miR-21 Expression Research Articles

MicroRNA-122 regulates inflammatory and autophagic proteins by downregulating pyruvate kinase M2 in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is one of the serious global health concerns, leading to non-alcoholic steatohepatitis (NASH), and to hepatocellular carcinoma (HCC). Despite its prevalence, the molecular mechanisms regulating NAFLD progression remain elusive. The present study aims to determine role of microRNA-122-mediated regulation of pyruvate kinase M2 (PKM2) on regulating inflammatory and autophagic proteins during the pathogenesis of NAFLD. Huh7 cells were incubated with free fatty acids (FFAs) or transfected with single guide RNA to PKM2 containing CRISPR-Cas9 system or miR-122 for up to 72h. C57BL/6 mice were fed with sham-operated control, choline sufficient L-amino acid defined (CSAA) or choline-deficient L-amino acid defined (CDAA) diet for 6, 18, 32 and 54weeks. The RNA or protein was isolated from the Huh7 cells and the liver tissue of the mice. RT-PCR was performed for miR-122 expression and Western blots were performed for PKM2, iNOS, COX2, Beclin-1, Atg7 and LC3-II. FFAs induced the expression of PKM2, iNOS and COX2, while decreased the expression of miR-122, Beclin-1, Atg7 and LC3-II. Overexpression of miR-122 resulted in decreased PKM2, iNOS and COX2 and increased Beclin-1, Atg7 and LC3-II. Silencing of PKM2 led to decreased iNOS and COX2 and increased Beclin-1, Atg7 and LC3-II. In CDAA fed-mice, there was a significant increase in PKM2, iNOS and COX2 and decreased miR-122, Beclin-1, Atg7 and LC3-II. The data showed that FFAs downregulated miR-122 expression, which resulted in the upregulation of PKM2, which in turn upregulated inflammatory proteins and downregulated autophagic proteins during the pathogenesis of NAFLD.

Plasma expression and bioinformatic analysis of Mir-16, Mir-132, Mir-146 and Mir-223 in patients with rheumatoid arthritis

BackgroundMicroRNAs (miRNAs) are involved in the pathogenesis of rheumatoid arthritis (RA) through modulating gene expression. AimTo assess the plasma expression of miR-16, miR-132, miR-146 and miR-223 in patients with RA and their relation to activity and severity of the disease and their potential value as biomarkers. Through bioinformatics study we aim to determine the predictor target genes of the studied miRNAs to clarify their role in RA pathogenesis. MethodsThe study comprised 73 patients suffering from RA and 50 healthy individuals. We used the disease activity score-28 (DAS-28) to assess disease activity. Joint damage was assessed by Kaarela and Kautiainen modification of Larsen scale. Anti-anticyclic citrullinated peptide (anti-CCP) antibodies, serum high sensitive C reactive protein (hsCRP) and rheumatoid factor (RF) were assayed by ELISA. Plasma miR-223, miR-146a, miR-16 and miR-132 were quantified by qRT-PCR followed by a simple dry laboratory analysis of the involved target genes of the studied miRNAs in RA pathogenesis by KEGG pathways. ResultsIn comparison to controls, RA patients showed overexpressed miR-146a, miR-223and miR-16, while miR-132 was down-regulated. Additionally, miR-146a correlated positively with DAS28, anti-CCP antibodies and RF. Bioinformatics revealed that the predicted targeted genes of miR-146a, miR-16, miR-223 and miR-132 are potential contributing factors for RA pathogenesis and bone degradation. ConclusionmiR-146a, miR-223, miR-16 and miR-132 may be potential non-invasive molecular biomarkers for RA diagnosis. Plasma miR-146a might be considered as potential biomarker for disease activity. The predicted genes targeted by miR-146a, miR-223, miR-16 and miR-132 are implicated in RA pathogenesis and ultimately can be used in future target therapeutic approach.

