Search

Hypoxic pulmonary hypertension (HPH), a prevalent subtype of pulmonary arterial hypertension, is characterized by pulmonary vasoconstriction (HPV) and vascular remodeling, accompanied by inflammatory responses. Recent in vivo studies have shown a critical role of the κ-opioid receptor (κ-OR) in modulating the aforementioned pathological processes. Specifically, macrophage-specific κ-OR-knockout models have shown inflammatory response exacerbation with pulmonary hypertension and vascular remodeling. Conversely, the novel κ-OR agonist Q-U50, 488H inhibits inflammatory pathways, thereby attenuating pulmonary vasoconstriction and vascular remodeling. The present study revealed that hypoxia promoted macrophage infiltration and pulmonary artery smooth muscle cell proliferation. Moreover, under these conditions, macrophages secreted interleukin (IL)-6, which triggered the signal transducer and activator of transcription 3 (STAT3)/miR-153-3p signaling cascade. Herein, we identified miR-153-3p downregulated κ-OR gene expression, which is a key contributor to HPV and remodeling, it was identified as a pivotal regulator of κ-OR mRNA levels. The pharmacological activation of κ-OR inhibited IL-6 release from macrophages and disrupted the IL-6/STAT3/miR-153-3p pathway. This dual action of κ-OR activation mitigated pulmonary artery contraction and remodeling, thereby offering a protective mechanism against HPH. The present findings have delineated a novel negative feedback loop driving HPH pathogenesis and suggested that targeting the κ-OR-IL-6-STAT3-miR-153-3p axis represented a promising therapeutic strategy against HPH., Competing Interests: Declaration of Competing interest The authors hereby declare that there are no conflicts of interest, financial or otherwise, that could have influenced the integrity and objectivity of the research conducted and presented in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract: Background: Growing evidence has found the critical role of circular RNAs (circRNAs) in sepsis-induced acute kidney injury (S-AKI). CircTMCO3 has been found to be involved in tumor microenvironment changes of ovarian cancer. This study aimed to explore whether circTMCO3 functions in S-AKI, and if so, to elucidate the molecular mechanism. Methods: CircTMCO3 expression was analyzed in lipopolysaccharide (LPS)-induced HK-2 cells and in the kidney tissues of mice treated with cecal ligation and puncture (CLP), respectively. Furthermore, the effects of circTMCO3 on S-AKI and the related mechanisms were evaluated in both models through gain- and/or loss-of-function strategies. Results: CircTMCO3 expression was suppressed in both S-AKI models. Upregulation of circTMCO3 mitigated LPS-induced apoptosis, oxidative stress, and inflammation in HK-2 cells. In contrast, circTMCO3 downregulation exacerbated LPS-induced injuries in HK-2 cells. Intravenous injection of circTMCO3 lentivirus to increase circTMCO3 expression improved renal function and attenuated kidney injury in S-AKI mice, as evidenced by the decrease in serum creatinine and blood urea nitrogen concentrations, amelioration of tubular pathological injury, reduction of renal cell apoptosis, and mitigation of oxidative stress and proinflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, circTMCO3 directly targeted miR-218-5p, and the mimic of which abolished the protective effect of circTMCO3 in cell models. ZEB2 was identified to be a target of miR-218-5p; its downregulation not only reversed the impacts of miR-218-5p inhibitor on S-AKI, but also mitigated the effects mediated by circTMCO3 upregulation in vitro . Conclusions: CircTMCO3 protects against S-AKI by regulating miR-218-5p/ZEB2 axis, thereby mediating antiapoptotic, antioxidant, and anti-inflammatory activities. This indicates that increasing circTMCO3 expression might be a future therapeutic method for S-AKI., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

In β‑thalassemia, excessive α‑globin chain impedes the normal development of red blood cells resulting in anemia. Numerous miRNAs, including miR‑6747‑3p, are aberrantly expressed in β‑thalassemia major (β‑TM), but there are no reports on the mechanism of miR‑6747‑3p in regulating red blood cell lineage development and fetal hemoglobin (HbF) expression. In the present study, RT‑qPCR was utilized to confirm miR‑6747‑3p expression in patients with β‑TM and the healthy controls. Electrotransfection was employed to introduce the miR‑6747‑3p mimic and inhibitor in both HUDEP‑2 and K562 cells, and red blood cell lineage development was evaluated by CCK‑8 assay, flow cytometry, Wright‑Giemsa staining and Benzidine blue staining. B‑cell lymphoma/leukemia 11A (BCL11A) was selected as a candidate target gene of miR‑6747‑3p for further validation through FISH assay, dual luciferase assay and Western blotting. The results indicated that miR‑6747‑3p expression was notably higher in patients with β‑TM compared with healthy controls and was positively related to HbF levels. Functionally, miR‑6747‑3p overexpression resulted in the hindrance of cell proliferation, promotion of cell apoptosis, facilitation of cellular erythroid differentiation and γ‑globin expression in HUDEP‑2 and K562 cells. Mechanistically, miR‑6747‑3p could specifically bind to the 546‑552 loci of BCL11A 3'‑UTR and induce γ‑globin expression. These data indicate that upregulation of miR‑6747‑3p affects red blood cell lineage development and induces HbF expression by targeting BCL11A in β‑thalassemia, highlighting miR‑6747‑3p as a potential molecular target for β‑thalassemia therapy.

To investigate the effect of miR-3571 on traumatic brain injury (TBI) via the regulation of neuronal apoptosis through F-box-only protein 31/phosphoinositide 3-kinase/protein kinase B (Fbxo31/PI3K/AKT). We established TBI rat and cell models. Hematoxylin‒eosin (HE) and Nissl staining were used to observe brain injury and the number of Nissl bodies, respectively. Cell proliferation and apoptosis were assessed by 5-ethynyl-2'-deoxyuridine (EdU), terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and flow cytometry. Gene and protein expression was measured via reverse transcription quantitative polymerase chain reaction (RT‒qPCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). In this study, miR-3571 was highly expressed in TBI models. Inhibition of miR-3571 expression can suppress autophagy, reduce the expression of proinflammatory cytokines, and reduce neuronal apoptosis, thus alleviating the pathological conditions of tissue congestion, edema and structural damage after TBI. These experiments demonstrated that miR-3571 could target and regulate the level of Fbxo31. Knockdown of Fbxo31 weakened the remission effect of the miR-3571 inhibitor on TBI and promoted neurological damage; moreover, overexpression of Fbxo31 enhanced the protective effect on neural function, whereas the PI3K/AKT pathway inhibitor LY294002 increased the damage caused by miR-3571 on neural function and weakened the protective effect of Fbxo31. In conclusion, miR-3571 regulates the PI3K/AKT signaling pathway by reducing Fbxo31 expression, promotes neuronal apoptosis and exacerbates TBI., Competing Interests: Compliance with ethical standards Conflict of interest The authors declare no competing interests. Consent for publication All the authors agreed on the publication of this manuscript. Ethics approval and consent to participate All animal procedures were approved by the Animal Ethics Committee of People’s Hospital of Hunan Province., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ischemic stroke is a leading cause of disability and mortality worldwide. Recently, increasing evidence implicates microRNAs (miRs) in the pathophysiology of ischemic stroke. Studies have shown that miR-15a/16-1 is abnormally expressed in brains after ischemic stroke, and its upregulation may increase ischemic damage. Given that sex and age are significant modifiers of stroke outcomes, here we investigated whether inhibiting miR-15a/16-1 with antagomirs mitigates cerebral ischemia/reperfusion (I/R) injury in a sex- and age-dependent manner. Young (3 months) and aged (18 months) male and female C57/BL mice underwent 1-h middle cerebral artery occlusion and 3-7 days reperfusion (tMCAO). We administered miR-15a/16-1 antagomir (30 pmol/g) or control antagomir (NC, 30 pmol/g) via tail vein 2 h post-MCAO. Neurobehavioral testing and infarct volume assessment were performed on days 3 and 7. Compared to controls, antagomir treatment significantly improved neurobehavioral outcomes and reduced infarct volume in tMCAO mice at day 7, with the effects being more pronounced in young mice. Notably, young female mice exhibited superior survival and sensorimotor function compared to young male mice. These results were also replicated in a permanent MCAO (pMCAO) mice model. This suggests miR-15a/16-1 antagomir and estradiol may synergistically regulate genes involved in neurovascular cell death, inflammation, and oxidative stress, with sex and age-dependent expression of miR-15a/16-1 and its targets likely underlying the observed variations. Overall, our findings identify miR-15a/16-1 antagomir as a promising therapeutic for ischemic stroke and suggest that sex and age should be considered when developing miR-based therapeutic strategies.

