glycolysis, and accelerated apoptosis in vitro. In mechanism, circ_0004630 might work as a sponge of miR-1208 to modulate LRRK2 expression. In addition, DUXAP8 deficiency cured neuroblastoma tumor growth in vivo. In conclusion, circ_0004630 knockdown might suppress NSCLC cell proliferation, metastasis, and glycolysis partly by the miR-1208/LRRK2 axis. Our findings hinted at an important theoretical basis for further elucidating the pathogenesis of NSCLC and targeted therapy., (© 2024 Wiley Periodicals LLC.)

The purpose of this research was to provide light on the functional role that the long noncoding RNA SPACA6P-AS plays in the biology of colorectal cancer (CRC). The presence of elevated SPACA6P-AS expression in colorectal cancer tissues is linked to advanced stages of the disease as well as a decreased overall survival rate. It has been demonstrated through knockdown tests conducted on CRC cell lines that SPACA6P-AS stimulates cell growth in both in vitro and in vivo settings. By acting as a competing endogenous RNA, SPACA6P-AS is able to modulate the levels of miR-339-5p and promote the proliferation of colorectal cancer cells by way of the miR-339-5p/FAM167AFAM167A signaling axis. Based on these findings, SPACA6P-AS is a promising candidate for both a prognostic marker and a therapeutic target in colorectal cancer., (© 2024 The Author(s). Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC.)

Breast cancer (BRCA) is one of the major threats to women's health worldwide. This study focuses on the roles of sorbin and SH3 domain-containing protein 2 (SORBS2) protein and microRNA-138-5p in the progression of BRCA, analyzing their regulatory effects on cancer cell proliferation, cell cycle, and migration ability. Using bioinformatics tools and experimental methods, the study found that SORBS2 is commonly underexpressed in BRCA. Additionally, it demonstrated that microRNA-138-5p can significantly inhibit tumor growth by suppressing SORBS2 expression, providing new molecular targets for BRCA treatment., (© 2024 Wiley Periodicals LLC.)

MicroRNAs (miRNAs) have key roles in the pathological processes of neuropathic pain. Here, our aim was to elucidate the function of miR-200a-3p as well as its related regulatory mechanism in neuropathic pain. An animal model of neuropathic pain was established by chronic constriction injury (CCI) induction. The knockdown experiments are performed by injecting a lentiviral construct intrathecally. MiR-200a-3p and bromodomain-containing protein 3 (BRD3) expression in rat spinal cord was determined using RT-qPCR. The mechanical, thermal, and cold responses in animals were assessed at the indicated time after surgery. The levels of inflammatory cytokines in rat spinal cord were measured by ELISA. The changes in NF-κB signaling-related molecules in rat spinal cord were determined using western blot and immunofluorescence. MiR-200a-3p was underexpressed in CCI rats in a time-dependent manner. Overexpression of miR-200a-3p decreased mechanical hyperalgesia and thermal sensitivity to attenuate neuropathic pain in rats. BRD3 was targeted by miR-200a-3p. Additionally, downregulation of BRD3 inhibited neuropathic pain progression. Moreover, overexpression of BRD3 rescued the effect of miR-200a-3p on NF-κB signaling and neuropathic pain in CCI rats. MiR-200a-3p attenuates neuropathic pain via downregulating BRD3 to block NF-κB signaling., (© 2024 Wiley Periodicals LLC.)

The mechanism by which specific miRNAs in NSCLC exosomes regulate NSCLC progression remains unclear. First, exosomes were isolated and identified. Exosomes were labeled with PKH26 for cell tracking studies. Subsequently, BEAS-2B cells and BEAS-2B cell exosomes were transfected with miR-20b-5p mimics or miR-20b-5p inhibitors, and cell proliferation was measured by EdU and CCK-8. cell migration and invasion were detected by wound healing tests and Transwell. The potential target of miR-20b-5p was predicted and verified by luciferase assay. Relative expression levels of miR-20b-5p and TGFBR2 were detected by qRT-PCR. Protein expression level was detected by Western blot. In addition, A549 cell exosomes were injected into mice through the tail vein and the pathological changes of lung tissue were detected by HE staining. Expression levels of E-cadherin and Vimentin in lung tissues were detected by immunohistochemistry. Our results also showed that high levels of miR-20b-5p in exosomes generated from NSCLC cells conceivably enter the cytoplasm of their own cells and by downregulating TGFBR2, accelerate NSCLC invasion, migration and EMT while promoting NSCLC cell proliferation. Exosome analysis using clinical plasma specimens revealed that miR-20b-5p expression was considerably improved in exosomes from NSCLC patients compared with those from healthy controls. In vitro and in vivo, exosomes with high levels of miR-20b-5p were linked to the progression of NSCLC. Our data suggest that exosomes with high levels of miR-20b-5p can increase development and metastasis of NSCLC cells by downregulating TGFBR2, which would serve as a predictive and diagnostic marker for NSCLC., (© 2024 Wiley Periodicals LLC.)

Prostate cancer (PCa) is one of the leading causes of cancer death among men worldwide. Circular RNAs (circRNAs) have been implicated in the pathogenesis of PCa. However, the precise action of circ_0001326 in PCa malignant progression is still unknown. The levels of circ_0001326, miR-577 and voltage dependent anion channel 1 (VDAC1) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, colony formation, apoptosis, migration and invasion were evaluated by the Cell Counting Kit-8 (CCK-8), EdU staining, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Targeted relationships among circ_0001326, miR-577 and VDAC1 were confirmed by dual-luciferase reporter assays. Xenograft experiments were performed to detect the role of circ_0001326 in tumor growth. Our data revealed that circ_0001326 was overexpressed in PCa tissues and cells. Circ_0001326 depletion repressed PCa cell proliferation, migration, and invasion and enhanced apoptosis in vitro, as well as hampered tumor growth in vivo. Mechanistically, circ_0001326 directly targeted miR-577, and VDAC1 was directly targeted and suppressed by miR-577. Moreover, the effects of circ_0001326 knockdown on PCa cell functional behaviors were mediated by miR-577. VDAC1 silencing phenocopied miR-577 overexpression in regulating PCa cell functional behaviors in vitro. Furthermore, circ_0001326 regulated VDAC1 expression through sponging miR-577. Our findings showed that circ_0001326 regulated PCa cell functional behaviors at least partly through targeting the miR-577/VDAC1 axis., (© 2024 Wiley Periodicals LLC.)

