miR-146a Expression Research Articles

METTL3 accelerates staphylococcal protein A (SpA)-induced osteomyelitis progression by regulating m6A methylation-modified miR-320a

Osteomyelitis (OM) is an inflammatory disease of bone infection and destruction characterized by dysregulation of bone homeostasis. Staphylococcus aureus (SA) has been reported to be the most common pathogen causing infectious OM. Recent studies have demonstrated that N6-methyladenosine (m6A) regulators are associated with the development of OM. However, the molecular mechanism of m6A modifications in OM remains unclear. Here, we investigated the function of methyltransferase-like 3 (METTL3)-mediated m6A modification in OM development. In this study, human bone mesenchymal stem cells (hBMSCs) were treated with staphylococcal protein A (SpA), a vital virulence factor of SA, to construct cell models of OM. Firstly, we found that METTL3 was upregulated in OM patients and SpA-induced hBMSCs, and SpA treatment suppressed osteogenic differentiation and induced oxidative stress and inflammatory injury in hBMSCs. Functional experiments showed that METTL3 knockdown alleviated the inhibition of osteogenic differentiation and the promotion of oxidative stress and inflammation in SpA-treated hBMSCs. Furthermore, METTL3-mediated m6A modification upregulated miR-320a expression by promoting pri-miR-320a maturation, and the mitigating effects of METTL3 knockdown on SpA-mediated osteogenic differentiation, oxidative stress and inflammatory responses can be reversed by miR-320 mimic. In addition, we demonstrated that phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) was a downstream target of miR-320a, upregulation of PIK3CA alleviated miR-320a-induced inhibition of osteogenic differentiation, and upregulation of oxidative stress and inflammatory responses during SpA infection. Finally, we found that silencing METTL3 alleviated OM development by regulating the miR-320a/PIK3CA axis. Taken together, our data demonstrated that the METTL3/m6A/miR-320a/PIK3CA axis regulated SpA-mediated osteogenic differentiation, oxidative stress, and inflammatory responses in OM, which may provide a new therapeutic strategy for OM patients.

Altered miR-10a gene expression in peripheral blood mononuclear cells correlates with frequency of T regulatory cells and cytokine profile in multiple sclerosis patients

A critical component in triggering and progressing autoimmune multiple sclerosis (MS) is the deregulation of immune responses, including dysfunction of T regulatory cells (Tregs), critical participants in the pathogenetic context of inflammation. It has been found that miRNAs have a crucial role in the induction of MS because dysregulation of miRNAs can result in defects in immunological tolerance. In this investigation, we examined the miR-10a contribution to MS disorder by comparing the altered expression of miR-10a in peripheral blood mononuclear cells (PBMCs) of 40 MS patients to 40 healthy controls. Additionally, we examined Tregs’ frequency in MS patients in compare with healthy controls. We evaluated the secreted levels of anti-inflammatory cytokines, such as IL-10 and TGF-B, in the serum of MS patients and their expression level in healthy controls’ and patients’ peripheral blood mononuclear cells (PBMCs). Then, we assessed the correlation between miR-10a expression with Treg frequency and levels of anti-inflammatory cytokines in serum. PBMCs from MS patients had downregulated expression of miR-10a, and a substantial correlation was found between this expression and a reduction in Treg cells’ frequency and the secreted anti-inflammatory cytokines associated with Tregs’ diminished functionality. In summary, our research demonstrated a strong correlation between Tregs’ frequency, lower levels of cytokines linked to Treg function, and lower expression of miR-10a in PBMCs. So, the alteration of miR-10a can be utilized as a probable therapeutic target for the prevention and management of MS disorder. However, further examination is requisite before this strategy become practical for use in the clinical setting

Repurposing Aprepitant: Can it protect against doxorubicin-induced Chemobrain beyond its antiemetic role?