The development of a bio-sensing strategy based on CRISPR/Cas that is exceptionally sensitive is crucial for the identification of trace molecules. Colorimetric miRNA detection utilizing CRISPR/Cas13a-triggered DNAzyme signal amplification was described in this article. The developed strategy was implemented for miRNA-21 detection as a proof of concept. The cleavage activity of Cas13a was triggered when the target molecule bonded to the Cas13a-crRNA complex and cleaved uracil ribonucleotides (rU) in the substrate probe. As a consequence, the S chain was liberated from the T chain that had been modified on magnetic beads (MB). The G-rich sections were then exposed when the catalytic hairpin assembly between the H1 and H2 probes was activated by the released T@MB. G-rich section can fold into G-quadruplex. By catalyzing the formation of green ABTS 3 - via HRP-mimicking G-quadruplex/hemin complexes, colorimetric measurements of miRNA can be achieved visually through DNAzyme-mediated signal amplification. The method demonstrated a low limit of detection of 27 fM and a high selectivity towards target miRNA eventually. As a result, the developed strategy provides a clinical application platform for the detection of miRNAs that is both ultrasensitive and extremely specific., Competing Interests: Declarations. Ethics Approval: This article does not contain any studies with human participants or animals performed by any of the authors. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Accumulation studies confirmed that oxidative stress caused by ischemia after myocardial infarction (MI) is an important cause of ventricular remodeling. Exosome secretion through hypoxic pretreatment adipose-derived mesenchymal stem cells (ADSCs) ameliorates myocardial damaging post-MI. However, if ADSCs exosome can improve the microenvironment and ameliorate cardiac damage post-MI still unknown. Next-generation sequencing (NGS) was used to study abnormally expressed circRNAs in hypoxic pretreatment ADSC exosomes (HExos) and untreated ADSC exosomes (Exos). Bioinformatics and luciferase reporting were used to elucidate interaction correlation related to circRNA, mRNA, and miRNA. HL-1 cells were used to analyze the reactive oxygen species (ROS) and apoptosis under hypoxic conditions using immunofluorescence and flow cytometry. An MI mouse model was constructed and the therapeutic effect of Exos was determined using immunohistochemistry, immunofluorescence, and ELISA. The results showed that HExos had a more pronounced treatment effect than ADSC Exos on cardiac damage amelioration after MI. NGS showed that circ-Stt3b plays a role in HExo-mediated cardiac damage repair after MI. Overexpression of circ-Stt3b decreased apoptosis, ROS level, and inflammatory factor expression in HL-1 cells under hypoxic conditions. Bioinformatics and luciferase reporting data validated miR-15a-5p and GPX4 as downstream circ-Stt3b targets. GPX4 downregulation or miR-15a-5p overexpression reversed protective effect regarding circ-Stt3b upon HL-1 cells after exposure to a hypoxic microenvironment. Overexpression of circ-Stt3b increased the treatment effect of ASDSC Exos on cardiac damage amelioration after MI. Taken together, the study results demonstrated that Exos from hypoxic pretreatment ADSCs ameliorate cardiac damage post-MI through circ-Stt3b/miR-15a-5p/GPX4 signaling activation and decreased ferroptosis., (© 2024. The Author(s).)

Mesenchymal stem cells (MSCs) have demonstrated promising therapeutic potential in the treatment of type 1 diabetes mellitus (T1DM); however, the underlying mechanism remains unclear. The primary pathological mechanism of T1DM involves activated T cells infiltrating the pancreas, leading to islet inflammation and the destruction of β-cells. However, the question of whether exosomes derived from MSCs can suppress the migration of T cells to the pancreas in the context of T1DM remains unresolved. In this study, we observed that miR-25 was highly expressed in MSCs exosomes and associated with signaling pathways related to cell migration. In vitro assay, we synthesized a miR-25 mimic and transiently transfected it into activated T cells, which revealed that miR-25 can effectively reduce the expression of CXCR3. Additionally, according to the in vivo T1DM mouse model, we found that there was a significant increase in miR-25 levels in T1DM mice treated with MSCs and the number of T cells decreased. Overall, our findings suggest that MSCs exosomes containing miR-25 can impede the infiltration of activated T cells into the pancreas in T1DM by repressing CXCR3 expression in these cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Na Li, Mei Han, Ning Zhou, Yong Tang, Xu-Shan Tang. MicroRNA-495 Confers Increased Sensitivity to Chemotherapeutic Agents in Gastric Cancer via the Mammalian Target of Rapamycin (mTOR) Signaling Pathway by Interacting with Human Epidermal Growth Factor Receptor 2 (ERBB2). Med Sci Monit, 2018; 24: CLR5990-5972. DOI: 10.12659/MSM.909458.

The clinical treatment of hepatocellular carcinoma (HCC) is still a heavy burden worldwide. Intracellular microRNAs (miRNAs) commonly express abnormally in cancers, thus they are potential therapeutic targets for cancer treatment. miR-21 is upregulated in HCC whereas miR-122 is enriched in normal hepatocyte but downregulated in HCC. In our study, we first generated a reporter genetic switch compromising of miR-21 and miR-122 sponges as sensor, green fluorescent protein (GFP) as reporter gene and L7Ae:K-turn as regulatory element. The reporter expression was turned up in miR-21 enriched environment while turned down in miR-122 enriched environment, indicating that the reporter switch is able to respond distinctly to different miRNA environment. Furthermore, an AAT promoter, which is hepatocyte-specific, is applied to increase the specificity to hepatocyte. A killing switch with AAT promoter and an apoptosis-inducing element, Bax, in addition to miR-21 and miR-122 significantly inhibited cell viability in Huh-7 by 70 % and in HepG2 by 60 %. By contrast, cell viability was not affected in five non-HCC cells. Thus, we provide a novel feasible strategy to improve the safety of miRNA-based therapeutic agent to cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is closely related to Epstein-Barr virus (EBV) infection. Long noncoding RNAs (lncRNAs) play important roles in cancers. However, the molecular mechanism underlying the roles of lncRNAs in EBV-associated NPC remains largely unclear. In this study, we confirmed that the expression of the lncRNA brain cytoplasmic 200 (BC200) was significantly increased in EBV-infected NPC cells and tissues. BC200 facilitated the growth and migration of NPC cells, suggesting that it participated in NPC progression by functioning as an oncogene. Mechanistically, BC200 was found to act as a ceRNA by sponging and inhibiting miR-6834-5p. Thymidylate synthetase (TYMS), whose high expression was reported to be an independent indicator of poor prognosis in NPC via an unknown mechanism, was identified as a target gene of miR-6834-5p in the present study. BC200 upregulated TYMS expression in a manner that depends on miR-6834-5p. TYMS was abnormally upregulated in EBV-positive NPC cells and tissues, and its ectopic expression contributed to the proliferation and migration of NPC cells. This study highlights the role of lncRNA BC200, which is upregulated by EBV, in promoting the development of NPC, suggesting that BC200-mediated ceRNA network may be valuable biomarkers for the diagnosis and treatment of EBV-associated NPC., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests that could have appeared to influence the work in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent years, a common-used antidiabetic drug, liraglutide, was identified with extra effects on lipid metabolism. Its effects against excessive lipid deposition in bone marrow were gained much attention but not well established. Our aim in the present study is to explore the interaction of miRNAs-mRNAs altered by liraglutide administration during bone marrow adipogenesis in diabetes. To establish the diabetic animal model, rats were treated with high fat diet (HFD) and STZ injection. We then identified the lowering effect of liraglutide on lipids metabolism in the diabetes. During this process, high-throughput sequencing and bioinformatics analyses on miRNAs extracted from bone marrow mesenchymal stem cells (BMSCs) were conducted after liraglutide administration. We then identified five differentially expressed miRNAs (miRNA-150-5p, miRNA-129-5p, miRNA-201-3p, miRNA-201-5p, and miRNA-214-5p). The expressions of the DE miRNAs were verified as temporal specific expression patterns in Day 3 and in Day 7. Among them, miRNA-150-5p expression was more stable and consistent with the sequencing data. Of interest, miR-150-5p overexpression facilitated adipogenesis of BMSCs. But this promotion was alleviated by liraglutide. The predicted target gene of miR-150-5p, GDF11, was validated to be involved in liraglutide alleviated BMSCs' lipid accumulation in diabetes. In vitro, liraglutide increased the GDF11 expression, rescued its down-expression by siGDF11 and inhibit the adipogenesis of BMSCs cultured in high glucose medium. In vivo, liraglutide reversed the HFD-STZ induced excessive lipid droplets by up-regulation of GDF11 expression, which was discounted by agomiR-150-5p injection. Above all, liraglutide might alleviate bone marrow fat accumulation via inactivating miR-150-5p/GDF11 axis in diabetes., Competing Interests: Declaration of Competing interest No potential conflict of interests was reported by the authors., (Copyright © 2024. Published by Elsevier B.V.)