This study aimed to explore the mechanism of the development of lung adenocarcinoma (LUAD) treated by astragalin. Transcriptome sequencing was performed to obtain the gene profile of LUAD treated by astragalin. Combining with bioinformatics analysis including differential gene screening, function enrichment analysis (gene ontology and KEGG), and ceRNA construction, we obtained the novel mechanism of lncRNA mediated miRNA/mRNA axis. Then, the cell experiments were performed to examine the role of lncRNA in cell proliferation, migration and invasion, and apoptosis for LUAD treated with astragalin. Moreover, the tumor formation in nude mice was carried out to detect the ceRNA mechanism in LUAD treated by astragalin in vivo. The lncRNA mediated ceRNA network was obtained, that is, LINC00852 LINC00582/miR-140-3p/PDPK1 played an important role in LUAD treated by astragalin. Function experiments indicated that si-LINC00852 inhibited LUAD cell proliferation, migration and invasion, and promoted cell apoptosis via miR-140-3p/PDPK1 (p < 0.05, p < 0.01). The animal experiments further confirmed that si-LINC00852 inhibited tumor growth through miR-140-3p/PDPK1 in vivo. Conversely, this study provides comprehensive insights into the diagnostic and therapeutic implications of LINC00582 in LUAD, LINC00582 mediated miR-140-3p/PDPK1 axis was the novel drug target of astragalin for treating LUAD., (© 2024 Wiley Periodicals LLC.)

Long non-coding RNAs (lncRNAs) have been reported to play a critical role in the progression and metastasis of osteosarcoma. Recently, long intergenic non-protein coding RNA 689 (linc00689) has been shown to be involved in glioma. However, the precise role of linc00689 in osteosarcoma is unknown. In this study, our data demonstrated that silencing linc00689 by siRNA markedly suppressed the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of MG63 and SAOS-2 cells. Bioinformatics analysis and dual-luciferase reporter assay revealed that linc00689 could bind to miR-129-5p. Moreover, NUSAP1 was a target of miR-129-5p and positively regulated by linc00689. Further, NUSAP1 overexpression enhanced MG63 cell behaviour and abolished the inhibitory effects of linc00689 knockdown on the proliferation, migration, invasion and EMT of MG63 cells. In conclusion, linc00689 exerts an oncogenic role in the progression of osteosarcoma, which works via the miR-129-5p/NUSAP1 axis., (© 2025 Company of the International Journal of Experimental Pathology (CIJEP).)

Cocaine abuse has been strongly linked to blood-brain barrier (BBB) dysfunction, though the exact mechanism by which cocaine disrupts the BBB remains unclear. In this study, we found that cocaine treatment reduces the expression of glucose transporter 1 (GLUT1) in brain microvascular endothelial cells, a key factor in cocaine-induced brain glucose uptake, BBB leakage, and cognitive impairment. Mechanistically, our results show that cocaine upregulates miR-320a, which in turn suppresses GLUT1 expression via the beta 2-adrenergic receptor (ADRB2). Notably, the administration of adeno-associated viruses encoding full-length GLUT1 or miR-320a inhibitors to the brain microvascular endothelium significantly mitigated cocaine-induced BBB leakage and cognitive deficits. Additionally, we discovered that melatonin, a well-known neuroprotective hormone, alleviates cocaine-induced BBB disruption and cognitive impairment. This protective effect of melatonin was mediated through the upregulation of miR-320a-dependent GLUT1 expression in brain endothelial cells via MT 1 receptor-mediated inhibition of the cAMP/PKA/CREB signaling pathway. In conclusion, our findings demonstrate that cocaine downregulates brain microvascular GLUT1, leading to BBB dysfunction, and highlight melatonin as a potential therapeutic agent for treating cocaine-related complications., (© 2024 John Wiley & Sons Ltd.)

MicroRNAs have been shown to play a critical role in lung inflammatory diseases. Here, we report that knocking out miR-144/451 in mice exacerbates lipopolysaccharide (LPS)-induced lung inflammation. The lung inflammation in mice was induced by intratracheal instillation of LPS. Loss-of-function experiments demonstrated that miR-144/451 gene knockout (KO) increased LPS-induced lung inflammation and oxidant stress compared with wild-type (WT) mice, as manifested by increased total bronchoalveolar lavage fluid cells and neutrophil counts, elevated TNF-α and IL-6 levels in bronchoalveolar lavage fluid, enhanced myeloperoxidase activity, and reduced catalase and glutathione peroxidase activity in lung tissues. We also found that LPS significantly decreased miR-451 expression in lung tissues and macrophages; while miR-451 overexpression in LPS-induced RAW264.7 cells remarkably reduced TNF-α and IL-6 levels as well as reactive oxygen species (ROS) production, suggesting a feedback loop might exist in inflammatory cells. Rac1 mRNA and protein levels were downregulated in miR-451-overexpressed RAW264.7 cells. Ex vivo stimulation experiments, performed using alveolar macrophages isolated from miR-144/451 KO mice, confirmed that Rac1 inhibitor alleviated levels of TNF-α and ROS in response to LPS stimulation compared with WT controls. Luciferase reporter assay demonstrated that STAT-3 is a direct target of miR-451. STAT-3 protein levels were elevated in miR-144/451 KO macrophages. LPS treatment also resulted in higher phosphorylation levels of STAT-3 in macrophages from KO mice than in WT cells. Our study identified miR-144/451 as an anti-inflammatory factor in LPS-induced lung inflammation that acts by downregulating Rac1 and STAT-3., (© 2024 Wiley Periodicals LLC.)