The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (DOX), but whether aprepitant can also assuage DOX-mediated chemobrain remains to be unveiled. Here, we scrutinized the potential neuroprotective effect and underlying mechanisms of aprepitant using DOX-induced chemobrain model, where rats were allocated into 4 groups (control, aprepitant, DOX, and DOX+ aprepitant). Cognitive deficits were assessed through behavioral tests and hippocampal structural alterations were determined by H&E and toluidine blue staining. Biochemical measurements were performed using ELISA, real-time quantitative PCR, western blotting, and immunohistochemical methods. Aprepitant improved cognitive responses, and hippocampal morphology, enhancing the presence of intact neurons. At the molecular tier, aprepitant significantly reduced hippocampal contents of SP and the inflammatory markers NF-κB and IL-1β. Additionally, it signified its antioxidant and antiapoptotic capacities by downregulating cleaved caspase-3 protein expression and curbing the content of malondialdehyde but boosted those of glutathione and Bcl-2. Aprepitant also downregulated the expression of miR-146a and turned off the endoplasmic reticulum (ER) stress cascade PERK/eIF-2α/ATF-4/CHOP. To recapitulate, aprepitant demonstrates a neuroprotective effect against DOX-mediated chemobrain by alleviating inflammatory, oxidative, and apoptotic responses, partly by reducing SP, ER stress, and miR-146a. These findings not only underscore the potential of aprepitant as a neuroprotective agent but also offer new understanding of the mechanisms behind chemobrain, leading to better therapeutic strategies for cancer patients.

Protective effects of Silibinin and cinnamic acid against paraquat-induced lung toxicity in rats: impact on oxidative stress, PI3K/AKT pathway, and miR-193a signaling.

Levels of reactive oxygen species (ROS) are the primary determinants of pulmonary fibrosis. It was discovered that antioxidants can ameliorate pulmonary fibrosis caused by prolonged paraquat (PQ) exposure. However, research on the precise mechanisms by which antioxidants influence the signaling pathways implicated in pulmonary fibrosis induced by paraquat is still insufficient. This research utilized a rat model of pulmonary fibrosis induced by PQ to examine the impacts of Silibinin (Sil) and cinnamic acid (CA) on pulmonary fibrosis, with a specific focus on pro-fibrotic signaling pathways and ROS-related autophagy. Lung injury induced by paraquat was demonstrated to be associated with oxidative stress and inflammation of the lungs, downregulated (miR-193a), and upregulated PI3K/AKT/mTOR signaling lung tissues. Expression levels of miR-193a were determined with quantitative real-time PCR, protein level of protein kinase B (Akt), and phosphoinositide 3-Kinase (PI3K) which were determined by western blot analysis. Hydroxyproline levels (HYP) and transforming growth factor-β1 (TGF-β1) were measured by ELISA, malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione peroxidase (GSH), and catalase and were measured in lung tissue homogenates colorimetrically using spectrophotometer. Long-term exposure to paraquat resulted in decreased PI3K/AKT signaling, decreased cell autophagy, increased oxidative stress, and increased pulmonary fibrosis formation. Silibinin and cinnamic acid also decreased oxidative stress by increasing autophagy and miR-193a expression, which in turn decreased pulmonary fibrosis. These effects were associated by low TGF-β1. Silibinin and cinnamic acid inhibited PQ-induced PI3K/AKT by stimulating miR-193-a expression, thus attenuating PQ-induced pulmonary fibrosis.

The Role of Extracellular Vesicles Derived from MicroRNA-146a–modified Mesenchymal Stem Cells in Modulating Inflammation in Experimental Glenohumeral Osteoarthritis

Glenohumeral osteoarthritis (GOA) is characterized by chronic inflammation leading to joint damage. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are promising therapies because of their immunomodulatory functions. The anti-inflammatory effects of EVs from human Adipose-derived MSCs (hADSCs) overexpressing microRNA (miR)-146a were investigated in experimental GOA in this study. hADSCs were transfected with a mimic negative control or miR-146a mimics. GOA was induced in C57/Bl6j mice, and subsequently, the animals were treated intra-articularly with phosphate-buffered saline, miR-146a EVs, or miR-control EVs. The expression of miR-146a and its targeted cytokines interleukin (IL)-4, IL-10, tumor necrosis factor-alpha (TNF-α), IL-17, and interferon-gamma (IFN-γ) were analyzed in the spleen of mice by enzyme-linked immunosorbent assay and in the articular cartilage by real-time polymerase chain reaction. miR-146a EVs showed enrichment of miR-146a. In GOA mice, miR-146a EV treatment significantly reduced expression levels of inflammatory cytokines IFN-γ, IL-17, and TNF-α and increased the anti-inflammatory cytokine IL-10 and IL-4 compared to controls. miR-146a EV treatment raised the anti-inflammatory cytokines and reduced the pro-inflammatory cytokines of the spleen in treated mice. This study demonstrates that EVs derived from hADSCs overexpressing miR-146a have enhanced anti-inflammatory potential in GOA by modulating cytokine expression and production. EVs engineered with inflammation-related miRNAs could be a cell-free therapeutic approach for GOA.