Background: Ischemic preconditioning-induced serum exosomes (IPC-exo) protected rat heart against myocardial ischemia/reperfusion injury. However, whether IPC-exo regulate replacement fibrosis after myocardial infarction (MI) and the underlying mechanisms remain unclear. MicroRNAs (miRs) are important cargos of exosomes and play an essential role in cardioprotection. We aim to investigate whether IPC-exo regulate post-MI replacement fibrosis by transferring cardioprotective miRs and its action mechanism., Methods: Exosomes obtained from serum of adult rats in control (Con-exo) and IPC groups were identified and analyzed, subsequently intracardially injected into MI rats following ligation. Their miRs profiles were identified using high-throughput miR sequencing to identify target miRs for bioinformatics analysis. Luciferase reporter assays confirmed target genes of selected miRs. IPC-exo transfected with selected miRs antagomir or NC were intracardially administered to MI rats post-ligation. Cardiac function and degree of replacement fibrosis were detected 4 weeks post-MI., Results: IPC-exo exerted cardioprotective effects against excessive replacement fibrosis. MiR sequencing and RT-qPCR identified miR-133a-3p as most significantly different between IPC-exo and Con-exo. MiR-133a-3p directly targeted latent transforming growth factor beta binding protein 1 (LTBP1) and protein phosphatase 2, catalytic subunit, alpha isozyme (PPP2CA). KEGG analysis showed that transforming growth factor-β (TGF-β) was one of the most enriched signaling pathways with miR-133a-3p. Comparing to injection of IPC-exo transfected with miR-133a-3p antagomir NC, injecting IPC-exo transfected with miR-133a-3p antagomir abolished protective effects of IPC-exo on declining excessive replacement fibrosis and cardiac function enhancement, while increasing the messenger RNA and protein expression of LTBP1, PPP2CA, and TGF-β1in MI rats., Conclusion: IPC-exo inhibit excessive replacement fibrosis and improve cardiac function post-MI by transferring miR-133a-3p, the mechanism is associated with directly targeting LTBP1 and PPP2CA, and indirectly regulating TGF-β pathway in rats. Our finding provides potential therapeutic effect of IPC-induced exosomal miR-133a-3p for cardiac repair., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Yang et al.)

Objective: Esophageal squamous cell carcinoma (ESCC) is commonly diagnosed with high mortality worldwide. Cell proliferation and cell apoptosis are essential biological processes for the development of cancers. MiR-16-5p, a critical member of miRNAs family, is involved in cell apoptosis and tumor progression. However, the role of miR-16-5p in regulating esophageal squamous cell carcinoma and the underlying mechanism remain unclear., Methods: In this study, we used human ESCC tissue samples and human esophageal cells to determine the expression level of miR-16-5p in ESCC tissues and cells. Cell Counting Kit-8 assay and flow cytometry were used to test cell proliferation and apoptosis. Western blotting was used to detect protein expression levels. The scratch assay was used to analyze the level of cell migration, and the transwell assay was used to analyze the invasive ability of tumor cells., Results: The expression of miR-16-5p was up-regulated in ESCC tissues and cells. Knockdown of miR-16-5p significantly inhibited cell proliferation and promoted cell apoptosis. The knockdown of miR-16-5p also restrained cell migration and invasion. We revealed that AMPK/mTOR signaling pathway participated in the regulation of ESCC progression., Conclusion: miR-16-5p may promote the proliferation, migration, and invasion of ESCC through modulating AMPK/mTOR signaling pathway., (© 2024 by the Association of Clinical Scientists, Inc.)

Lung cancer is one of the most common malignant tumors in humans and the leading cause of cancer-related deaths worldwide. The microRNA-34 (miR-34) family is dysregulated in various human cancers and is an important family of tumor suppressor genes among microRNAs. The miR-34 family is downregulated in lung cancer. It inhibits cell proliferation, metastasis, and invasion, arrests the cell cycle, and induces apoptosis or senescence by negatively regulating many oncogenes. It is commonly used to detect and treat lung cancer. This study describes the regulatory role of the miR-34 family in lung cancer and the associated research advances in treatment., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: BPD is a refractory disease affecting preterm infants with alveolar dysplasia and declined pulmonary function. However, the molecular mechanism underlying BPD is largely unknown. To explore the pathogenic mechanism of BPD and to facilitate better diagnosis and treatment of this disease., Method: The DEMs and DEGs in BPD vs. Control samples from the miRNA expression data in GSE108754 and mRNA expression data in the GSE108755 were screened, followed by the construction of the miRNA-mRNA regulatory network. DEGs PPI network and hub DEGs analysis were constructed by using the STRING database and Cytoscape software. Functional and pathway enrichment analyses were then performed for these DEGs and DEMs based on the ClusterProfiler package in the R and the miRWalk database. The k-mean algorithm is used to perform clustering analysis of DEGs. Cellular experiments (flow cytometry, western blot, RT-PCR, dual-luciferase reporter assay) were used to validate the results of bioinformatics., Results: We obtained 20 DEMs and 262 DEGs. A 15 DEMs-11 DEGs regulatory network was constructed. miR-3202-RAG1 is a core sub-network. Hyperoxia induced a cell model of BPD. The upregulation of RAG1 and downregulation of miR-3202 were observed in BPD cells. Furthermore, siRNA targeting RAG1 was transfected into BEAS-2B cells to inhibit its expression and miR-3202 mimics was transfected into the cells to increase its expression. Inhibition of RAG1 and elevation of miR-3202 inhibit cell apoptosis and reduce ROS level caused by hyperoxia. A double-luciferase reporter assay revealed that miR-3202 directly targets RAG1., Conclusion: The miRNA-3202/RAG1 axis contributes into BPD-induced cell apoptosis and ROS production. The present study provides a probable target for the treatment of BPD., Competing Interests: Declaration of Competing Interest there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Tooth morphogenesis is a critically ordered process manipulated by a range of signaling factors. Particularly, the involvement of fine-tuned signaling mediated by non-coding RNAs has been of longstanding interest. Here, we revealed a double-negative feedback loop acted by a long non-coding RNA (LOC102159588) and a microRNA (miR-133b) that modulated tooth morphogenesis of miniature swine. Mechanistically, miR-133b repressed the transcription of LOC102159588 through downstream target Sp1. Conversely, LOC102159588 not only inhibited the transport of pre-miR-133b from the nucleus to the cytoplasm by regulating exportin-5 but also served as a sponge in the cytoplasm, suppressing functional miR-133b. Together, the double-negative feedback loop maintained normal tooth morphogenesis by modulating endogenous apoptosis. Related disruptions would lead to an arrest of tooth development and may result in tooth malformations., Competing Interests: Declaration of competing interest All authors disclosed no conflict of interest to competing or financial of this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

There is an urgent need to accurately quantify microRNA (miRNA)-based Alzheimer's disease (AD) biomarkers, which have emerged as promising diagnostic biomarkers. In this study, we present a rapid and universal approach to establishing a target miRNA-triggered rolling circle amplification (RCA) detection strategy, which achieves ultrasensitive detection of several targets, including miR-let7a-5p, miR-34a-5p, miR-206-3p, miR-9-5p, miR-132-3p, miR-146a-5p, and miR-21-5p. Herein, the padlock probe contains three repeated signal strand binding regions and a target miRNA-specific region. The target miRNA-specific region captures miRNA, and then the padlock probe is circularized with the addition of T4 DNA ligase. Subsequently, an RCA reaction is triggered, and RCA products containing multiple signal strand binding regions are generated to trap abundant fluorescein-labeled signal strands. The addition of exonuclease III (Exo III) causes signal strand digestion and leads to RCA product recycling and liberation of fluorescein. Ultimately, graphene oxide (GO) does not absorb the liberated fluorescein because of poor mutual interaction. This method exhibited high specificity, sensitivity, repeatability, and stability toward let-7a, with a detection limit of 19.35 fM and a linear range of 50 fM to 5 nM. Moreover, it showed excellent applicability for recovering miRNAs in normal human serum. Our strategy was applied to detect miRNAs in the plasma of APP/PS1 mice, demonstrating its potential in the diagnosis of miRNA-associated disease and biochemical research.

Introduction: Apigenin is a natural flavonoid compound with promising potential for the attenuation of myocardial hypertrophy (MH). The compound can also modulate the expression of miR-185-5p that both promote MH and suppress autophagy. The current attempts to explain the anti-MH effect of apigenin by focusing on changes in miR-185-5p-mediated autophagy., Methods: Hypertrophic symptoms were induced in rats using transverse aortic constriction (TAC) method and in cardiomyocytes using Ang II and then handled with apigenin. Changes in myocardial function and structure and cell viability and surface area were measured. The role of miR-185-5p in the anti-MH function of apigenin was explored by detecting changes in autophagic processes and miR-185-5p/SREBP2 axis., Results: TAC surgery induced weight increase, structure destruction, and collagen deposition in hearts of model rats. Ang II suppresses cardiomyocyte viability and increased cell surface area. All these impairments were attenuated by apigenin and were associated with the restored level of autophagy. At the molecular level, the expression of miR-185-5p was up-regulated by TAC, while the expression of SREBP2 was down-regulated, which was reserved by apigenin both in vivo and in vitro. The induction of miR-185-5p in cardiomyocytes could counteracted the protective effects of apigenin., Discussion: Collectively, the findings outlined in the current study highlighted that apigenin showed anti-MH effects. The effects were related to the inhibition of miR-185-5p and activation of SREBP, which contributed to the increased autophagy., Competing Interests: The authors declare that they have no competing interests in this work., (© 2024 Yan et al.)