While Dicer plays an important antiviral role through the RNAi pathway in plants and invertebrates, its contribution to antiviral immunity in vertebrates and more specifically mammals is more controversial. The apparent limited RNAi activity in mammalian cells has been attributed to the reduced long dsRNA processive activity of mammalian Dicer, as well as a functional incompatibility between the RNAi and IFN pathways. Why Dicer has lost this antiviral activity in the profit of the IFN pathway is still unclear. We propose that the primary direct antiviral activity of Dicer has been functionally replaced by other sensors in the IFN pathway, leading to its specialization toward microRNA maturation. As a result, Dicer can regulate the innate immune response and prevent basal activation of the IFN pathway in mammals. Here, we discuss this hypothesis, highlighting how the adaptation of the helicase domain of mammalian Dicer may be key to this process., (© 2024 The Author(s). BioEssays published by Wiley Periodicals LLC.)

Lung adenocarcinoma (LUAD) emerges as one of the most lethal malignant tumors worldwide. Platinum-based combination chemotherapy remains one of the main methods for patients with advanced LUAD. Due to the resistance, the effect of this chemotherapy was not satisfactory. Therefore, studying the mechanism of cisplatin (DDP) resistance is essential for promoting the effect of this therapeutic strategy. Therefore, this work sought to probe the impact of E2F Transcription Factor 7 (E2F7) on LUAD resistance and the molecular regulatory mechanism. The mRNA expression level of the target gene E2F7 in LUAD was predicted by bioinformatics analysis, and regulatory miRNA upstream of the target gene was identified. The mRNA and protein expression of E2F7 in LUAD cells was detected through quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot, respectively. The expression of miR-195-5p in LUAD cells was measured via qRT-PCR. E2F7 high and low expression groups underwent enrichment analysis by utilizing Gene Set Enrichment Analysis software. The targeting relationship of miR-195-5p and E2F7 was validated by conducting a dual-luciferase reporter assay. The cell viability was tested through cell counting kit-8. The cell cycle was examined by flow cytometry. DNA damage level was determined via Comet assay and Western blot assay. The findings indicated that the mRNA and protein levels of E2F7 were high in LUAD. MiR-195-5p was the regulatory miRNA upstream of E2F7, and lowly expressed in LUAD. The cell experiments suggested that E2F7 advanced the DDP resistance of LUAD cells by repressing DNA damage. Finally, the rescue assay manifested that miR-195-5p overexpression could abate inhibition of E2F7 overexpression on the DNA damage and the DDP sensitivity of LUAD cells. MiR-195-5p raised the DDP sensitivity of LUAD cells by advancing the DNA damage in LUAD cells via inhibition of E2F7., (© 2024 Wiley Periodicals LLC.)

Cisplatin-based chemotherapy is the mainstay of therapeutic agents for lung cancer. Hence, we investigated the role and mechanism of circ&#95;0006225 in tumorigenesis and cisplatin resistance in lung cancer. Levels of circ&#95;0006225, microRNA (miR)-1236-3p and ankyrin repeat domain 22 (ANKRD22) were detected. Cell cisplatin (DDP) sensitivity and growth were determined by Cell Counting Kit-8, cell colony formation, 5-ethynyl-2'-deoxyuridine, and murine xenograft assays, respectively. A high level of circ&#95;0006225 in lung cancer tissues and cells with cisplatin resistance was observed. Circ&#95;0006225 deletion elevated cisplatin sensitivity and constrained proliferation in DDP-resistant lung cancer cells in vitro. Mechanistically, Circ&#95;0006225 was confirmed to modulate ANKRD22 by sequestering miR-1236-3p. Furthermore, the suppressive effects of circ&#95;0006225 downregulation on cisplatin resistance and proliferation in DDP-resistant lung cancer cells were reversed by miR-1236-3p inhibition or ANKRD22 overexpression. Besides that, circ&#95;0006225 silencing also repressed cisplatin resistance and tumor growth in lung cancer in vivo. In conclusion, knockdown of circ&#95;0006225 restrained the growth and reduced cisplatin resistance in lung cancer by the miR-1236-3p/ANKRD22 axis, suggesting a better effective therapeutic target for overcoming cisplatin resistance in lung cancer patients., (© 2024 Wiley Periodicals LLC.)

Coronary artery disease (CAD) causes myocardial ischemia, narrowing or occlusion of the lumen. Although great progress has been made in the treatment of CAD, the existing treatment methods do not meet the clinical needs, so it is urgent to find new treatment methods. The aim of this study was to investigate the mechanism of action of miR-148a-3p in alleviating CAD by inhibiting vascular endothelial cell injury and to provide new ideas for the treatment of CAD. A cell model was constructed by lipopolysaccharide (LPS) induction of vascular endothelial cells, and a CAD rat model was established by a high-fat diet and intraperitoneal injection of posterior pituitary hormone. Relevant indices were detected by RT-qPCR, ELISA, Western blot, MTT, and flow cytometry. The results indicate that in LPS-induced vascular endothelial cell assays, miR-148a-3p inhibited the upregulation of PCSK9, thereby suppressing the NF-κB signaling pathway and promoting vascular endothelial cell proliferation. Overexpression of PCSK9 and the addition of NF-κB signaling pathway activator increased vascular endothelial cell apoptosis. In animal experiments, miR-148a-3p alleviated the symptoms of CAD rats, whereas overexpression of PCSK9 promoted apoptosis and increased atheromatous plaque area in CAD rats. In conclusion, miR-148a-3p inhibits the NF-κB signaling pathway through downregulation of PCSK9, thereby protecting vascular endothelial cells and alleviating CAD., (© 2024 Wiley Periodicals LLC.)

Colorectal cancer (CRC) represents a substantial challenge to public health. Despite extensive research, the pathogenesis of CRC is not yet fully elucidated, hindering the development of effective therapeutic strategies. Recent advancements have underscored the importance of Non-coding RNAs in tumor biology. Our research identified a significant upregulation of Linc00475 in CRC, which correlated with reduced survival rates among CRC patients. Consequently, this study aimed to elucidate the mechanisms by which Linc00475 contributed to CRC progression. Employing a comprehensive array of experimental techniques-including CCK-8 assays, colony formation assays, flow cytometry, quantitative PCR (qPCR), western blot analysis, and in vivo tumorigenesis assays-we have demonstrated that Linc00475 enhances CRC cell proliferation. Further analysis revealed that Linc00475 directly interacted with miR-107, leading to its downregulation. Moreover, our findings confirmed that miR-107 directly targeted CDK6, which was markedly downregulated following Linc00475 silencing. In vivo experiments further indicated that the silencing of Linc00475 markedly inhibited the proliferation of CRC cells. Collectively, our findings suggested that Linc00475 facilitated CRC cell proliferation through the regulation of the miR-107/CDK6 axis, thereby providing a novel perspective for understanding the molecular mechanisms underlying CRC development., (© 2024 Wiley Periodicals LLC.)