Effect of Curcumin-Mediated miR-449 on Diabetic Nephropathy

This study assessed the mechanism for curcumin-mediated miR-449 regulating PACS-2 in diabetic nephropathy under nursing intervention. A diabetic nephropathy model was constructed, in which rats were fasted for 12 hours before experiments and injected with Streptozotocin (STZ) at a ratio of 45–65 mg/kg (30–60 mg STZ). When the rats aged 8 weeks, they were given intraperitoneal injection of curcumin and tissue histological morphology was detected to ensure successful model construction. HE staining observed the morphological changes in renal tissue, while immunohistochemistry detected the expression of PACS-2 and PACS-2 related proteins. Nursing intervention could reduce serum creatinine, fasting blood glucose, urea nitrogen and proteinuria levels. After nursing intervention, the levels of IL-6, hs-CRP and TNF-α in patients were significantly decreased (p < 0.05), and miR-499 expression increased after nursing intervention. After curcumin treatment, the red staining of entire kidney cytoplasm in the control and experimental groups became lighter. Moreover, the expression of miR-449 in the kidney tissue was significantly increased after curcumin treatment. Since PACS-2 plays an important role in kidney injury, curcumin largely normalized kidney injury as shown by serum BUN levels after curcumin treatment in the rat model. Turmeric, a traditional Chinese medicine, has a bitter taste and warm nature. It might facilitate blood circulation and remove blood stasis, and relieving chest pain and heartache. Curcumin as the main active ingredient of turmeric, has been proven to inhibit the abnormal proliferation of diabetic nephropathy. Under the influence of effective nursing care, the patient’s physical condition was improved, which was mainly reflected in the related inflammatory indicators. Studies have shown that fibronectin, which is an important indicator for PACS-2, plays a decisive role in fibrosis. Our testing found that, curcumin significantly reduced the expression of PACS-2 during treatment. Nursing intervention can therefore effectively improve inflammatory response and renal function of diabetic nephropathy through curcumin-mediated miR-449 regulation of PACS-2.

MiR-155 mediated regulation of PKG1 and its implications on cell invasion, migration, and apoptosis in preeclampsia through NF-κB pathway

BackgroundPreeclampsia (PE) is a severe pregnancy complication characterized by complex molecular interactions. Understanding these interactions is crucial for developing effective therapeutic strategies.MethodsThis study applies a pharmacometabolomics approach to explore the roles of miR-155 and PKG1 in PE, focusing on the regulatory influence of the NF-κB signaling pathway. Blood metabolomic profiles were analyzed, and bioinformatics tools, IHC staining, Western blot (WB) analysis, and immunofluorescence (IF) localization were employed to determine the expression and function of miR-155 and PKG1. Cell invasion, migration, proliferation, and apoptosis assays were conducted to assess miR-155’s modulation of PKG1. Additionally, RT-qPCR and WB analysis elucidated NF-κB-mediated regulation mechanisms.ResultsOur findings indicate significant metabolic alterations associated with miR-155 modulation of PKG1, with NF-κB acting as a critical upstream regulator. The study demonstrates that miR-155 affects cellular functions such as invasion, migration, proliferation, and apoptosis through PKG1 modulation. Furthermore, the NF-κB signaling pathway regulates miR-155 expression, contributing to the pathological processes of PE.ConclusionThis study provides a proof of concept for using pharmacometabolomics to understand the molecular mechanisms of PE, suggesting new therapeutic targets and advancing personalized medicine approaches. These insights highlight the potential of pharmacometabolomics to complement genomic and transcriptional data in disease characterization and treatment strategies, offering new avenues for therapeutic intervention in PE.

MicroRNA-21 expression as a novel diagnostic and prognostic biomarker in oral cancer: A narrative review

MicroRNA-21 expression as a novel diagnostic and prognostic biomarker in oral cancer: A narrative review

Huazhi Rougan Granule Alleviates Liver and Intestinal Damage in Non-Alcoholic Fatty Liver Disease by Regulating miR-122 Expression and TLR4/MyD88/NF-κB Pathway Activation.