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and multiple vital organs, but the immunological pathogenesis of SSc remains unclear. We show here that miR-19b promotes Th9 cells that exacerbate SSc. Specifically, miR-19b and interleukin (IL)-9 increase in CD4 + T cells in experimental SSc in mice induced with bleomycin. Inhibiting miR-19b reduces Th9 cells and ameliorates the disease. Mechanistically, transforming growth factor beta (TGF-β) plus IL-4 activates pSmad3-Ser 213 and TRAF6-K63 ubiquitination by suppressing NLRC3. Activated TRAF6 sequentially promotes TGF-β-activated kinase 1 (TAK1) and nuclear factor κB (NF-κB) p65 phosphorylation, leading to the upregulation of miR-19b. Notably, miR-19b activated Il9 gene expression by directly suppressing atypical E2F family member E2f8. In patients with SSc, higher levels of IL9 and MIR-19B correlate with worse disease progression. Our findings reveal miR-19b as a key factor in Th9 cell-mediated SSc pathogenesis and should have clinical implications for patients with SSc., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this study, the expression profiles of miR-148a were constructed in eight different ovine tissues, including mammary gland tissue, during six different developmental periods. The effect of miR-148a on the viability, proliferation, and milk fat synthesis of ovine mammary epithelial cells (OMECs) was investigated, and the target relationship of miR-148a with two predicted target genes was verified. The expression of miR-148a exhibited obvious tissue-specific and temporal-specific patterns. miR-148a was expressed in all eight ovine tissues investigated, with the highest expression level in mammary gland tissue ( p < 0.05). Additionally, miR-148a was expressed in ovine mammary gland tissue during each of the six developmental periods studied, with its highest level at peak lactation ( p < 0.05). The overexpression of miR-148a increased the viability of OMECs, the number and percentage of Edu-labeled positive OMECs, and the expression levels of two cell-proliferation marker genes. miR-148a also increased the percentage of OMECs in the S phase. In contrast, transfection with an miR-148a inhibitor produced the opposite effect compared to the miR-148a mimic. These results indicate that miR-148a promotes the viability and proliferation of OMECs in Small-tailed Han sheep. The miR-148a mimic increased the triglyceride content by 37.78% ( p < 0.01) and the expression levels of three milk fat synthesis marker genes in OMECs. However, the miR-148a inhibitor reduced the triglyceride level by 87.11% ( p < 0.01). These results suggest that miR-148a promotes milk fat synthesis in OMECs. The dual-luciferase reporter assay showed that miR-148a reduced the luciferase activities of DNA methyltransferase 1 ( DNMT1 ) and peroxisome proliferator-activated receptor gamma coactivator 1-A ( PPARGC1A ) in wild-type vectors, suggesting that they are target genes of miR-148a. The expression of miR-148a was highly negatively correlated with PPARGC1A (r = -0.789, p < 0.001) in ovine mammary gland tissue, while it had a moderate negative correlation with DNMT1 (r = -0.515, p = 0.029). This is the first study to reveal the molecular mechanisms of miR-148a underlying the viability, proliferation, and milk fat synthesis of OMECs in sheep.

The 5-year survival for non-small cell lung cancer (NSCLC) remains <20 %, primarily due to the early symptoms of lung cancer are inconspicuous. Prompt identification and medical intervention could serve as effective strategies for mitigating the death rate. We therefore set out to identify biomarkers to help diagnose NSCLC. CircRNA microarray and qRT-PCR reveal that sputum circ&#95;0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC, which can enhance the proliferation and clone formation, regulate the cell cycle, and accelerate the migration and invasion of NSCLC cells. Circ&#95;0006949 and miR-4673 are predominantly co-localized in the cytoplasm of NSCLC cell lines and tissues; it upregulates GLUL by adsorption of miR-4673 through competing endogenous RNAs mechanism. The circ&#95;0006949/miR-4673/GLUL axis exerts pro-cancer effects in vitro and in vivo. Circ&#95;0006949 can boost GLUL catalytic activity, and they are highly expressed in NSCLC tissues and correlate with poor prognosis. In summary, circ&#95;0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC. This novel sputum circRNA is statistically more predictive than conventional serum markers for NSCLC diagnosis. Non-invasive detection of patients with early-stage NSCLC using sputum has shown good potential for routine diagnosis and possible screening., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: None. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Periodontitis is a chronic inflammatory disease mediated by dysbiosis of the oral microflora, resulting in the destruction of periodontal tissue. Increasing evidence suggested that mesenchymal stem cell (MSCs) and exosomes derived from MSCs play a critical role in periodontal tissue regeneration. However, whether stem cells from exfoliated deciduous teeth (SHED)-secreted exosomes can improve the therapeutic potential of periodontitis is largely unknown., Objective: Here, we aim to evaluate the effect of SHED-exosomes on inflammation, apoptosis and osteogenic differentiation in periodontitis., Methods: The periodontitis cell model was constructed by stimulating periodontal ligament stem cells (PDLSCs) with lipopolysaccharide (LPS), and the periodontitis rats were established by ligation., Results: First, we isolated exosomes from the SHED, and we figured out that exosomes secreted by SHED were enriched in miR-92a-3p and the exosomes enhanced proliferation and osteogenic differentiation and reduced apoptosis and inflammatory responses in PDLSCs. In addition, we found that SHED-exosomes alleviated inflammatory effect and elevated the expression of osteogenic-related genes in periodontitis rat model. Moreover, miR-92a-3p targeted downstream Krüppel-Like Transcription Factor 4 (KLF4) and regulated the PI3K/AKT pathway. Finally, our data indicated that upregulation of KLF4 or activation of PI3K/AKT by 740Y-P counteracted the inhibitory effect of SHED-exosomes on periodontitis progression., Conclusion: Taken together, our finding revealed that exosomal miR-92a-3p derived from SHED contributed to the alleviation of periodontitis development and progression through inactivating the KLF4/PI3K/AKT signaling pathway, which may provide a potential target for the treatment of periodontitis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

An increasing number of circRNAs have been found to be involved in the development of gastric cancer. However, the function of circ&#95;0003789 in regulating gastric cancer progression is unclear. Here, we aimed to investigate the expression, function and molecular mechanism of circ&#95;0003789 in gastric cancer pathogenesis. Circ&#95;0003789, miR-429 and ZFP36 ring finger protein like 2 (ZFP36L2) mRNA were quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was illustrated by 5-Ethynyl-2'-deoxyuridine (Edu), cell counting kit-8 (CCK-8) and colony formation assays. Apoptosis was determined by flow cytometry. Protein level was detected by Western blotting assay. Xenograft assays were used for functional analysis of circ&#95;0003789 in vivo. The relationship between miR-429 and circ&#95;0003789 or ZFP36L2 was predicted by starbase3.0 online database and identified by dual luciferase reporter assay. The expression levels of circ&#95;0003789 and ZFP36L2 were significantly upregulated in gastric cancer tissues and cells, while the expression of miR-429 was downregulated. Downregulation of circ&#95;0003789 inhibited gastric cancer cell growth and invasion and promoted apoptosis in vitro. Circ&#95;0003789 acted as a sponge of miR-429. Moreover, miR-429 silencing by miR-429 inhibitors attenuated the effects of circ&#95;0003789 interference on cell growth, apoptosis and invasion. ZFP36L2 was targeted by miR-429, and the effects of miR-429 on cell growth, invasion and apoptosis were attenuated by ZFP36L2 overexpression. Circ&#95;0003789 could enhance ZFP36L2 expression by interacting with miR-429. Silencing of circ&#95;0003789 inhibited tumor growth in vivo. Circ&#95;0003789 regulates tumor progression in gastric cancer through miR-429/ZFP36L2 axis. This finding implies that circ&#95;0003789 may be a therapeutic target for gastric cancer., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: Background: Diabetic nephropathy (DN) is a complication of diabetes that is the leading cause of death in diabetic patients. Circular RNA (circRNA) is a hot topic in the research of human diseases. However, the role of circ&#95;Supt3 in DN remains unclear. Methods: High glucose (HG) treatment of mouse podocyte (MPC5) cells to mimic DN cell injury. Quantitative real-time polymerase chain reaction was performed to detect the expression of circ&#95;Supt3, microRNA-185-5p (miR-185-5p), and GTPase-activating protein-binding protein 2 (G3bp2). 5-Ethynyl-2'-deoxyuridine (EdU) and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium Bromide (MTT) assays were used to examine cell proliferation, and flow cytometry was used to detect cell apoptosis. Western blot was used to assess the levels of relative proteins. Enzyme-linked immunosorbent assay detected the inflammation cytokines. Dual-luciferase reporter and RNA pull-down assays were used to confirm the interaction of miR-185-5p and circ&#95;Supt3 or G3bp2. Results: Circ&#95;Supt3 and G3bp2 were highly expressed and miR-185-5p expression was diminished in DN mice. HG treatment inhibited cell proliferation and accelerated cell apoptosis and inflammation response, and the knockdown of circ&#95;Supt3 reversed these effects. Bioinformatics predicted that circ&#95;Supt3 contained a binding site for miR-185-5p, and G3bp2 was a direct target of miR-185-5p. Circ&#95;Supt3 regulated G3bp2 expression by miR-185-5p. Moreover, the circ&#95;Supt3/miR-185-5p/G3bp2 axis regulated the cell behavior of HG-induced MPC5 cells. Conclusion: Our findings suggest that the knockdown of circ&#95;Supt3 protects mouse MPC5 cells against HG-induced cell injury via the miR-185-5p/G3bp2 axis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Pathological myocardial hypertrophy is a common early clinical manifestation of heart failure, with noncoding RNAs exerting regulatory influence. However, the molecular function of circular RNAs (circRNAs) in the progression from cardiac hypertrophy to heart failure remains unclear. To uncover functional circRNAs and identify the core circRNA signaling pathway in heart failure, we construct a global triple network (microRNA, circRNA, and mRNA) based on the competitive endogenous RNA (ceRNA) theory. We observe that cardiac hypertrophy-related circRNA (circRNA CHRC), within the ceRNA network, is down-regulated in both transverse aortic constriction mice and Ang-II--treated primary mouse cardiomyocytes. Silencing circRNA CHRC increases cross-sectional cell area, atrial natriuretic peptide, and β-myosin heavy chain levels in primary mouse cardiomyocytes. Further screening shows that circRNA CHRC targets the miR-431-5p/KLF15 axis implicated in heart failure progression in vivo and in vitro. Immunoprecipitation with anti-Ago2-RNA confirms the interaction between circRNA CHRC and miR-431-5p, while miR-431-5p mimics reverse Klf15 activation caused by circRNA CHRC overexpression. In summary, circRNA CHRC attenuates cardiac hypertrophy via sponging miR-431-5p to maintain the normal level of Klf15 expression., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