Background: Triple-negative breast cancer, a subtype of breast cancer, is characterized by a poor prognosis. Recent studies have shown that miRNA30b acts as an oncogene and is vital for the proliferation of malignancies across various systems. This study aimed to elucidate the impact of miRNA30b on the proliferation, migration, and invasion capabilities of breast cancer cells in vitro . Methods: Triple-negative breast cancer cell lines MDA-MB-231 were transiently transfected with miRNA30b inhibitor, mimic, or the negative control by Lipofectamine 2000. Successful transfection was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Functional assays, including CCK8, clone formation, scratch, and transwell assays, were conducted to evaluate the proliferation, invasion, and migration ability of MDA-MB-231 cells in each group. The target protein of miRNA30b was determined using an online prediction data website, and the dual-luciferase assay confirmed whether there was a binding site between miRNA30b and ADAM12. The effect was further verified by Western blot analysis. Results: MDA-MB-231 cells were transfected with miRNA30b inhibitor, mimic, and negative control. miRNA30b expression was downregulated in the cells. Relative to the negative control group, miRNA30b expression significantly increased in the mimic group and decreased in the miRNA30b inhibitor group, with the differences being statistically significant. The miRNA30b mimic group exhibited a significant increase in miRNA30b expression and a corresponding promotion of cell proliferation, colony formation, and migration. Conversely, the miRNA30b inhibitor group displayed significantly reduced miRNA30b expression and suppressed cell proliferation, colony formation, and migration abilities compared to the negative control cells. Bioinformatics software predicted ADAM12 as a potential target of miRNA30b. Dual-luciferase assays confirmed the presence of a binding site between miRNA30b and ADAM12. Western blot analysis revealed that overexpression of miRNA30b downregulated ADAM12 expression in MDA-MB-231 cells. Conclusions: miRNA30b could promote proliferation, migration, and invasion of TNBC cell lines MDA-MB-231. The effect of miRNA30b on triple-negative breast cancer would be achieved partly at least through inhibiting the expression of ADAM12., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Qing-hua Yin et al.)

Objective: Doxorubicin (DOX) is an extensively used chemotherapeutic agent that induces cardiotoxicity. Studies have reported that exercise (EXE) can alleviate DOX-induced cardiotoxicity. Therefore, this study aimed to explore the mechanism by which EXE attenuates DOX-induced myocardial injury. Methods: In this study, cell and animal models of DOX-induced myocardial injury were constructed. The animal model was subjected to EXE intervention. Results: In this study, in vitro experiments revealed that miR-30d-5p negatively regulated polypeptide N-acetylgalactosaminyltransferase 7 (GALNT7) and that GALNT7 negatively regulated the expression of thyroid stimulating hormone receptor (TSHR). miR-30d-5p downregulated the expression of GALNT7, promoted the expression of TSHR, and promoted macrophage M1 polarization, thus aggravating cardiomyocyte injury. In vivo experiments revealed that EXE intervention significantly downregulated miR-30d-5p and TSHR expression, upregulated GALNT7, reduced inflammation, and promoted M2 macrophage polarization, thereby alleviating DOX-induced myocardial injury. In addition, overexpression of miR-30d-5p or knockdown of GALNT7 weakened the intervention effect of EXE, whereas overexpression of GALNT7 or knockdown of TSHR promoted the effect of EXE. Conclusion: EXE can modulate the miR-30d-5p/GALNT7 axis to inhibit the expression of TSHR, thereby regulating the polarization of macrophages to the M2 phenotype and ultimately alleviating DOX-induced myocardial injury, which provides new targets and strategies for the clinical treatment of myocardial injury., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Haiyan Wu et al.)

Propionate metabolism is important in the development of diabetes, and fibrosis plays an important role in diabetic nephropathy (DN). However, there are no studies on biomarkers related to fibrosis and propionate metabolism in DN. Hence, the current research is aimed at evaluating biomarkers associated with fibrosis and propionate metabolism and to explore their effect on DN progression. The GSE96804 (DN : control = 41 : 20) and GSE104948 (DN : control = 7 : 18) DN-related datasets and 924 propionate metabolism-related genes (PMRGs) and 656 fibrosis-related genes (FRGs) were acquired from the public database. First, DN differentially expressed genes (DN-DEGs) between the DN and control samples were sifted out via differential expression analysis. The PMRG scores of the DN samples were calculated based on PMRGs. The samples were divided into the high and low PMRG score groups according to the median scores. The PM-DEGs between the two groups were screened out. Second, the intersection of DN-DEGs, PM-DEGs, and FRGs was taken to yield intersected genes. Random forest (RF) and recursive feature elimination (RFE) analyses of the intersected genes were performed to sift out biomarkers. Then, single gene set enrichment analysis was conducted. Finally, immunoinfiltrative analysis was performed, and the transcription factor (TF)-microRNA (miRNA)-mRNA regulatory network and the drug-gene interaction network were constructed. There were 2633 DN-DEGs between the DN and control samples and 515 PM-DEGs between the high and low PMRG score groups. In total, 10 intersected genes were gained after taking the intersection of DN-DEGs, PM-DEGs, and FRGs. Seven biomarkers, namely, SLC37A4, ACOX2, GPD1, angiotensin-converting enzyme 2 (ACE2), SLC9A3, AGT, and PLG, were acquired via RF and RFE analyses, and they were found to be involved in various mechanisms such as glomerulus development, fatty acid metabolism, and peroxisome. The seven biomarkers were positively correlated with neutrophils. Moreover, 8 TFs, 60 miRNAs, and 7 mRNAs formed the TF-miRNA-mRNA regulatory network, including USF1-hsa-mir-1296-5p-AGT and HIF1A-hsa-mir-449a-5p-ACE2. The drug-gene network contained UROKINASE-PLG, ATENOLOL-AGT, and other interaction relationship pairs. Via bioinformatic analyses, the risk of fibrosis and propionate metabolism-related biomarkers in DN were explored, thereby providing novel ideas for research related to DN diagnosis and treatment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Sha Li et al.)