miR-122 is upregulated in non-alcoholic fatty liver disease (NAFLD) liver tissue, and knockdown of miR-122 protects hepatocytes from lipid metabolism disorders. This study aimed to investigate whether Huazhi Rougan Granule (HRG) alleviates NAFLD liver and intestinal injury by regulating the miR-122-mediated TLR4/MyD88/NF-κB pathway. Rats with NAFLD were constructed by high-fat feeding. Serum levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured using a fully automated biochemical instrument. Histopathological changes in the liver and small intestine were observed by HE staining. QRT-PCR detected the expression level of miR-122 in the liver tissues. The protein expression of TLR4, MyD88, NF- κB p65, and p-p65 in liver tissues was detected by western blotting. HRG slowed down the weight gain of NAFLD rats, decreased (P<0.05) the levels of TC, TG, ALT, AST, TNF-α, IL-1β, IL-6, LPS, and Hpt, improved the pathological status of liver and small intestine tissues, upregulated (P<0.05) the expression of ZO-1 and Occludin, downregulated (P<0.05) the protein expression of TLR4, MyD88, and p-p65, and inhibited (P<0.05) the expression of miR-122. HRG may alleviate hepatic and intestinal injuries in rats with NAFLD by regulating the miR-122-mediated TLR4/MyD88/NF-κB pathway.

Reduced Levels of miR-145-3p Drive Cell Cycle Progression in Advanced High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) is the most lethal form of gynecologic cancer, with limited treatment options and a poor prognosis. Epigenetic factors, such as microRNAs (miRNAs) and DNA methylation, play pivotal roles in cancer progression, yet their specific contributions to HGSOC remain insufficiently understood. In this study, we performed comprehensive high-throughput analyses to identify dysregulated miRNAs in HGSOC and investigate their epigenetic regulation. Analysis of tissue samples from advanced-stage HGSOC patients revealed 20 differentially expressed miRNAs, 11 of which were corroborated via RT-qPCR in patient samples and cancer cell lines. Among these, miR-145-3p was consistently downregulated post-neoadjuvant therapy and was able to distinguish tumoural from control tissues. Further investigation confirmed that DNA methylation controls MIR145 expression. Functional assays showed that overexpression of miR-145-3p significantly reduced cell migration and induced G0/G1 cell cycle arrest by modulating the cyclin D1-CDK4/6 pathway. These findings suggest that miR-145-3p downregulation enhances cell proliferation and motility in HGSOC, implicating its restoration as a potential therapeutic target focused on G1/S phase regulation in the treatment of HGSOC.

Evaluating the roles of microRNAs associated with nonalcoholic fatty liver disease in hepatocellular carcinoma tumorigenesis: a systematic review and network analysis.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with high morbidity and mortality. The rapidly increasing incidence of NAFLD is becoming an essential precursor of HCC globally. MicroRNAs (miRNAs) are involved in the progression of NAFLD and HCC. Potential miRNAs associated with NAFLD in HCC tumorigenesis were identified through a systematic review, and their roles were evaluated by data mining analysis. The biological function of the potential miRNA and its target genes in NAFLD and HCC were evaluated by bioinformatic analysis. MIR122 was identified as the potential miRNA associated with NAFLD and HCC. Then, MIR122 expression was significantly lower in HCC patients, and higher MIR122 levels were associated with significantly better overall survival. Next, the biological functions of MIR122 and target genes were predicted to be involved in inflammation, fibrosis, cell proliferation, invasion, metastasis, and apoptosis. In particular, the FOXO signaling pathway may regulate the above biological functions. MIR122 was suggested to be involved in progressing from NAFLD to HCC through the PI3K/AKT/FOXO pathway. PROSPERO, identifier: CRD 42024517940.

Abstract A007: Characterization of miR-141 and miR-145 expression in cancer stem cells of metastatic prostate cancer patients