Determination of the role of miR-451a on Plasmodium falciparum red blood cell stages, oxidative stress, and proteomic profiling.

This study examines the feasibility and effects of introducing microRNA mimic into red blood cells (RBCs) at the initial phases of Plasmodium falciparum 3D7 (Pf3D7) infection. The aim is to determine the correlation between increased expression of miR-451a and parasitaemia. In this study miR-mimic-451a labelled with Cy3 and transfected into control and infected RBCs using lipofectamine and analysed using the fluorescence microscopy and flow cytometry. The study demonstrated the efficacy of miR-451a by treating pre-and post-transfected control RBCs and Pf3D7-infected RBCs with miR-mimic-451a. We also examined its impact on % growth inhibition of Pf3D7, oxidative stress markers (Luminometry, LPO, SOD, CAT, GSH and GPx). Additionally, determination of pH, haemoglobin (Hb), and proteomic profile performed using SDS-PAGE. Modified expression level of mir-451a has the potential to change the progression of the infection and yielded a 50% decrease in parasitaemia within 48h. Moreover, transfected samples were shown to be efficacious in counteracting the oxidative stress-induced alterations during Pf3D7 infection and enable to return the cells towards the normalcy. Modified proteomic profile of transfected iRBCs demonstrates the correlation between overexpression of miRNA and protein expression. where, the major changes were observed in the heavy molecular weight proteins more than 57kDa. The study reveals promising effects of miR-mimic-451a enrichment during RBC stages of Pf3D7, offering insights into potential malaria therapeutic strategies and potential biomedical research implications.

MiR-146a Is Mutually Regulated by High Glucose-Induced Oxidative Stress in Human Periodontal Ligament Cells.

The high-glucose conditions caused by diabetes mellitus (DM) exert several effects on cells, including inflammation. miR-146a, a kind of miRNA, is involved in inflammation and may be regulated mutually with reactive oxygen species (ROS), which are produced under high-glucose conditions. In the present study, we used human periodontal ligament cells (hPDLCs) to determine the effects of the high-glucose conditions of miR-146a and their involvement in the regulation of oxidative stress and inflammatory cytokines using Western blotting, PCR, ELISA and other methods. When hPDLCs were subjected to high glucose (24 mM), cell proliferation was not affected; inflammatory cytokine expression, ROS induction, interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) expression increased, but miR-146a expression decreased. Inhibition of ROS induction with the antioxidant N-acetyl-L-cysteine restored miR-146a expression and decreased inflammatory cytokine expression compared to those under high-glucose conditions. In addition, overexpression of miR-146a significantly suppressed the expression of the inflammatory cytokines IRAK1 and TRAF6, regardless of the glucose condition. Our findings suggest that oxidative stress and miR-146a expression are mutually regulated in hPDLCs under high-glucose conditions.

Serum microRNA-181a Expression Level in Patients with Acute Liver Failure and Its Correlation with Prognosis.

This paper examined miR-181a expression in the serum of patients with acute liver failure (ALF) and investigated the impact of its expression in the prognosis of ALF patients. A total of 112 ALF patients (ALF group) and 100healthy controls during the same period (control group) were recruited as study subjects, and ALF patients were separated into the survival group and the death group. Serum ALT, AST, SCr, TBil, PTA, and International Normalized Ratio (INR) indices as well as serum miR-181a expression were assessed by using a fully automated biochemistry analyzer and RT-qPCR. Patients in the ALF group were evaluated using the Model for End-Stage Liver Disease (MELD) score. Correlation between serum miR-181a expression and MELD scores of ALF patients was processed by Pearson correlation analysis, and the diagnostic value of miR-181a level for the occurrence of ALF was estimated by ROC curve analysis. Multivariate logistic regression analysis was executed to assess the factors influencing the occurrence of death in ALF patients. ALF patients had higher levels of ALT, AST, TBiL, SCr, INR and miR-181a and lower PTA levels in comparison to healthy controls. Serum miR-181a expression level in ALF patients revealed a significant positive correlation with MELD score. Multivariate logistic regression analysis unveiled that TBil, INR, SCr, and miR-181a were the independent risk factors for the occurrence of death in ALF patients, and that PTA was an independent protective factor for the prognosis of ALF patients. miR-181a exhibited a favorable diagnostic value in ALF and its prognosis. miR-181a expression is upregulated in the serum of ALF patients, and it can be utilized as an indicator for ALF diagnostic and prognostic assessment.