Background: Curcumin is a polyphenol compound with anticancer effects. We aimed to review the anti-neoplastic effects of curcumin on urogenital cancers, by regulating different microRNA expressions. Methods: A systematic search was conducted in Medline (PubMed), Embase, Scopus, and Web of Science up to the end of August 2024. All English, in vitro, and observational studies that evaluated the effect of curcumin on preventing or treating urogenital cancers through its impact on microRNA expression were included. In vivo or silico studies were excluded. Result: A total of 2549 records were found. Finally, 25 studies were included. Twelve studies assessed the effect of curcumin on prostate cancer, six studies on ovarian cancer, three studies on cervical cancer, three studies on bladder cancer, and one study on renal cancer. MicroRNAs are small noncoding RNAs that regulate the post-transcriptional pathways. They possess pivotal roles in different fundamental mechanisms in cells such as differentiation, migration, apoptosis, and proliferation. Curcumin exerts its anticancer effects on urogenital neoplasms by upregulating tumor suppressor microRNAs (miR-143, miR-145, miR-Let-7, miR-101, miR-3127, miR-3178, miR-1275, miR-3198, miR-1908, miR-770, miR-1247, miR-411, miR-34a, miR-383, miR-708, miR-483, miR-199a, miR-335, miR-503, miR-10b, miR-551a, miR-9, miR-203, miR-7110, miR-29b, and miR-126) and downregulating oncogenic microRNAs (miR-21, miR-210, miR-382, miR-654, miR-494, miR-193b, miR-671, miR-222, miR-23b, miR-664, miR-183, miR-214, miR-320a, miR-23a, miR-30a, miR-320d, miR-1285, miR-32, miR-181a, miR-205, miR-216a, miR-1246, and miR-106b). Conclusion: Cell proliferation is inhibited, and cell apoptosis is induced by curcumin in different urogenital cancers through suppressing oncogenic microRNAs or provoking tumor suppressor microRNAs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Sadegh Mazaheri-Tehrani et al.)

Background: Baicalein has been used to treat inflammation-related diseases; nevertheless, its specific mechanism of action is unclear. Therefore, we examined the protective effects of baicalein on lipopolysaccharide-induced damage to AR42J pancreatic acinar cells (PACs) and determined its mechanism of action for protection., Methods: An in vitro cell model of acute pancreatitis (AP) was established using lipopolysaccharide (LPS) (1 mg/L)-induced PACs (AR42J), and the relative survival rate was determined using the 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) technique. Flow cytometry was applied to evaluate the apoptotic rates of AR42J PACs. The RNA and protein expression of miR-224-5p, poly ADP-ribose polymerase-1 (PARP1), nuclear transcription factor- κ B65 (NF- κ B65), phospho-kappa B alpha(p-I κ B- α ), interleukin(IL)-18R, NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), gasdermin D (GSDMD), apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1 was detected based on the WB and RT-PCR assays. IL-1 β , IL-6, IL-18, and TNF- α expression levels in AR42J cells were measured via ELISA method. The cell morphology was examined using the AO/EB method., Results: The experiment confirmed a significant increase in the activity of AR42J cells treated with various doses of baicalein. Moreover, IL-1 β , IL-6, TNF- α , and IL-18 expression levels in AR42J cells were dramatically reduced ( P   < 0.05), while miR-224-5p level was obviously enhanced. The protein and gene expression of PARP1, NF- κ B65, p-I κ B- α , IL-18R, GSDMD, ASC, NLRP3, and caspase-1 was obviously decreased ( P < 0.05). Apoptosis in AR42J cells was significantly reduced with significant improvement in cell morphology., Conclusion: Baicalein may significantly alleviate LPS-induced AR42J PAC damage by inhibiting the inflammatory response and pyroptosis. Its mode of action might be linked to higher miR-224-5p expression, which inhibits the PARP1/NF- κ B and NLPR3/ASC/caspase-1/GSDMD pathways., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Ming-Wei Liu et al.)