Abstract Background: Prostate cancer (PCA) is the second most prevalent cancer globally and the fifth leading cause of cancer-related mortality. However, effective prognostic biomarkers for metastatic PCA remain lacking. Recent research highlights the role of microRNAs (miRNAs) in regulating cancer stem cells (CSCs) and influencing tumour progression across various cancers. Therefore, in this we investigated the effects of miR-141 and miR-145 expression on the metastatic PCA of CSCs and assessed their potential role as biomarkers for metastatic PCA prognosis. Methods: The expression levels of miR-141 and miR-145 were quantified using real-time qPCR. Flow cytometry was employed to assess the levels of prostate cancer stem cells (PCSCs) in tissue samples from patients with localized (non-metastatic) and metastatic PCA. Results: Our findings revealed a significant increase in miR-141 expression, accompanied by elevated levels of CD44^high/CD24^low and CD133^high, in metastatic PCA compared to localized PCA. Conversely, reduced miR-145 expression was associated with enhanced stemness characteristics, as indicated by increased CD44^high/CD24^low and CD133^high levels, in metastatic PCA compared to localized PCA. Additionally, prostate-specific antigen (PSA) and testosterone levels exhibited a significant rise (p&amp;lt;0.001), while apoptosis rates decreased in both localized and metastatic PCA compared to localized PCA. Conclusions: The collective findings of this study suggest that miR-141 and miR-145, in conjunction with CSC markers, hold promise as diagnostic and prognostic tools for PCA. They may also be valuable for detecting minimal residual disease and improving therapeutic strategies for managing metastatic PCA. Citation Format: Kamla Kant Shukla, Gautam Ram Choudhary. Characterization of miR-141 and miR-145 expression in cancer stem cells of metastatic prostate cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A007.

MicroRNA 223 Enhances ABCA1 Protein Stability and Supports Efflux in Cholesterol-Burdened Macrophages.

Macrophages are present in all vertebrates as part of the innate immune system, which protects from pathogens and scavenges sterol rich, cellular debris and modified lipoproteins. Thus, resident macrophages are prone to excessive levels of intracellular cholesterol esters. Intramacrophage cholesterol esters can efflux via cell surface transporters, ABCA1 and ABCG1, to lipoprotein carriers such as apo-AI and HDL. Systemically, Apo-AI and HDL facilitate trafficking of cholesterol back to the liver, in a process called reverse cholesterol transport. Impaired macrophage cholesterol efflux is a primary factor in the etiology of atherosclerosis. We hypothesized that microRNA 223 (miR-223) regulated macrophage LDL metabolism, due to predicted binding to Sp1 and Sp3 mRNA, transcriptional regulators of ABCA1 expression. Primary mouse (WT, miR-223 KO) macrophages were loaded with acetylated LDL and stimulated with LPS to form an inflammatory foam cell phenotype. miR-223 KO foam cells demonstrated impaired efflux to both apo-AI and HDL. While transcriptional regulation was intact in miR-223 KO foam cells, ABCA1 protein degradation was greatly accelerated. Blockade of both proteasomal and lysosomal degradation pathways rescued miR-223 deficiency-mediated ABCA1 degradation to the WT levels. Our findings demonstrate that miR-223 expression in macrophages is required for maintenance of ABCA1 and ABCG1 proteins.

The circulatory levels and bone expression of MIR21, 34a, 155 and their target genes in a section of Egyptian Population

Bone tissue is constantly regenerated and repaired through a finely balanced process known as bone remodeling. Many miRNAs act as regulators of the signaling pathways involved in bone metabolic processes to maintain tissue homeostasis. This study aimed to assess the circulating levels of MIR21, MIR34a, and MIR155 in human serum and their bone expression, and the expression of bone turnover-related genes which can reflect the bone quality. This prospective study was conducted on 60 patients (30 males and 30 females) indicated for surgical interventions for neural decompression +/- fixation. Relative quantification of expression of MIR21, miR34a, and MIR155 and bone related genes was assayed using PCR. The serum levels of osteocalcin and Serum Bone Alkaline Phosphatase (sBAP) were assayed using a human ELISA kit. The main finding of the present work was the strong positive association between the circulating levels of only miR21 and MIR155 and their bone expression in the population under study and with bone markers and target genes Also, a positive association was found between both bone expression and circulating MIR21 levels with age and sBAP. These results suggest that the circulating levels of these microRNAs as early markers for the predication of bone quality.