MicroRNA is regarded as a significant biomarker for cancer diagnosis, disease process evaluation and therapeutic guidance, and dual-parameter measurement may contribute to a more accurate and realistic assessment. To meet the urgent need for simultaneous detection of multiple biomarkers, we combined three-dimensional DNAzyme motors with single molecule imaging technique to construct a convenient, intuitive, and sensitive approach for the simultaneous detection of dual miRNAs in the free state or in extracellular vesicles. Quantification of target miRNAs can be realized through the detection of amplified fluorescence signals generated by the target miRNA-initiated cleavage of fluorescent substrate strands by the DNAzyme motors. The practicability was systematically validated with microRNA-21-5p and microRNA-10b-5p as targets, acquiring a satisfactory sensitivity sufficient to detect low abundance targets at 0.5 or 1 pM to 100 pM. Besides, the extracellular vesicular miRNAs can be conveniently detected without extraction. The clinical applicability was verified with a series of extracellular vesicles from clinical samples, which exhibited good distinguishability between colorectal cancer patients and healthy donors. In addition to the advantages of good specificity and high sensitivity, the system has potential to be easily adapted by minor alteration of the DNA sequences and fluorophore sets for detection of multiple miRNAs and even other types of biomarkers such as proteins. Therefore, it shows promise to be widely applied in various fields such as early diagnosis of cancer and its prognostic assessment.

MicroRNA (miRNA), a type of non-coding RNA, is crucial for controlling gene expression. Among the various miRNA families, miR166 stands out as a highly conserved group found in both model and crop plants. It plays a key role in regulating a wide range of developmental and environmental responses. In this review, we explore the diverse sequences of MIR166s in major crops and discuss the important regulatory functions of miR166 in plant growth and stress responses. Additionally, we summarize how miR166 interacts with other miRNAs and highlight the potential for enhancing agronomic traits by manipulating the expression of miR166 and its targeted HD-ZIP III genes.

By employing an aptamer as the bridge and combining catalytic hairpin assembly with the Au aggregation amplification effect, a lateral flow assay (LFA) is designed for simultaneous detection of liver cancer-associated miRNA and exosomes. The LFA can differentiate between liver cancer patients and healthy individuals with simple operation and high accuracy.

Ethnopharmacological Relevance: Liujunzi formula has been used to treat liver cancer in China for many years, but its underlying mechanism remains unclear. We previously found that decreased expression of miR-122-3p was associated with liver cancer. In this study, we aimed to explore the target of miR-122-3p and the effect of the Liujunzi formula on miR-122-3p and its downstream events in liver cancer., Material and Methods: Bioinformatics pinpointed potential targets of miR-122-3p. The actual target was confirmed by miRNA mimic/inhibitor transfections and a dual-luciferase reporter assay. RNA-seq looked at downstream genes impacted by this target. Flow cytometry checked for changes in T cell apoptosis levels after exposing them to liver cancer cells. Gene expression was measured by RT-qPCR, western blotting, and immunofluorescence staining., Results: Cell experiments found the Liujunzi extract (LJZ) upregulated miR-122-3p and in a dose-dependent manner. Bioinformatics analysis found UBE2I was a potential target of miR-122-3p, which was validated through experiments using miRNA mimics/inhibitors and a dual-luciferase reporter assay. RNA-seq data implicated the NF-κB pathway as being downstream of the miR-122-3p/UBE2I axis, further confirmed by forcing overexpression of UBE2I. Bioinformatic evidence suggested a link between UBE2I and T cell infiltration in liver cancer. Given that the NF-κB pathway drives PD-L1 expression, which can inhibit T cell infiltration, we investigated whether PD-L1 is a downstream effector of miR-122-3p/UBE2I. This was corroborated through mining public databases, UBE2I overexpression studies, and tumor-T cell co-culture assays. In addition, we also confirmed that LJZ downregulates UBE2I and NF-κB/PD-L1 pathways through miR-122-3p. LJZ also suppressed SUMOylation in liver cancer cells and protected PD-1 + T cells from apoptosis induced by co-culture with tumor cells. Strikingly, a miR-122-3p inhibitor abrogated LJZ's effects on UBE2I and PD-L1, and UBE2I overexpression rescued the LJZ-mediated effects on NF-κB and PD-L1., Conclusions: miR-122-3p targets UBE2I, thereby suppressing the NF-κB signaling cascade and downregulating PD-L1 expression, which potentiates anti-tumor immune responses. LJZ bolsters anti-tumor immunity by modulating the miR-122-3p/UBE2I/NF-κB/PD-L1 axis in liver cancer cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: This study aimed to explore the specific pathways by which HOX transcript antisense intergenic RNA contributes to the pathogenesis of unexplained recurrent spontaneous abortion., Methods: Real-time quantitative PCR was employed to assess the differential expression levels of HOX transcript antisense intergenic RNA in chorionic villi tissues from unexplained recurrent spontaneous abortion patients and women with voluntarily terminated pregnancies. HTR-8/SVneo served as a cellular model. Knockdown and overexpression of HOX transcript antisense intergenic RNA in the cells were achieved through siRNA transfection and pcDNA3.1 transfection, respectively. Cell viability, migration, and invasion were evaluated using cell counting kit-8, scratch, and Transwell assays, respectively. The interaction among the HOX transcript antisense intergenic RNA /miR-1277-5p/fibrillin 2 axis was predicted through bioinformatics analysis and confirmed through in vitro experiments. Furthermore, the regulatory effects of the HOX transcript antisense intergenic RNA /miR-1277-5p/fibrillin 2 signaling axis on cellular behaviors were validated in HTR-8/SVneo cells., Results: We found that HOX transcript antisense intergenic RNA was downregulated in chorionic villi tissues from unexplained recurrent spontaneous abortion patients. Overexpression of HOX transcript antisense intergenic RNA significantly enhanced the viability, migration, and invasion of HTR-8/SVneo cells, while knockdown of HOX transcript antisense intergenic RNA had the opposite effects. We further confirmed the regulatory effect of the HOX transcript antisense intergenic RNA /miR-1277-5p/fibrillin 2 signaling axis in unexplained recurrent spontaneous abortion. Specifically, HOX transcript antisense intergenic RNA and fibrillin 2 were found to reduce the risk of unexplained recurrent spontaneous abortion by enhancing cell viability, migration, and invasion, whereas miR-1277-5p exerted the opposite effects., Conclusion: HOX transcript antisense intergenic RNA promotes unexplained recurrent spontaneous abortion development by targeting inhibition of miR-1277-5p/fibrillin 2 axis., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To explore how miRNA-28-3p targets BIN1 and affects the biological behavior of nasopharyngeal carcinoma cells, and to evaluate its potential as a predictive biomarker for NPC., Methods: We studied 100 nasopharyngeal carcinoma patients who underwent surgery between January 2021 and January 2022. Tissues from tumors and adjacent normal areas were analyzed. Participants were categorized into two groups: one with nasopharyngeal carcinoma and another with adjacent normal tissue. Additionally, the nasopharyngeal carcinoma cell line CNE-2 was divided into three groups: an untreated control, a negative control with NC plasmid, and a test group treated with a miRNA-28-3p inhibitor. Key techniques included PCR, Western blotting, CCK-8, flow cytometry, focusing on the interactions between miRNA-28-3p and BIN1 and their predictive significance for NPC., Results: miRNA-28-3p levels were significantly higher in nasopharyngeal carcinoma tissues compared to adjacent normal tissues (P < .05). The predictive performance of miRNA-28-3p for NPC featured an AUC > 0.75 with sensitivity and specificity both exceeding 70% (P < .001). In nasopharyngeal carcinoma cells, miRNA-28-3p levels were significantly elevated compared to normal cells (P < .05). Transfection with the miRNA-28-3p inhibitor increased apoptosis and BIN1 protein levels while reducing cell proliferation, invasion, and migration significantly (P < .05)., Conclusion: miRNA-28-3p is overexpressed in nasopharyngeal carcinoma and inhibits tumor cell proliferation, migration, and invasion, while promoting apoptosis by targeting BIN1. The level of miRNA-28-3p expression serves as a sensitive indicator for predicting nasopharyngeal carcinoma, affirming its potential as a diagnostic biomarker and underscoring the significance of these findings in enhancing understanding and clinical management of NPC.