Unveiling the therapeutic potential of miR-146a: Targeting innate inflammation in atherosclerosis.

Atherosclerosis is the foremost vascular disease, precipitating debilitating complications. Although therapeutic strategies have historically focused on reducing cholesterol deposition, recent insights emphasize the pivotal role of inflammation. Innate inflammation significantly contributes to plaque instability and rupture, underscoring the need for intervention across all disease stages. Numerous studies have highlighted the therapeutic potential of targeting innate immune pathways in atherosclerosis, revealing significant advancements in understanding the molecular mechanisms underlying inflammatory processes within arterial lesions. Notably, research has demonstrated that the modulation of microRNA-146a (miR-146a) expression impacts innate inflammation, effectively halts atherosclerosis progression, and enhances plaque stability by targeting interleukin-1 receptor-associated kinase (IRAK) and activating TNF receptor-associated factor 6 (TRAF6), a signalling pathway involving toll-like receptors (TLRs). Understanding the intricate mechanisms involved is crucial. This study provides a comprehensive analysis of the evidence and underlying mechanisms through which miR-146a exerts its effects. Integrating these findings into clinical practice may herald a transformative era in managing atherosclerotic cardiovascular disease.

Endometriotic lesions and their recurrence: A Study on the mediators of immunoregulatory (TGF-β/miR-20a) and stemness (NANOG/miR-145)

Endometriosis is a common estrogen-dependent disease that involves various cellular processes. Additionally, miRNAs play a crucial role in the development of the disease as an important component of the microenvironment. In this study, tissue specimens of eutopic and ectopic lesions of 20 women, whose endometriosis was later approved by the pathology laboratory, were biopsied through laparoscopy. As a control group, endometrial tissue specimens were collected from 20 women who underwent curettage for reasons unrelated to endometriosis. The expression levels of miR-20A and miR-145 and their target genes, TGF-β and NANOG, were measured in these samples as markers of stemness and immunomodulatory properties, respectively. The study also aimed to compare the expression levels of target genes and miRNAs in ectopic lesions regarding endometriosis recurrence post-surgery. The study revealed that the expression of TGF-β and NANOG genes was significantly upregulated in endometriotic tissues compared to the control group. There was also a notable increase in miR-20A and miR-145 expression in the endometriotic tissues compared to the control group. While there was no significant correlation between the expression of miR-20a and TGF-β, we observed a negative correlation between the expression level of miR-145 and NANOG. Additionally, the ROC curve analysis emphasized miR-14 as a potential biomarker for endometriosis over miR-20a. However, our findings on disease recurrence underscore the importance of miR-20a in the early detection of endometriosis recurrence.

Mechanisms underlying TRPV4-mediated regulation of miR-146a expression.

Persistent inflammation is a major contributor in the development of various inflammatory diseases like atherosclerosis. Our study investigates how transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, interacts with microRNA-146a (miR-146a), within the context of inflammation and atherosclerosis. Micro-RNAs play a critical role in controlling gene expression, and miR-146a is notable for its anti-inflammatory actions. TRPV4 is activated by diverse soluble and mechanical stimuli, and often associated with inflammatory responses in various diseases. Here, we find that TRPV4 negatively regulates miR-146a expression in macrophages, especially following stimulation by lipopolysaccharides or alterations in matrix stiffness. We show that in atherosclerosis, a condition characterized by matrix stiffening, TRPV4 decreases miR-146a expression in aortic tissue macrophages. We find that TRPV4's impact on miR-146a is independent of activation of NFκB, Stat1, P38, and AKT, but is rather mediated through a mechanism involving histone deacetylation instead of DNA methylation at the miR-146a promoter site. Furthermore, we show that N-terminal residues 1 to 130 in TRPV4 is essential in suppression of miR-146a expression in LPS-stimulated macrophages. Altogether, this study identifies a regulatory mechanism of miR-146a expression by TRPV4 which may open new potential therapeutic strategies for managing inflammatory diseases.