BIOM-33. INVESTIGATING MIR-21 AS A NON-INVASIVE PROGNOSTIC BIOMARKER IN GLIOMA PATIENTS IN RESOURCE CONSTRAINT SETTINGS

Abstract BACKGROUND Glioma treatment remains challenging due to high recurrence rates and resistance to treatment. Diagnosis and follow-up in resource-constrained regions often leads to significant patient attrition. Serum microRNA (miRNA) expression profiles are shown to be expressed in tumor tissue and peripheral samples, offering a pathway for non-invasive, repetitive liquid biopsies. miR-21 shows promise in many populations; however, there is a dearth of data from our region. METHODOLOGY we collected 89 intraoperative tumor tissue samples, 42 pre- and post-operative serum samples from glioma patients, and included 10 control tissue samples along with 8 normal serum samples and analyzed for miR-21 expression through qPCR. Serum samples were collected before tumor resection and post-surgery (pre- and post-operative). Correlational analysis with molecular markers IDH, Ki-67, ATRX, p53, and survival curves through the Kaplan-Meier method were calculated in high and low miR-21 expression groups, The hazard ratio was quantitatively determined using Cox regression analysis, considering both univariate associations and multivariate correlations with clinical parameters. RESULTS miR-21 expression in tissue increased with higher grades of glioma (p=0.00064), of patients above 50 years (p=0.0027), and shows a positive correlation with tumor volume (r= 0.22, p=0.081). IDH-wildtype (p=2.06e-03) and high Ki-67 (p=2.50e-03) expression in tumors showed significant upregulation of miR-21 compared to IDH-mutant and low Ki-67. Patients with low miR-21 expression had significantly longer overall survival (OS) than patients with high miR-21 expression (p =0.006). Quantitative hazard analysis indicates that patients in the high expression group have a 2.77 times higher risk of mortality (95% CI: upper - 0.19, lower - 0.92), in comparison to patients in the low expression group (p= 0.008). CONCLUSION Our findings validate the future utility of miR-21 as a serum assay to help diagnose and assess treatment response in different grades of glioma, within our population. Keywords: Glioma, Biomarker, Molecular markers, Liquid biopsy

MicroRNA-24 therapeutic potentials in infarction, stroke, and diabetic complications.

The prevalence of cardiovascular events, stroke, and diabetes worldwide underscores the urgent need for effective and minimally invasive treatments. With nearly 20million annual casualties attributed to cardiovascular diseases and an estimated 463million people living with diabetes in 2022. Identifying promising therapeutic candidates is paramount. MicroRNAs, short nucleic acids involved in regulating gene expression, emerge as potential game-changers. Among these, microRNA-24 (miR-24), a hypoxia-sensitive player in endothelial vessels, has protective roles against diverse vascular complications. Following heart infarction and stroke, elevating miR-24 expression proves beneficial by mitigating oxidative stress, inflammation, and apoptosis while enhancing cell survival. It reduces cardiac fibrosis in heart disease, regulates aberrant angiogenesis in cerebral hemorrhagic strokes, and enhances the functionality of cardiomyocytes and brain neurons. In diabetic conditions, augmenting miR-24 expression mitigates complications. Further, being miR-24 also expressed by the skeletal muscle (i.e., myo-miR) in response to exercise, this miRNA may participate in the complex molecular network that systemically spreads the beneficial effects of physical exercise. This review provides a comprehensive vision of the molecular mechanisms underpinning the miR-24 protective effects, offering new insights into its therapeutic potential and proposing a novel avenue for medical intervention.

Binding-driven forward tearing protospacer activated CRISPR-Cas12a system and applications for microRNA detection

CRISPR-Cas12a system, characterized by its precise sequence recognition and cleavage activity, has emerged as a powerful and programmable tool for molecular diagnostics. However, current CRISPR-Cas12a-based nucleic acid detection methods, particularly microRNA (miRNA) detection, necessitate additional bio-engineering strategies to exert control over Cas12a activity. Herein, we propose an engineered target-responsive hairpin DNA activator (TRHDA) to mediate forward tearing protospacer activated CRISPR-Cas12a system, which enables direct miRNA detection with high specificity and sensitivity. Target miRNA specifically binding to hairpin DNA can drive forward tearing protospacer in the stem sequence of hairpin structure, facilitating the complementarity between crRNA spacer and protospacer to activate Cas12a. Upon the hairpin DNA as input-responsive activator of Cas12a, a universal biosensing method enables the multiple miRNAs (miR-21, let-7a, miR-30a) detection and also has exceptional capability in identifying single-base mismatches and distinguishing homologous let-7/miR-30 family members. Besides, TRHDA-mediated Cas12a-powered biosensing has realized the evaluation of miR-21 expression levels in diverse cellular contexts by intracellular imaging. Considering the easy programmability of hairpin DNA in responsive region, this strategy could expand for the other target molecules detection (e.g., proteins, micromolecules, peptides, exosomes), which offers significant implications for biomarkers diagnostics utilizing the CRISPR-Cas12a system toolbox.Graphical abstract