Abstract: The role of microRNAs in regulating tubulointerstitial fibrosis, a key feature of progressive chronic kidney disease, is of significant importance. LIN28A has been reported to attenuate renal fibrosis in obstructive nephropathy. Here, our objective was to investigate the precise biological function of the miR-92a-3p/LIN28A axis in tubulointerstitial fibrosis. The human renal proximal tubular epithelial (HK-2) cell line was exposed to transforming growth factor (TGF)-β1, establishing an in vitro model mimicking tubulointerstitial fibrosis. Luciferase reporter assay was utilized to investigate the relationship between miR-92a-3p and LIN28A. Cell transfection techniques were employed to modify the expression of miR-92a-3p and LIN28A. An in vivo model of tubulointerstitial fibrosis was created by inducing unilateral ureteral obstruction (UUO) in C57BL/6N mice. Our initial observations showed that TGF-β1 treatment of HK-2 cells and the UUO mice model led to an increase in miR-92a-3p expression and a decrease in LIN28A expression. We confirmed that miR-92a-3p directly targeted LIN28A in HK-2 cells. In TGF-β1-stimulated HK-2 cells, knocking down miR-92a-3p notably reduced the levels of alpha smooth muscle actin and vimentin and concurrently enhanced the expression of E-cadherin. These changes were counteracted upon transfection with si-LIN28A. Thus, directing interventions toward miR-92a-3p holds the potential to emerge as a viable therapeutic approach for addressing tubulointerstitial fibrosis., (Copyright © 2024 Copyright: © 2024 Journal of Physiological Investigation.)

Acute coronary artery blockage leads to acute myocardial infarction (AMI). Cardiomyocytes are terminally differentiated cells that rarely divide. Treatments preventing cardiomyocyte loss during AMI have a high therapeutic benefit. Accumulating evidence shows that microRNAs (miRNAs) may play an essential role in cardiovascular diseases. This study aims to explore the biological function and underlying regulatory molecular mechanism of miR-322-5p on myocardial infarction (MI). This study's miR-322-5p is downregulated in MI-injured hearts according to integrative bioinformatics and experimental analyses. In the MI rat model, miR-322-5p overexpression partially eliminated MI-induced changes in myocardial enzymes and oxidative stress markers, improved MI-caused impairment on cardiac functions, inhibited myocardial apoptosis, attenuated MI-caused alterations in TGF-β, p-Smad2, p-Smad4, and Smad7 protein levels. In oxygen-glucose deprivation (OGD)-injured H9c2 cells, miR-322-5p overexpression partially rescued OGD-inhibited cell viability and attenuated OGD-caused alterations in the TGF-β/Smad signaling. miR-322-5p directly targeted Smurf2 and inhibited Smurf2 expression. In OGD-injured H9c2 cells, Smurf2 knockdown exerted similar effects to miR-322-5p overexpression upon cell viability and TGF-β/Smad signaling; moreover, Smurf2 knockdown partially attenuated miR-322-5p inhibition effects on OGD-injured H9c2 cells. In conclusion, miR-322-5p is downregulated in MI rat heart and OGD-stimulated rat cardiomyocytes; the miR-322-5p/Smurf2 axis improves OGD-inhibited cardiomyocyte cell viability and MI-induced cardiac injuries and dysfunction through the TGF-β/Smad signaling., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir-treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.

Brace root architecture is a critical determinant of maize's stalk anchorage and nutrition uptake, influencing root lodging resistance, stress tolerance, and plant growth. To identify the key microRNAs (miRNAs) in control of maize brace root growth, we performed small RNA sequencing using brace root samples at emergence and growth stages. We focused on the genetic modulation of brace root development in maize through manipulation of miR390 and its downstream regulated auxin response factors ( ARFs ). In the present study, miR167, miR166, miR172, and miR390 were identified to be involved in maize brace root growth in inbred line B73. Utilizing short tandem target mimic (STTM) technology, we further developed maize lines with reduced miR390 expression and analyzed their root architecture compared to wild-type controls. Our findings show that STTM390 maize lines exhibit enhanced brace root length and increased whorl numbers. Gene expression analyses revealed that the suppression of miR390 leads to upregulation of its downstream regulated ARF genes, specifically ZmARF11 and ZmARF26 , which may significantly alter root architecture. Additionally, loss-of-function mutants for ZmARF11 and ZmARF26 were characterized to further confirm the role of these genes in brace root growth. These results demonstrate that miR390, ZmARF11 , and ZmARF26 play crucial roles in regulating maize brace root growth; the involved complicated molecular mechanisms need to be further explored. This study provides a genetic basis for breeding maize varieties with improved lodging resistance and adaptability to diverse agricultural environments.

Methyltransferase-like 3 (METTL3) is a crucial element of N6-methyladenosine (m 6 A) modifications and has been extensively studied for its involvement in diverse biological and pathological processes. In this study, we explored how METTL3 affects the differentiation of stem cells from the apical papilla (SCAPs) into odonto/osteoblastic lineages through gain- and loss-of-function experiments. The m 6 A modification levels were assessed using m 6 A dot blot and activity quantification experiments. In addition, we employed Me-RIP microarray experiments to identify specific targets modified by METTL3. Furthermore, we elucidated the molecular mechanism underlying METTL3 function through dual-luciferase reporter gene experiments and rescue experiments. Our findings indicated that METTL3 +/- mice exhibited significant root dysplasia and increased bone loss. The m 6 A level and odonto/osteoblastic differentiation capacity were affected by the overexpression or inhibition of METTL3. This effect was attributed to the acceleration of pre-miR-665 degradation by METTL3-mediated m 6 A methylation in cooperation with the "reader" protein YTHDF2. Additionally, the targeting of distal-less homeobox 3 (DLX3) by miR-665 and the potential direct regulation of DLX3 expression by METTL3, mediated by the "reader" protein YTHDF1, were demonstrated. Overall, the METTL3/pre-miR-665/DLX3 pathway might provide a new target for SCAP-based tooth root/maxillofacial bone tissue regeneration., (© 2024. The Author(s).)

Renal fibrosis (RF) stands as a pivotal pathological process in the advanced stages of chronic kidney disease (CKD), and impeding its progression is paramount for delaying the advancement of CKD. The miR-10 family, inclusive of miR-10a and miR-10b, has been implicated in the development of various fibrotic diseases. Nevertheless, the precise role of miR-10 in the development of RF remains enigmatic. In this study, we utilized both an in vivo model involving unilateral ureteral obstruction (UUO) in mice and an in vitro model employing TGF-β1 stimulation in HK-2 cells to unravel the mechanism underlying the involvement of miR-10a/b in RF. The findings revealed heightened expression of miR-10a and miR-10b in the kidneys of UUO mice, accompanied by a substantial increase in p-Smad3 and renal fibrosis-related proteins. Conversely, the deletion of these two genes led to a notable reduction in p-Smad3 levels and the alleviation of RF in mouse kidneys. In the in vitro model of TGF-β1-stimulated HK-2 cells, the co-overexpression of miR-10a and miR-10b fostered the phosphorylation of Smad3 and RF, while the inhibition of miR-10a and miR-10b resulted in a decrease in p-Smad3 levels and RF. Further research revealed that miR-10a and miR-10b, through binding to the 3'UTR region of Vasohibin-1 (VASH-1), suppressed the expression of VASH-1, thereby promoting the elevation of p-Smad3 and exacerbating the progression of RF. The miR-10 family may play a pivotal role in RF.