OncomiR-181a promotes carcinogenesis by repressing the extracellular matrix proteoglycan decorin in hepatocellular carcinoma

BackgroundProteoglycans are important tumor microenvironment extracellular matrix components. The regulation of key proteoglycans, such as decorin (DCN), by miRNAs has drawn attention since they have surfaced as novel therapeutic targets in cancer. Accordingly, this study aimed at identifying the impact of miR-181a in liver cancer and its regulatory role on the extracellular matrix proteoglycan, DCN, and hence on downstream oncogenes and tumor suppressor genes.ResultsDCN was under-expressed in 22 cirrhotic and HCC liver tissues compared to that in 11 healthy tissues of liver transplantation donors. Conversely, miR-181a was over-expressed in HCC liver tissues compared to that in healthy liver tissues. In silico analysis predicted that DCN 3’UTR harbors two high-score oncomiR-181a binding regions. This was validated by pmiRGLO luciferase reporter assay. Ectopic miR-181a expression into HuH-7 cells repressed the transcript and protein levels of DCN as assessed fluorometrically and by western blotting. DCN siRNAs showed similar results to miR-181a, where they both enhanced the cellular viability, proliferation, and clonogenicity. They also increased Myc and E2F and decreased p53 and Rb signaling as assessed using reporter vectors harboring p53, Rb, Myc, and E2F response elements. Our findings demonstrated that miR-181a directly downregulated the expression of its direct downstream target DCN, which in turn affected downstream targets related to cellular proliferation and apoptosis.ConclusionTo our knowledge, this is the first study to unveil the direct targeting of DCN by oncomiR-181a. We also highlighted that miR-181a affects targets related to cellular proliferation in HCC which may be partly mediated through inhibition of DCN transcription. Thus, miR-181a could be a promising biomarker for the early detection and monitoring of liver cancer progression. This would pave the way for the future targeting of the oncomiR-181a as a therapeutic approach in liver cancer, where miR-181a-based therapy approach could be potentially combined with chemotherapy and immunotherapy for the management of liver cancer.

MiRNA expression affects survival in patients with obstructive sleep apnea and metastatic colorectal cancer

IntroductionThe relationship between obstructive sleep apnea (OSA) and cancer has been recognized for some time now. However, little is known about the mechanisms by which sleep apnea promotes tumorigenesis and the impact of OSA on survival after cancer diagnosis. In the last few years, research has focused on the exploration of different biomarkers to understand the mechanisms underlying this relationship and miRNAs, non-coding single strands of about 22 nucleotides that post-transcriptionally regulate gene expression, have emerged as possible actors of this process.The aim of the study was to evaluate the impact of OSA on survival of metastatic colorectal cancer (mCRC) patients based on the expression of specific miRNAs. MethodsThe expression of 6 miRNAs, respectively miR-21, miR-23b, miR-26a, miR-27b, miR-145 and miR-210, was analyzed by qRT-PCR in patients’ sera. Response to first-line therapy, Kaplan-Meier curves of overall and progression-free survival were used to evaluate survival in mCRC patients with and without OSA stratified for the expression of miRNAs. ResultsThe expression of miR-21, miR-23b, miR-26a and miR-210 was significantly upregulated in mCRCs with OSA compared to no OSA. In mCRC patients with OSA and increasing expression of miR-21, miR-23b, miR-26a and miR-210 risk of progression after first-line therapy was higher and both overall and progression-free survival were significantly worst. Conversely, as miR-27b and miR-145 expression increased, the life expectancy of patients diagnosed with OSA and mCRC improved markedly. ConclusionsThis study highlights the relevance of specific miRNAs on OSA in mCRCs and their significance as non-invasive biomarkers in predicting the prognosis in patients with mCRC and OSA.

Association between IL-6, miRNA-146a, MALAT1 genetic polymorphisms and risk of rheumatoid arthritis.

Aim: This study aimed to investigate the associations between single nucleotide polymorphisms (SNPs) of IL-6 (-174G/C), microRNA146a (rs2910164C/G) and MALAT1 (rs619586A/G) and susceptibility to rheumatoid arthritis (RA) in Egyptians.Methods: SNPs were genotyped in 101 RA patients and 104 controls. Expression levels were evaluated either by Enzyme-linked immunosorbent assay (ELISA) for IL-6 or quantitative real-time PCR (qRT-PCR) for miR-146a and MALAT1.Results: IL-6-174 GC (OR=3.422) genotype, IL-6-174 C allele (OR=2.565), miR-146a (rs2910164) CG (OR=2.190) and MALAT1 (rs619586) AA (OR=4.125) genotypes and A allele (OR=6.122) could be considered as risk factors for RA. An increase in the expression of IL-6, miR-146a and MALAT1 was detected in RA patients, which was independent of any SNP.Conclusion: SNPs of IL-6, miR-146a and MALAT1were linked to RA predisposition in Egyptians.