MiR-144/451: A Regulatory Role in Inflammation.

Inflammation is the natural defense mechanism of the body in response to injury, infection, or other stimuli. Excessive or persistent inflammatory responses can lead to the development of inflammatory diseases. Therefore, elucidating the regulatory mechanisms of inflammatory cells is crucial for understanding the pathogenesis of such diseases and devising novel therapeutic approaches. Moreover, miR-144/451 plays an important role in erythroid maturity and tumour development. Herein, we have reviewed the regulatory role of miR-144/451 in inflammation. Papers on miR-144, miR-451, and inflammation were retrieved from PubMed and Web of Science to be analysed and summarised. miR-144/451 plays a significant role in modulating inflammatory responses. Pro- and anti-inflammatory gene transcription is regulated by miR-144/451 binding to the 3' untranslated regions. Studies have shown that miR-451 inhibits the activation of various inflammatory cells, including macrophages, neutrophils, and T lymphocytes, thereby reducing the release of inflammatory mediators. However, miR-144 expression varies in different inflammatory diseases. miR-144 expression is downregulated in macrophages after induction by lipopolysaccharide, cysteine, or Mycobacterium tuberculosis, which promotes the secretion of inflammatory mediators; nonetheless, miR-144-3p overexpression in macrophages can aggravate atherosclerosis. Meanwhile, miR-144 overexpression prevents disruption of the lung endothelial cell barrier, whereas it exacerbates endothelial cell injury in Crohn's disease. miR-144/451 may serve as a potential target for the treatment of inflammatory diseases.

Oncogenic miRNAs dependent photothermal-immunotherapy enhanced by on-demand manipulation of immunosuppressive microenvironment using engineered gold nanoparticles for effective treatment of primary and metastatic tumor

Although photothermal-immunotherapy has emerged as a promising strategy to treat malignant tumor, unexpected thermal damage, continuous tumor migration and immunosuppressive microenvironment still limit its application. To improve the therapeutic efficacy, two types of engineered gold nanoparticles (SNAs@CCM and SNA2@CCM-Man) were fabricated. The SNAs@CCM are cancer cell membrane (CCM, tumor targeting agent) coated spherical nucleic acids (SNAs, miR-21 catcher and photothermal agent). The SNAs contained two types (SNA1 and SNA2), which are gold nanoparticles grafted with the first half and second half of anti-miR-21 oligonucleotide, respectively. The SNA2@CCM-Man are CCM coated SNA2 (miR-21 catcher) in which the CCM was functionalized by mannose (Man, macrophage targeting agent). These nanoparticles were expected to not only perform miR-21 dependent photothermal-immunotherapy in tumor cells to precisely damage primary tumor and activate the anti-tumor immune response against metastatic tumor, but also restrain the miR-21 expression in tumor-associated M2-type macrophages to promote their polarization to tumor-suppressed M1-type macrophages for on-demand manipulation of immunosuppressive microenvironment avoiding immune escape. After injection, the SNAs@CCM and SNA2@CCM-Man would respectively internalize by tumor cells and M2-type macrophages via homologous targeting of cancer cell membranes and receptor-ligand interactions of mannose. Upon entry into tumor cells, the SNAs specifically hybridized with the over-expressed miR-21 in these cells, thereby silencing the oncogenic miR-21 and leading to significant intracellular aggregation of SNAs. These aggregated SNAs not only served as miR-21 catcher, but performed a strong absorption in the near-infrared region acting as in situ photothermal agents. Under NIR irradiation, these photothermal agents enable highly selective photothermal-immunotherapy, inducing the immunogenic death of primary tumors and subsequent anti-tumor immune responses via the maturation of dendritic cells (DCs) and activation of T cells. Moreover, the miR-21 plunder process also effectively inhibited the migration of tumor cells to further enhance the therapeutic efficacy. Simultaneously, the similar miR-21 capture process mediated by SNA2 in M2 macrophages continuously induced macrophage polarization towards the anti-tumor M1 type, which was able to reverse the immunosuppressive microenvironment in tumor tissue to avoid immune escape and enhance immunotherapy. Both in vivo and in vitro experiments demonstrated that our nanoparticles could inhibit the primary tumor and its metastasis through miR-21-dependent photothermal immune activation and directional polarization of macrophages, providing a promising strategy for on-demand synchronous modulation of tumor cells and immune cells in tumor tissues for better malignant tumor therapy.