Bone metastasis is the primary cause of death among patients with advanced prostate cancer (PCa). PCa tends to spread to bones and acquire the bone-like phenotype, causing osteoblastic bone metastasis. Unfortunately, there is no effective treatment for this condition. However, melatonin, which regulates our circadian rhythm, has been found to have anti-tumor properties. It has yet to be established whether it is effective in treating osteoblastic PCa metastasis. Our findings show that melatonin inhibits the production of endothelin-1 (ET-1) in osteoblastic PCa cells, suppressing osteoblast differentiation. Clinical results indicate that bone metastatic PCa patients have higher levels of ET-1 compared to nonmetastatic PCa patients. Furthermore, melatonin-induced miR-let-7f-5p inhibits ET-1-promoted osteoblast differentiation in osteoblastic PCa. Melatonin also suppresses the property of osteomimicry in osteoblastic PCa cells. Importantly, in the intratibia injection PCa metastasis model, melatonin decreased osteoblastic PCa tumor growth, inhibiting ET-1 production and osteoblast differentiation in vivo. Taken together, melatonin inhibits osteoblastic PCa-regulated osteoblastogenesis by reducing ET-1 production through upregulation of miR-let-7f-5p, while suppressing the property of osteomimicry in osteoblastic PCa. Melatonin therapy could be a promising approach to treating bone metastasis in osteoblastic PCa., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with non-alcoholic fatty liver disease (NAFLD) often exhibit hepatic steatosis and dyslipidemia. Studies have shown that intestinal microorganisms are closely related to the occurrence of NAFLD and atherosclerosis. Our previous study has underscored the protective role of microRNA-30a-5p (miR-30a-5p) against atherosclerosis., Methods and Results: In the present study, we aimed to elucidate the effect and underlying mechanism of the intestinal microorganisms of miR-30a-5p knockout (KO) mice on NAFLD. Our findings demonstrated that KO exacerbated high-fat diet (HFD)-induced hepatic steatosis and disrupted liver function, as evidenced by elevated levels of total cholesterol, low-density lipoprotein, alanine aminotransferase, aspartate transaminase, and total bile acids in serum. Fecal microbiota from HFD-fed KO mice induced hepatic steatosis, dyslipidemia, and higher levels of enzymes indicative of liver damage in wild-type mice. Remarkably, KO mice significantly intensified the above effects. 16s rDNA sequencing and metabolomics of the intestinal microbiota in the HFD-treated KO and WT mice showed that the loss of miR-30a-5p resulted in intestinal microbiota imbalance and was highly related to the arachidonic acid metabolic pathway. Targeted metabolomic in the liver tissues unveiled upregulation of COX-related (PGF2a, 8-iso-PGF2a and PGF2) and LOX-related (LTB4, LTD4, 12S-HETE and 15S-HETE) factors in HFD-treated KO mice. Immunohistochemistry and transcriptional analyses showed that miR-30a-5p affected arachidonic acid metabolism through the LOX/COX pathways. Besides, COX/LOX pathways and hepatic steatosis were reversed after reintroducing miR-30a-5p in HFD-treated KO mice., Conclusions: This study reveals the pivotal mechanism by which miR-30a-5p and intestinal microbes regulate hepatic steatosis and abnormal lipid metabolism, offering promising avenues for NAFLD and atherosclerosis therapeutics., Highlights: MiR-30a-5p deletion aggravated hepatic steatosis and lipid disorder induced by an HFD in mice. Gut microbiota participated in the regulation of hepatic steatosis in the context of miR-30a-5p. Gut microbiota metabolism-related arachidonic acid metabolic pathway contributed to miR-30a-5p-regulated hepatic steatosis and lipid disorder. Reintroducing miR-30a-5p reversed hepatic steatosis and arachidonic acid metabolism disorder caused by HFD and miR-30a-5p deletion., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Feline primary hypertrophic cardiomyopathy (HCM) is an intrinsic myocardial disease characterized by concentric hypertrophy of the left ventricle. In the present study, we investigated the microRNA-mRNA regulatory network in feline myocardial tissue affected by primary (HCMI) and secondary HCM (HCMII). MRNA expression levels of sarcomeric genes, including, TNNT2, TNNI3, MYH7, MYBPC3, TPM1 and ACTC1 were assessed in the FFPE myocardial tissues. FFPE tissues from healthy cats were sequenced by the NGS, to explore, in the entire non-deposited miRNome, the expression level of microRNAs targeting the complementary sequences of selected sarcomeric mRNAs. The sarcomeric genes TNNT2, MYH7, MYBPC3 and TPM1 showed a statistically significant upregulation in HCMI compared to HCMII (p < .01), except ACTC1 which was downregulated (p < .01); TNNI3 showed no statistically significant difference. In HCMII miR-122-5p, miR-338-3p, miR-484, miR-370-3p, miR-92b-3p, miR-375 and miR-370-3p showed a significant upregulation (p < .01) compared to control. The exception was miR-30a-5p which showed downregulation. Worthy of note is the 4-fold higher expression of miR-370-3p, a key regulator of MYBPC3, in HMCI compared to HMCII. This research does not solve the aetiological mystery of HCM, but it may help to find a way to help diagnose and define the prognosis of HCM in cats., (© 2024 The Author(s). International Journal of Experimental Pathology published by John Wiley & Sons Ltd on behalf of Company of the International Journal of Experimental Pathology (CIJEP).)

Helicobacter pylori (HP) is considered a major risk factor for gastric cancer (GC) and during this process, cytotoxin‑associated gene A (CagA) plays in essence. The study mainly focused on the molecular mechanism of circular RNA 0046854 (circ&#95;0046854) in HP-induced GC. Clinically, 56 cases of GC and normal tissues were collected, and the GC tissues were divided into HP-negative GC tissues (HP - ) and 33 HP-positive GC tissues (HP + ). Tissue expression of circ&#95;0046854, microRNA (miR)-511-3p and colony-stimulating factor 1 (CSF1) was tested. BGC-823/Cisplatin (DDP) resistant strain was induced and cell growth and DDP resistance were detected after HP infection. In vivo experiments were performed using a mouse xenograft model. The relationship between circ&#95;0046854, miR-511-3p and CSF1 was confirmed. GC tissues especially HP + cancer tissues expressed high circ&#95;0046854 and CSF1 and low miR-511-3p. HP-induced circ&#95;0046854 expression in GC cells through CagA. Inhibition of circ&#95;0046854 or miR-511-3p elevation inhibited the growth and DDP resistance in GC cells. Circ&#95;0046854 acted as a sponge for miR-511-3p, which targeted CSF1. Restoring CSF1 could abolish the inhibitory effect of miR-511-3p overexpression on CagA + HP-induced GC progression in vitro. Circ&#95;0046854 silencing repressed tumor growth and aggrandized the inhibiting effects of DDP on tumorigenesis in vivo. Circ&#95;0046854/miR-511-3p/CSF1 axis may be involved in the development of HP-induced GC, thus providing new ideas for studying the mechanism of HP-related gastric diseases., (© 2024 Wiley Periodicals LLC.)