MiRNA-193a-mediated WT1 suppression triggers podocyte injury through activation of the EZH2/β-catenin/NLRP3 pathway in children with diabetic nephropathy

Diabetic nephropathy (DN), an eminent etiology of renal disease in patients with diabetes, involves intricate molecular mechanisms. Recent investigations have elucidated microRNA-193a (miR-193a) as a pivotal modulator in DN, although its precise function in podocyte impairment remains obscure. The present study investigated the role of miR-193a in podocyte injury via the WT1/EZH2/β-catenin/NLRP3 pathway. This study employed a comprehensive experimental approach involving both in vitro and in vivo analyses. We utilized human podocyte cell lines and renal biopsy samples from pediatric patients with DN. The miR-193a expression levels in podocytes and glomeruli were quantified via qRT‒PCR. Western blotting and immunofluorescence were used to assess the expression of WT1, EZH2, β-catenin, and NLRP3 inflammasome components. Additionally, the study used luciferase reporter assays to confirm the interaction between miR-193a and WT1. The impact of miR-193a manipulation was observed by overexpressing WT1 and inhibiting miR-193a in podocytes, followed by analysis of downstream pathway activation and inflammatory markers. We found upregulated miR-193a in podocytes and glomeruli, which directly targeted and suppressed WT1, a crucial podocyte transcription factor. WT1 suppression, in turn, activated the EZH2/β-catenin/NLRP3 pathway, leading to inflammasome assembly and proinflammatory cytokine production. Overexpression of WT1 or inhibition of miR-193a attenuated these effects, protecting podocytes from injury. This study identified a novel mechanism by which miR-193a-mediated WT1 suppression triggers podocyte injury in DN via the EZH2/β-catenin/NLRP3 pathway. Targeting this pathway or inhibiting miR-193a may be potential therapeutic strategies for DN.

Dysregulation of miR-223, miR-146a, and miR-193a Expression Profile in Acute and Chronic Phases of Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice.

Multiple sclerosis (MS) is a chronic autoimmune disease with an unknown etiology. The purpose of this research was to assess miR-223, miR-146a, and miR-193a in acute and chronic phases of experimental autoimmune encephalomyelitis (EAE) mice to consider the possible role of these genes in the pathogenesis of MS. EAE induction was given by myelin oligodendrocyte glycoprotein peptide on female C57BL/6 mice. Clinical scores and other criteria were followed daily until day 21 for the acute group and day 77 for the chronic group. At the end of the course, inflammation and demyelination of the central nervous system (CNS) were assessed by histological analysis. MicroRNA expression levels were assessed by real-time PCR. EAE development attenuated in the chronic group, and histological analysis showed less infiltration and demyelination in the chronic group compared to the acute group. The upper expression of miR-223 is demonstrated in the acute phase of EAE. Moreover, the expression levels of miR-146a and miR-193a decreased in the chronic phase of EAE. MiR-223 showed a highly coordinated elevation in the acute phase both in vivo and in vitro. MiR-146a shares a pathway with miR-223 through effecting IL-6 expression. Further studies are needed to reveal their impact on EAE and possible applications as drug targets and biomarkers.

Evaluating the Serum Level of ACTH and Investigating the Expression of miR-26a, miR-34a, miR-155-5p, and miR-146a in the Peripheral Blood Cells of Multiple Sclerosis Patients.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disorder affecting white and gray matter. This study aimed to investigate the association between clinical outcomes in MS patients and the levels of certain molecules in their serum, including ACTH, IL-17, and specific miRNAs: miR-26a, miR-34a, miR-155-5p, and miR-146a. Fifty healthy people and 75 blood samples from MS patients were selected. MS patients had higher expression levels of IL-17, miR-26a, miR-34a, and miR-146a compared to healthy individuals (p < 0.0001). There was no significant difference in miR-155-5p expression between the two groups (p = 0.203). MS patients also had higher serum levels of ACTH compared to the normal population (p < 0.0001). In MS patients, there was a negative correlation between IL-17 and miR-155-5p expression levels (p = 0.048, r = - 0.229). Similarly, a significant negative correlation was observed between ACTH and miR-155-5p in the control group (p = 0.044, r = - 0.286). The study's analysis revealed no significant difference in the expression of miR-155-5p between MS patients and normal individuals; the study's examination revealed that the expression level of IL-17, miR-26a, miR-34a, and miR-146a was higher in MS patients than in normal individuals.