Epigenetic Mechanisms of Aluminum-Induced Neurotoxicity and Alzheimer's Disease: A Focus on Non-Coding RNAs.

Aluminum (Al) is known to induce neurotoxic effects, potentially contributing to Alzheimer's disease (AD) pathogenesis. Recent studies suggest that epigenetic modification may contribute to Al neurotoxicity, although the mechanisms are still debatable. Therefore, the objective of the present study was to summarize existing data on the involvement of epigenetic mechanisms in Al-induced neurotoxicity, especially AD-type pathology. Existing data demonstrate that Al exposure induces disruption in DNA methylation, histone modifications, and non-coding RNA expression in brains. Alterations in DNA methylation following Al exposure were shown to be mediated by changes in expression and activity of DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs). Al exposure was shown to reduce histone acetylation by up-regulating expression of histone deacetylases (HDACs) and impair histone methylation, ultimately contributing to down-regulation of brain-derived neurotrophic factor (BDNF) expression and activation of nuclear factor κB (NF-κB) signaling. Neurotoxic effects of Al exposure were also associated with aberrant expression of non-coding RNAs, especially microRNAs (miR). Al-induced patterns of miR expression were involved in development of AD-type pathology by increasing amyloid β (Aβ) production through up-regulation of Aβ precursor protein (APP) and β secretase (BACE1) expression (down-regulation of miR-29a/b, miR-101, miR-124, and Let-7c expression), increasing in neuroinflammation through NF-κB signaling (up-regulation of miR-9, miR-125b, miR-128, and 146a), as well as modulating other signaling pathways. Furthermore, reduced global DNA methylation, altered histone modification, and aberrant miRNA expression were associated with cognitive decline in Al-exposed subjects. However, further studies are required to evaluate the contribution of epigenetic mechanisms to Al-induced neurotoxicity and/or AD development.

Exosomal Delivery of miR-155 Inhibitor can Suppress Migration, Invasion, and Angiogenesis Via PTEN and DUSP14 in Triple-negative Breast Cancer.

Triple-Negative Breast Cancer (TNBC) is the most common type of breast cancer (BC). In order to develop effective treatments for TNBC, it is vital to identify potential therapeutic targets. Angiogenesis stimulates tumor growth and metastasis in TNBC, and miR-155 plays a crucial role in this process. The exosome is a nano-sized vesicle that carries many cargoes, including miRNAs. The present study investigated the effect of exosomal delivery of miR-155 antagomir on tumor migration, invasion, and angiogenesis in TNBC. From MDA-MB-231 cells, exosomes were extracted, characterized, and loaded with miR-155 antagomir using electroporation. The expression of miR-155 and its target genes, including PTEN and DUSP14, was analyzed using RTqPCR. The wound-healing and transwell assays were used to measure cell migration and invasion. Furthermore, angiogenesis was evaluated by tube formation and chorioallantoic membrane (CAM) assays. The results indicated that exosomal delivery of miR-155 antagomir to HUVEC cells significantly suppressed miR-155 expression while upregulating PTEN and DUSP14. The tube formation properties of HUVEC cells were also significantly reduced following treatment with exosomes containing miR-155 antagomirs, and these results were confirmed using CAM assay. The migration and invasion of MDA-MB-231 cells were significantly reduced after treatment with miR-155 antagomir-loaded exosomes. It was found that miR-155 antagomir delivery using exosomes can inhibit migration, invasion, and angiogenesis viaPTEN and DUSP14 in TNBC.