Extracellular vesicles (EVs) derived from Mesenchymal Stromal Cells (MSCs) have shown promising therapeutic potential for multiple diseases, including intervertebral disc degeneration (IDD). Nevertheless, the limited production and unstable quality of EVs hindered the clinical application of EVs in IDD. Selenomethionine (Se-Met), the major form of organic selenium present in the cereal diet, showed various beneficial effects, including antioxidant, immunomodulatory and anti-apoptotic effects. In the current study, Se-Met was employed to treat MSCs to investigate whether Se-Met can facilitate the secretion of EVs by MSCs and optimize their therapeutic effects on IDD. On the one hand, Se-Met promoted the production of EVs by enhancing the autophagy activity of MSCs. On the other hand, Se-Met pretreated MSC-derived EVs (Se-EVs) exhibited an enhanced protective effects on alleviating nucleus pulposus cells (NPCs) senescence and attenuating IDD compared with EVs isolated from control MSCs (C-EVs) in vitro and in vivo. Moreover, we performed a miRNA microarray sequencing analysis on EVs to explore the potential mechanism of the protective effects of EVs. The result indicated that miR-125a-5p is markedly enriched in Se-EVs compared to C-EVs. Further in vitro and in vivo experiments revealed that knockdown of miR-125a-5p in Se-EVs (miR KD -Se-EVs) impeded the protective effects of Se-EVs, while overexpression of miR-125a-5p (miR OE -Se-EVs) boosted the protective effects. In conclusion, Se-Met facilitated the MSC-derived EVs production and increased miR-125a-5p delivery in Se-EVs, thereby improving the protective effects of MSC-derived EVs on alleviating NPCs senescence and attenuating IDD., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Brusatol (Bru), a main extract from traditional Chinese medicine Brucea javanica, has been reported to exist antitumor effect in many tumors including melanoma. However, the underlying mechanism in its anti-melanoma effect still need further exploration. Here, we reported that the protein expression of KLF4 in melanoma cells were significantly downregulated in response to brusatol treatment. Overexpression of KLF4 suppressed brusatol-induced melanoma cell apoptosis; while knockdown of KLF4 enhanced antitumor effects of brusatol on melanoma cells not only in vitro but also in vivo. Further studies on the mechanism revealed that KLF4 bound to the promoter of NCK2 directly and facilitated NCK2 transcription, which suppressed the antitumor effect of brusatol on melanoma. Furthermore, our findings showed that miR-150-3p was dramatically upregulated under brusatol treatment which resulted in the downregulation of KLF4. Our results suggested that the miR-150-3p/KLF4/NCK2 axis might play an important role in the antitumour effects of brusatol in melanoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons. LncRNA small nucleolar RNA host gene 14 (SNHG14) was found to promote neuron injury in PD. Here, we investigated the mechanisms of SNHG14 in PD process. In vivo or in vitro PD model was established by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice or 1-methyl-4-phenylpyridinium (MPP +)-stimulated SK-N-SH cells. The expression of genes and proteins was measured by qRT-PCR and Western blot. In vitro assays were conducted using ELISA, CCK-8, colony formation, EdU, flow cytometry, and Western blot assays, respectively. The oxidative stress was evaluated by determining the production of superoxide dismutase (SOD) and malondialdehyde (MDA). The direct interactions between miR-375-3p and NFAT5 (Nuclear factor of activated T-cells 5) or SNHG14 was verified using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. SNHG14 and NFAT5 were elevated, while miR-375-3p was decreased in MPTP-mediated PD mouse model and MPP + -induced SK-N-SH cells. Knockdown of SNHG14 or NFAT5, or overexpression of miR-375-3p reversed MPP + -induced neuronal apoptosis, inflammation, and oxidative stress. Mechanistically, SNHG14 directly bound to miR-375, which targeted NFAT5. Inhibition of miR-375-3p abolished the inhibitory activity of SNHG14 knockdown on MPP + -evoked neuronal damage. Besides that, NFAT5 up-regulation counteracted the effects of miR-375-3p on MPP + -mediated neuronal damage. SNHG14 contributed to MPP + -induced neuronal injury by miR-375/NFAT5 axis, suggesting a new insight into the pathogenesis of PD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Coronary atherosclerotic heart disease (CAD) is an inflammatory vascular disease caused by atherosclerosis. Long non-coding RNAs are involved in the pathophysiological process of coronary heart disease. Here we investigated the regulatory effects of lncRNA PVT1 (PVT1) in human coronary artery endothelial cells (HCAECs). Methods: qRT-PCR and western blot were performed to detect gene and protein expressions. CCK-8, flow cytometry and wound healing assays were used to determine cell viability, apoptosis and migration of HCAECs. The binding relationship among miR-532-3p, PVT1 and MAPK1 was verified by dual luciferase reporter assay. Results: Overexpression of PVT1 markedly reduced cell apoptosis and increased cell proliferation and migration. However, miR-532-3p upregulation suppressed cell proliferation and migration and promoted apoptosis of HCAECs. PVT1 suppressed the expression of miR-532-3p via directly targeting miR-532-3p. And miR-532-3p overexpression abolished the effect of PVT1 upregulation on proliferation and apoptosis in HCAECs. Furthermore, MAPK1 acted as a target gene of miR-532-3p and miR-532-3p inhibited MAPK1 expression. Conclusion: PVT1 promoted MAPK1 expression by targeting miR-532-3p, thus inhibiting HCAECs apoptosis and promoting cell proliferation, suggesting PVT1 might have great potential as a therapeutic target for CAD.

Objective: To construct a competitive endogenous RNA (ceRNA) regulatory network in blood exosomes of patients with ovarian cancer (OC) using bioinformatics and explore its pathogenesis., Methods: The exoRbase2.0 database was used to download blood exosome gene sequencing data from patients OC and normal controls and the expression profiles of exosomal mRNA, long non-coding RNA (lncRNA), and circular RNA (circRNA) were detected independently using R language for differential expression analysis. TargetScan and miRanda databases were combined for the prediction and differential expression of mRNA-binding microRNAs (miRNA). The miRcode and starBase databases were used to predict miRNAs that bind to differentially expressed lncRNAs and circRNAs repectively. The relevant mRNA, circRNA, lncRNA and their corresponding miRNA prediction data were imported into Cytoscape software for visualization of the ceRNA network. The R language and KEGG Orthology-based Annotation System (KOBAS) were used to execute and illustrate the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Hub genes were identified using The CytoHubba plugin., Results: Thirty-one differentially expressed mRNAs, 17 differentially expressed lncRNAs, and 24 differentially expressed circRNAs were screened. Cytoscape software was used to construct the ceRNA network with nine mRNA nodes, two lncRNA nodes, eight circRNA nodes, and 51 miRNA nodes. Both GO and KEGG were focused on the Spliceosome pathway, indicating that spliceosomes are closely linked with the development of OC, while heterogenous nuclear ribonucleoprotein K and RNA binding motif protein X-linked genes were the top 10 score Hub genes screened by Cytoscape software, including two lncRNAs, four mRNAs, and four circRNAs. In patients with OC, the expression of eukaryotic translation initiation factor 4 gamma 2 (EIF4G2), SERPINE 1 mRNA binding protein 1 (SERBP1), ribosomal protein L15 (RPL15) and human leukocyte antigen complex P5 (HCP5) was significantly higher whereas that of testis expressed transcript, Y-linked 15 and DEAD-box helicase 3 Y-linked genes was lower compared to normal controls Immunocorrelation scores revealed that SERBP1 was significantly and negatively correlated with endothelial cells and CD4+ T cells and positively correlated with natural killer (NK) cells and macrophages, respectively; RPL15 was significantly positively correlated with macrophages and endothelial cells and negatively correlated with CD8+ T cells and uncharacterized cells, respectively. EIF4G2 was significantly and negatively correlated with endothelial cells and CD4+ T cells, and positively correlated with uncharacterized cells, respectively. Based on the survival data and the significant correlation characteristics derived from the multifactorial Cox analysis (P < 0.05), the survival prediction curves demonstrated that the prognostic factors associated with 3-year survival in patients with OC were The prognostic factors associated with survival were Macrophage, RPL15., Conclusion: This study successfully constructs a ceRNA regulatory network in blood exosomes of OV patients, which provides the specific targets for diagnosis and treatment of OC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Umbilical cord-derived mesenchymal stem cell (UCMSC) transplantation has been deeply explored for premature ovarian insufficiency (POI) disease. However, the associated mechanism remains to be researched. To explore whether and how the microRNA 21 (miR-21) functions in POI mice with UCMSCs transplantation, the autoimmune-induced POI mice model was built up, transplanted with or without UCMSCs transfect with the LV-hsa-miR-21-5p/LV-hsa-miR-21-5p-inhibition, with the transfection efficiency analyzed by QRT-PCR. Mice hormone secretion and the anti-Zona pellucida antibody (AZPAb) levels were analyzed, the ovarian morphological changes and folliculogenesis were observed, and the ovarian apoptosis cells were detected to evaluate ovarian function. The expression and localization of the PTEN/Akt/FOXO3a signal pathway-related cytokines were analyzed in mice ovaries.Additionally, the spleen levels of CD8 + CD28-T cells were tested and qualified with its significant secretory factor, interleukin 10 (IL-10). We found that with the LV-hsa-miR-21-5p-inhibition-UCMSCs transplantation, the mice ovarian function can be hardly recovered than mice with LV-NC-UCMSCs transplantation, and the PTEN/Akt/FOXO3a signal pathway was activated. The expression levels of the CD8 + CD28-T cells were decreased, with the decreased levels of the IL-10 expression. In contrast, in mice with the LV-hsa-miR-21-5p-UCMSCs transplantation, the injured ovarian function can be reversed, and the PTEN/AKT/FOXO3a signal pathway was detected activated, with the increased levels of the CD8 + CD28-T cells, and the increased serum levels of IL-10. In conclusion, miR-21 improves the ovarian function recovery of POI mice with UCMSCs transplantation, and the mechanisms may be through suppressing the PTEN/AKT/FOXO3a signal pathway and up-regulating the circulating of the CD8 + CD28-T cells., (© 2024. The Author(s).)