Introduction: Temporomandibular joint osteoarthritis (TMJ OA) is a major disease that affects maxillofacial health and is characterised by cartilage degeneration and subchondral bone remodelling. Obesity is associated with the exacerbation of pathological manifestations of TMJ OA. However, the underlying mechanism between adipose tissue and the TMJ axis remains limited., Objectives: To evaluate the effects of obesity and the adipose tissue on the development of TMJ OA., Methods: The obesity-related metabolic changes in TMJ OA patients were detected by physical signs and plasma metabolites. The effects of adipose tissue-derived EVs (Ad-EVs) on TMJ OA was investigated through histological and cytological experiments as well as gene editing technology. Alterations of Ad-EVs in obese state were identified by microRNA-seq analysis and the mechanism by which EVs affect TMJ OA was explored in vitro and in vivo., Results: Obesity and the related metabolic changes were important influencing factors for TMJ OA. Ad-EVs from obese mice induced marked chondrocyte apoptosis, cartilage matrix degradation and subchondral bone remodelling, which exacerbated the development of TMJ OA. Depletion of Ad-EVs secretion by knocking out the geranylgeranyl diphosphate synthase (Ggpps) gene in adipose tissue significantly inhibited the obesity-induced aggravation of TMJ OA. MiR-3074-5p played an important role in this process ., Conclusions: Our work unveils an unknown link between obese adipose tissue and TMJ OA. Targeting the Ad-EVs and the miR-3074-5p may represent a promising therapeutic strategy for obesity-related TMJ OA., Key Points: High-fat-diet-induced obesity aggravate the progression of TMJ OA in mice. Obese adipose tissue participates in cartilage damage through the altered miRNA in extracellular vesicles. Inhibition of miR-3074-5p/SMAD4 pathway in chondrocyte alleviated the effect of HFD-EVs on TMJ OA., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Renowned for their role in haemostasis and thrombosis, platelets are also increasingly recognized for their contribution in innate immunity, immunothrombosis and inflammatory diseases. Platelets express a wide range of receptors, which allows them to reach a variety of activation endpoints and grants them immunomodulatory functions. Activated platelets release extracellular vesicles (PEVs), whose formation and molecular cargo has been shown to depend on receptor-mediated activation and environmental cues. This study compared the immunomodulatory profiles of PEVs generated via activation of platelets by different receptors, glycoprotein VI, C-type lectin-like receptor 2 and combining all thrombin-collagen receptors. Functional assays in vivo in zebrafish and in vitro in human macrophages highlighted distinct homing and secretory responses triggered by the PEVs. In contrast, omics analyses of protein and miRNA cargo combined with physicochemical particle characterization found only subtle differences between the activated PEV types, which were insufficient to predict their different immunomodulatory functions. In contrast, constitutively released PEVs, formed in the absence of an exogenous activator, displayed a distinct immunomodulatory profile from the receptor-induced PEVs. Our findings underscore that PEVs are tunable through receptor-mediated activation. To truly comprehend their role(s) in mediating platelet functions among immune cells, conducting functional assays is imperative., (© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Oxidative stress is crucial in ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC). Intestinal epithelial cells (IECs) are an important component of the intestinal barrier. In previous studies, we have demonstrated that suppressing microRNA-222-3p (miR-222-3p) can protect against oxidative stress in IECs, which ameliorates colonic injuries in UC mice and prevents the conversion of UC to CAC. In this case, we hope to explore whether moxibustion can alleviate UC and CAC by inhibiting miR-222-3p based on mouse models of UC and CAC. After herb-partitioned moxibustion (HPM) intervention, the disease activity index (DAI) and colon macroscopic damage index (CMDI) were significantly reduced in UC mice, and the number and volume of intestinal tumors were decreased considerably in CAC mice. Meanwhile, we found that HPM suppressed miR-222-3p expression and upregulated the mRNA and protein expression of Brahma-related gene 1 (BRG1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), while inhibiting Kelch-like ECH-associated protein 1 (Keap1) expression in IECs of UC and CAC mice. With changes in reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and inflammatory cytokines interleukin (IL)-1 β and tumor necrosis factor (TNF)- α ), we verified that HPM protects against oxidative stress and inflammation in IECs of UC and CAC mice. The effect of HPM was inhibited in miR-222-3p overexpression mice, further demonstrating that the protective effect of HPM on UC and CAC mice was through inhibiting miR-222-3p. In summary, HPM regulates the BRG1/Nrf2/HO-1 pathway by inhibiting miR-222-3p to attenuate oxidative stress in IECs in UC and CAC., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2024 Xuejun Wang et al.)

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment (TME) and can induce functional polarization of tumor macrophages. This study aimed to explore the effect of CAFs-derived exosome LINC01833 on the malignant biological behavior of non-small cell lung cancer (NSCLC) cells and its mechanism. Tumor tissues (n = 3) and adjacent noncancerous tissues (n = 3) were collected from patients with NSCLC, and fibroblasts (CAF, NF) were isolated from the two tissues. Expression of LINC01833/miR-335-5p/VAPA in NSCLC clinical tissues and cell lines was detected by RT-qPCR. Exosomes of CAFs and NFs were isolated by ultracentrifugation. Cell proliferation, migration, invasion, and M2 macrophage polarization were detected by MTT, transwell, wound-healing assay, and flow cytometry assay, while western blot was used to verify the expression of M2 macrophage polarization-related proteins. Tumor volume weight and M2 macrophage polarization were detected by tumor xenografts in nude mice. LINC01833 was highly expressed in NSCLC tumor tissues and cells. Knockdown of LINC01833 exosomes could significantly inhibit proliferation, migration, invasion of NSCLC cells, and M2 macrophage polarization of THP-1 cells, while simultaneous knockdown of miR-335-5p on the above basis could reverse the effect of knockdown of LINC01833. In vivo experiments also indicated that knockdown of LINC01833 exosomes suppressed tumor growth and M2 macrophage polarization. CAF-derived LINC01833 exosomes can promote the proliferation, migration and invasion of NSCLC cells and M2 macrophage polarization by inhibiting miR-335-5p and regulating VAPA activity., (© 2024 Wiley Periodicals LLC.)