MiR-126 accelerates renal injury induced by UUO via inhibition PI3K/ IRS-1/ FAK signaling induced M2 polarization and endocytosis in macrophages

To investigate the role and molecular mechanism of miR-126 in unilateral ureteral occlusion (UUO). We used bioinformatics to analyse miRNAs specifically expressed in UUO. The mouse model of UUO was established using RAW264.7 cells cultured in vitro and in vivo. The mice were divided into control group, miR-126-NC (negative control) group and miR-126-KD (knockdown) group. Then the relative expression of miR-126 was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), the renal fibrosis was detected by Masson staining, and the protein expression of CD68, collagen I and collagen III in the kidney was detected by immunofluorescence assay. Immunohistochemistry detects α-SMA expression. Moreover, Western blotting was performed to measure the expressions of p-PI3K, CD163, CD206, CD86, iNOS, IL-1β, p-FAK, p-Rac-1, p-IRS-1 and MMP9. The relative fluorescence intensity of F-actin and p-FAK was detected by immunofluorescence assay, and the phagocytosis ability of macrophages was determined by phagocytosis assay with fluorescent microspheres. Bioinformatics analysis reveals miR-126-specific overexpression in UUO. Successful transfection of miR-126-NC and miR-126-KD was confirmed by RT-PCR. The selective reduction of miR-126 was validated by Masson, immunohistochemistry and immunofluorescence staining to decrease the area of UUO-induced renal fibrosis and to lower the expression of CD68, α-SMA, collagen I, and collagen III. The reduction of iNOS expression may also be achieved with selective knockdown of miR-126, as verified by cell tests. enhances the phagocytic ability of macrophages and the expression of p-PI3K, CD206, p-FAK, F-actin, p-Rac-1, p-IRS-1 and MMP9. MiR-126 can inhibit the PI3K signaling pathway, promote M1 macrophage polarization, and suppress the activation of FAK and Rac-1, thus accelerating the progression of UUO.

MiR-103–3p attenuates liver injury with severe acute pancreatitis by inhibiting pyroptosis through miR-103–3p/NLRP1 axis

BackgroundSevere acute pancreatitis (SAP) is a common digestive system disorder in clinical practice, and it is often associated with liver damage in patients with severe acute pancreatitis. Several studies have indicated that pyroptosis plays a role in liver damage following severe acute pancreatitis (SAP). However, the precise mechanisms remain unclear. This study aims to elucidate the association and specific mechanisms between liver injury following SAP and pyroptosis, providing theoretical support for research on SAP-induced liver injury. MethodsA rat model of SAP with concomitant liver injury was successfully established. The expression levels of miR-103–3p across different liver tissue groups were quantified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Bioinformatic analyses and dual-luciferase reporter assays confirmed that NLRP1 is a direct target of miR-103–3p. In vivo assessments of miR-103–3p levels were performed, and the extent of cell pyroptosis during liver injury post-SAP was evaluated through western blotting, qRT-PCR, scanning electron microscopy, histopathology, immunofluorescence, and immunohistochemistry. The role of miR-103–3p in regulating NLRP1-mediated pyroptosis and its impact on SAP-induced liver injury were validated. ResultsThis study reports that following SAP-induced liver injury, the expression of miR-103–3p in liver tissue was significantly decreased, and cell pyroptosis was involved in the process of liver injury. Experimental validation indicated that NLRP1 was a downstream target of miR-103–3p. Overexpression of miR-103–3p in vitro significantly alleviated the severity of liver injury following SAP, while simultaneously inhibiting cell pyroptosis. ConclusionThese findings indicate that pyroptosis may be linked to SAP-induced liver injury and that miR-103–3p mitigates hepatocyte pyroptosis by reducing liver injury through the suppression of NLRP1 expression.