Background: In recent years,the lack of specific markers for the diagnosis of colorectal cancer has led to an upward trend in both morbidity and mortality from this condition. There is an urgent need to identify molecular biomarkers that contribute to early cancer detection. This study aimed to identify specific exosomal microRNAs that hold potential as diagnostic biomarkers for CRC., Methods: We screened for differentially expressed miRNAs using the CRC exosome dataset GSE39833. To validate the results in the public database, we collected serum from 168 CRC patients and 168 healthy volunteers. The expression levels of exosomal miR-1470 in healthy volunteers and CRC patients were analyzed using qRT-PCR. To evaluate the diagnostic potential of the selected miR-1470 in distinguishing CRC patients from healthy controls, we analyzed its receiver operating characteristic curve. To explore the biological functions of miR-1470 in CRC cell lines, we detected the miR-1470's ability to regulate the growth and metastasis of CRC cells by CCK8, transwell and other assays after transfection of miR-1470 in SW480, HCT-116 cells., Results: Exosomal miR-1470 exhibited significant up-regulation in CRC patients compared to healthy volunteers. The ROC curve analysis revealed an area under the curve (AUC) of 0.74 (95% confidence interval: 0.6876-0.7920) for exosomal miR-1470, indicating its potential as a diagnostic biomarker. Furthermore, the expression level of miR-1470 in CRC patients showed correlations with age, metastasis, and HDL content. We overexpressed miR-1470 in CRC cell lines. CCK8 proliferation assay showed that miR-1470 promoted the proliferation ability of SW480 and HCT-116 cells. Transwell assay showed that miR-1470 promoted the migration and invasion ability of SW480 and HCT-116 cells., Conclusion: This suggested that non-invasive diagnosis of CRC is possible by detecting the level of miR-1470 in exosomes, which has important implications for early detection and treatment of this disease., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Podocyte apoptosis exerts a crucial role in the pathogenesis of DN. Recently, long noncoding RNAs (lncRNAs) have been gradually identified to be functional in a variety of different mechanisms associated with podocyte apoptosis. This study aimed to investigate whether lncRNA Glis2 could regulate podocyte apoptosis in DN and uncover the underlying mechanism. The apoptosis rate was detected by flow cytometry. Mitochondrial membrane potential (ΔΨM) was measured using JC-1 staining. Mitochondrial morphology was detected by MitoTracker Deep Red staining. Then, the histopathological and ultrastructure changes of renal tissues in diabetic mice were observed using periodic acid-Schiff (PAS) staining and transmission electron microscopy. We found that lncRNA Glis2 was significantly downregulated in high-glucose cultured podocytes and renal tissues of db/db mice. LncRNA Glis2 overexpression was found to alleviate podocyte mitochondrial dysfunction and apoptosis. The direct interaction between lncRNA Glis2 and miR-328-5p was confirmed by dual luciferase reporter assay. Furthermore, lncRNA Glis2 overexpression alleviated podocyte apoptosis in diabetic mice. Taken together, this study demonstrated that lncRNA Glis2, acting as a competing endogenous RNA (ceRNA) of miRNA-328-5p, regulated Sirt1-mediated mitochondrial dysfunction and podocyte apoptosis in DN., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The inherent heterogeneity of tumor-derived exosomes holds great promise for enhancing the precision of cancer diagnostics. MicroRNAs (miRNAs) encapsulated in tumor-associated exosomes have emerged as valuable biomarkers for the early detection of cancers. Nevertheless, the flexible structure and inherent instability of RNA limit its application in biological diagnostics. The CRISPR-Cas13a system, distinguished by its target-responsive "collateral effect", represents a powerful tool for advancing cancer diagnostics. In this study, we harness the CRISPR-Cas13a system as an innovative signal amplification tool to image cancer-related exosomal miRNA in situ. Furthermore, we capitalize on the thermophoretic aggregation effect exhibited by gold nanoparticles (Au NPs) to consolidate the fluorescent signals generated by the CRISPR-Cas13a system. Subsequently, the developed nanoprobe is applied to detect lung cancer-related exosomal miRNA from human serum, enabling the aggregated visualization of low-abundance cancer exosomes in individuals with lung cancer compared with healthy individuals. This sensitive thermophoretic aggregation assay provides a diagnostic tool for lung cancer in the clinic.

Ethnopharmacological Relevance: Angelica Sinensis Radix (ASR) is a commonly used Chinese medicine known for its effects on tonifying blood, promoting blood circulation, and alleviating pain associated with menstrual regulation. Additionally, it has been used in the treatment of vascular cognitive impairment (VCI). The primary pharmacodynamic agent within ASR is volatile oil of Angelica Sinensis Radix (VOASR), which has demonstrated efficacy in combating cognitive impairment, although its mechanism remains unclear., Objective: This study aimed to elucidate the potential molecular mechanisms underlying VOASR's improvement of cognitive function in cerebral ischemic mice., Methods: A model of cerebral ischemic mice was established through unilateral common carotid artery occlusion (UCCAO) surgery, followed by intervention with VOASR. Cognitive function was assessed using the Morris water maze (MWM) test, while RT-qPCR was utilized to measure the differential expression of miR-301a-3p in the hippocampus. To evaluate cognitive function and hippocampal protein differences, wild-type mice and miR-301a-3p knockout mice were subjected to the MWM test and iTRAQ protein profiling. The relationship between miR-301a-3p and potential target genes was validated through a Dual-Luciferase Reporter experiment. RT-qPCR and Western blot were employed to determine the differential expression of Ppp2ca and synaptic plasticity-related proteins in the mouse hippocampus., Results: Intervention with VOASR significantly improved cognitive impairment in cerebral ischemic mice and reduced the expression of miR-301a-3p in the hippocampus. Our findings suggest that miR-301a-3p may regulate cognitive function by targeting Ppp2ca. Furthermore, VOASR intervention led to an increase in the expression of Ppp2ca and synaptic plasticity-related proteins., Conclusion: Our study indicates that VOASR may be involved in regulating cognitive function by inhibiting miR-301a-3p, consequently increasing the expression of Ppp2ca and synaptic plasticity proteins. These results provide a new target and direction for the treatment of cognitive dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no conflict interests in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Fluorouracil (5-FU) might produce serious cardiac toxic reactions. miRNA-199a-5p is a miRNA primarily expressed in myocardial cells and has a protective effect on vascular endothelium. Under hypoxia stress, the expression level of miRNA-199a-5p was significantly downregulated and is closely related to cardiovascular events such as coronary heart disease, heart failure, and hypertension. We explored whether 5-FU activates the endoplasmic reticulum stress ATF6 pathway by regulating the expression of miRNA-199a-5p in cardiac toxicity., Methods: This project established a model of primary cardiomyocytes derived from neonatal rats and treated them with 5-FU in vitro . The expression of miRNA-199a-5p and its regulation were explored in vitro and in vivo ., Results: 5-FU decreases the expression of miRNA-199a-5p in cardiomyocytes, activates the endoplasmic reticulum stress ATF6 pathway, and increases the expression of GRP78 and ATF6, affecting the function of cardiomyocytes, and induces cardiac toxicity. The rescue assay further confirmed that miRNA-199a-5p supplementation can reduce the cardiotoxicity caused by 5-FU, and its protective effect on cardiomyocytes depends on the downregulation of the endoplasmic reticulum ATF6 signaling pathway., Conclusions: 5-FU can down-regulate expression of miRNA-199a-5p, then activate the endoplasmic reticulum stress ATF6 pathway, increase the expression of GRP78 and ATF6, affect the function of cardiomyocytes, and induce cardiac toxicity.

Background: IGF2BP3 functions as an RNA-binding protein (RBP) and plays a role in the posttranscriptional control of mRNA localization, stability, and translation. Its dysregulation is frequently associated with tumorigenesis across various cancer types. Nonetheless, our understanding of how the expression of the IGF2BP3 gene is regulated remains limited. The specific functions and underlying mechanisms of IGF2BP3, as well as the potential benefits of targeting it for therapeutic purposes in bladder cancer, are not yet well comprehended., Methods: The mRNA and protein expression were examined by RT-qPCR and western blotting, respectively. The methylation level of CpG sites was detected by Bisulfite sequencing PCR (BSP). The regulation of IGF2BP3 expression by miR-320a-3p was analyzed by luciferase reporter assay. The functional role of IGF2BP3 was determined through proliferation, colony formation, wound healing, invasion assays, and xenograft mouse model. The regulation of HMGB1 by IGF2BP3 was investigated by RNA immunoprecipitation (RIP) and mRNA stability assays., Results: We observed a significant elevation in IGF2BP3 levels within bladder cancer samples, correlating with more advanced stages and grades, as well as an unfavorable prognosis. Subsequent investigations revealed that the upregulation of IGF2BP3 expression is triggered by copy number gain/amplification and promoter hypomethylation in various tumor types, including bladder cancer. Furthermore, miR-320a-3p was identified as another negative regulator in bladder cancer. Functionally, the upregulation of IGF2BP3 expression exacerbated bladder cancer progression, including the proliferation, migration, and invasion of bladder cancer. Conversely, IGF2BP3 silencing produced the opposite effects. Moreover, IGF2BP3 expression positively correlated with inflammation and immune infiltration in bladder cancer. Mechanistically, IGF2BP3 enhanced mRNA stability and promoted the expression of HMGB1 by binding to its mRNA, which is a factor that promotes inflammation and orchestrates tumorigenesis in many cancers. Importantly, pharmacological inhibition of HMGB1 with glycyrrhizin, a specific HMGB1 inhibitor, effectively reversed the cancer-promoting effects of IGF2BP3 overexpression in bladder cancer. Furthermore, the relationship between HMGB1 mRNA and IGF2PB3 is also observed in mammalian embryonic development, with the expression of both genes gradually decreasing as embryonic development progresses., Conclusions: Our present study sheds light on the genetic and epigenetic mechanisms governing IGF2BP3 expression, underscoring the critical involvement of the IGF2BP3-HMGB1 axis in driving bladder cancer progression. Additionally, it advocates for the investigation of inhibiting IGF2BP3-HMGB1 as a viable therapeutic approach for treating bladder cancer., (© 2024. The Author(s).)