Background: To investigate the involvement of LINC02605 in the progression of paediatric Mycoplasma pneumoniae pneumonia (MPP)., Methods: One hundred and thirty-two children with MPP (90 simple MPP and 42 MPP + diarrhoea) were enrolled, and their plasma was collected for detection of LINC026505 expression. CCK-8 kit and commercial apoptosis kit were introduced to determine cell growth and apoptosis. In silico prediction analyses were conducted to predict the downstream miRNA for LINC02605, following verification by dual luciferase reporter assay. The lipid-associated membrane proteins (LAMPs) were used to treat A549 and Coca-2 cells., Results: LIN02605 was highly expressed in the MPP, especially in MPP complicated with diarrhoea. LINC02605 downregulation in A549 cells correlated with significant suppression of cell apoptosis rate and growth inhibition rate in vitro. Introduction of miR-539-5p inhibited luciferase activity in a reporter system containing the wild-type LINC02605 and CXCL1. After stimulation with LAMPs, overexpression of LINC02605 and CXCL1 and inhibition of miR-539-5p were found. miR-539-5p and CXCL1 knockdown resulted in a rescue effect on the LINC02605-inhibited cell apoptosis. LAMPs induced IL-1β in intestinal epithelial cells and IL-1β induced LINC02605 expression in A549 cells., Conclusions: LINC02605 was upregulated in MPP and miR-539-5p was a target for LINC02605. LINC02605 may be involved in the crosstalk between the gastrointestinal tract and the respiratory tract., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Circular RNA (circRNA) plays important role in hepatocellular carcinoma (HCC) progression. However, the role and mechanism of circETV6 in HCC progression remain unclear. The levels of circETV6, ETV6, miR-383-5p, and PTPRE were tested by quantitative reverse-transcription polymerase chain reaction. Cell functions were assessed using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, 5-ethynyl-2'-deoxyuridine assay, colony formation assay, wound healing assay, transwell assay, and flow cytometry. The protein levels of poptosis-related markers and PTPRE were determined by western blot analysis. RNA interaction was analyzed by dual-luciferase reporter assay and RNA pull-down assay. A xenograft model was established to assess circETV6 roles in vivo. CircETV6 was highly expressed in HCC tissues and cells. CircETV6 knockdown repressed HCC cell proliferation, migration, invasion, and cell cycle, while accelerated apoptosis. CircETV6 targeted miR-383-5p, and miR-383-5p inhibition reversed the regulation of circETV6 knockdown on HCC cell progression. CircETV6 promoted PTPRE level via targeting miR-383-5p. Overexpressed PTPRE abolished the inhibition effect of miR-383-5p on HCC cell progression. In addition, circETV6 knockdown slowed HCC tumor growth in vivo. CircETV6 might facilitate HCC progression via the miR-383-5p/PTPRE axis, providing a novel target for HCC treatment., (© 2024 Wiley Periodicals LLC.)

Microsporidia, a group of unicellular eukaryotic parasites, rely intensely on secretory effectors for successful invasion and proliferation within host cells. This review focuses on the identification, characterization, and functional roles of effectors, including secretory proteins and microRNAs. The adhesion proteins like the Ricin-B-lectin facilitate initial invasion, which binds to the host cell surface. Once inside, microsporidia deploy a range of effectors to modulate host immune responses, such as serpin proteins, and redirect host cell metabolism to meet the parasite's nutritional needs through hexokinase. Some effectors such as microRNAs, alter the host gene expression to create a more favorable intracellular parasitic environment. In conclusion, the secretory effectors of microsporidia play a pivotal role spanning from host cell invasion to intracellular establishment. In the future, more effectors secreted by microsporidia will be studied, which will not only help to elucidate the molecular mechanism of pathogenic manipulation of the host but also help to provide the potential targets for anti-parasitic treatments., (© 2024 International Society of Protistologists.)

Osteosarcoma (OS) is the most frequent bone malignancy in humans. Previous evidence suggest that circ&#95;0032463 is an oncogenic circular RNA (circRNA) in various cancers, including OS. However, the molecular mechanism of circ&#95;0032463 involved in OS is still unclear. Circ&#95;0032463, microRNA-145-5p (miR-145-5p), GDNF receptor alpha 1 (GFRA1), and Wilms tumor 1-associated protein (WTAP) levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, apoptosis, migration, invasion, and angiogenesis were analyzed using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and tube formation assays. Western blot analysis was performed to measure matrix metalloproteinase 2 (MMP2), MMP9, GFRA1, and WTAP protein levels. Binding between miR-145-5p and circ&#95;0032463 or GFRA1 was confirmed using a dual-luciferase reporter and pull-down assay. The biological role of circ&#95;0032463 on OS cell growth was also analyzed using a xenograft tumor model in vivo. Methylated RNA immunoprecipitation assay validated the interaction between WTAP and circ&#95;0032463. Circ&#95;0032463, GFRA1, and WTAP levels were increased, and miR-145-5p was decreased in OS tissues and cells. Circ&#95;0032463 deficiency might hinder OS cell proliferation, migration, invasion, angiogenesis, and promote apoptosis in vitro. Mechanically, circ&#95;0032463 worked as a miR-145-5p sponge to increase GFRA1 expression. Repression of circ&#95;0032463 knockdown on tumor cell growth was proved in vivo. Besides, N6-methyladenosine (m6A) modification facilitates the biogenesis of circ&#95;0032463. Taken together, m6A-mediated biogenesis of circ&#95;0032463 facilitates OS cell malignant biological behavior partly via regulating the miR-145-5p/GFRA1 axis, suggesting a promising molecular marker for OS treatment., (© 2024 Wiley Periodicals LLC.)

The involvement of let-7 in the occurrence and progression of various cancers has been well-documented. However, the precise molecular mechanisms underlying its impact on oral cancer development remain unclear. In this study, we aimed to elucidate the role of let-7 in oral cancer progression and investigate its underlying molecular mechanisms. The expression of let-7 and high mobility group A2 (HMGA2) mRNA was assessed using the quantitative reverse transcription polymerase chain reaction. Western blot analysis was employed to detect the expression of key proteins in the PI3K/AKT signaling pathway as well as HMGA2 protein levels. The targeting relationship between let-7 and HMGA2 was predicted through bioinformatics methods and confirmed via luciferase reporter gene assay. The effects of let-7 and HMGA2 on the functionality of oral cancer cells were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation assay, Transwell assay, wound healing assay, and Annexin V/PI apoptosis assay. Additionally, the impact of let-7 on the growth of oral cancer cells in vivo was investigated by inducing subcutaneous tumor formation in nude mice. Let-7 effectively suppresses the proliferation, migration, and invasion of oral cancer cells by inhibiting the activation of the PI3K/AKT signaling pathway. HMGA2, a downstream target gene of let-7, exhibits high expression in oral cancer. However, overexpression of HMGA2 diminishes the inhibitory effects induced by let-7 overexpression on the proliferation, migration, and invasion of oral cancer cells. The occurrence and progression of oral cancer cells are inhibited by Let-7 through the downregulation of HMGA2, potentially mediated by the inhibition of PI3K/AKT signaling pathway activation., (© 2024 Wiley Periodicals LLC.)