MicroRNAs Regulate the Expression of Genes Related to the Innate Immune and Inflammatory Response in Rabbits Infected with Lagovirus europaeus GI.1 and GI.2 Genotypes.

MicroRNAs (miR) are a group of small, non-coding RNAs of 17-25 nucleotides that regulate gene expression at the post-transcriptional level. Dysregulation of miRNA expression or function may contribute to abnormal gene expression and signaling pathways, leading to disease pathology. Lagovirus europaeus (L. europaeus) causes severe disease in rabbits called rabbit hemorrhagic disease (RHD). The symptoms of liver, lung, kidney, and spleen degeneration observed during RHD are similar to those of acute liver failure (ALF) and multi-organ failure (MOF) in humans. In this study, we assessed the expression of miRs and their target genes involved in the innate immune and inflammatory response. Also, we assessed their potential impact on pathways in L. europaeus infection-two genotypes (GI.1 and GI.2)-in the liver, lungs, kidneys, and spleen. The expression of miRs and target genes was determined using quantitative real-time PCR (qPCR). We assessed the expression of miR-155 (MyD88, TAB2, p65, NLRP3), miR-146a (IRAK1, TRAF6), miR-223 (TLR4, IKKα, NLRP3), and miR-125b (MyD88). We also examined biomarkers of inflammation: IL-1β, IL-6, TNF-α, and IL-18 in four tissues at the mRNA level. Our study shows that the main regulators of the innate immune and inflammatory response in L. europaeus/GI.1 and GI.2 infection, as well as RHD, are miR-155, miR-223, and miR-146a. During infection with L. europaeus/RHD, miR-155 has both pro- and anti-inflammatory effects in the liver and anti-inflammatory effects in the kidneys and spleen; miR-146a has anti-inflammatory effects in the liver, lungs and kidneys; miR-223 has anti-inflammatory effects in all tissues; however, miR-125b has anti-inflammatory effects only in the liver. In each case, such an effect may be a determinant of the pathogenesis of RHD. Our research shows that miRs may regulate three innate immune and inflammatory response pathways in L. europaeus infection. However, the result of this regulation may be influenced by the tissue microenvironment. Our research shows that infection of rabbits with L. europaeus/GI.1 and GI.2 genotypes causes an overexpression of two critical acute phase cytokines: IL-6 in all examined tissues and TNF-α (in the liver, lungs, and spleen). IL-1β was highly expressed only in the lungs after L. europaeus infection. These facts indicate a strong and rapid involvement of the local innate immune and inflammatory response in L. europaeus infection-two genotypes (GI.1 and GI.2)-and in the pathogenesis of RHD. Profile of biomarkers of inflammation in rabbits infected with L. europaeus/GI.1 and GI.2 genotypes are similar regarding the nature of changes but are different for individual tissues. Therefore, we propose three inflammation profiles for L. europaeus infection for both GI.1 and GI.2 genotypes (pulmonary, renal, liver, and spleen).

The hijacking of HBV by small extracellular vesicles inhibits M1 macrophages to facilitate immune evasion

Small extracellular vesicles (sEVs) have the ability to transfer genetic material between cells, but their role in mediating HBV infection and regulating M1 macrophages to promote immune evasion remains unclear. In this study, we utilized PMA + LPS + IFN-γ to induce THP-1 into M1 macrophages. We then extracted sEVs from HepG2.2.15 cell and treated the M1 macrophages with these sEVs. QPCR detection revealed the presence of HBV-DNA in the M1 macrophages. Additionally, RT-qPCR and WB analysis demonstrated a significantly decreased in the expression of TLR4, NLRP3, pro-caspase-1, caspase-1p20, IL-1β and IL-18 in the M1 macrophages (P < 0.05). Furthermore, RT-qPCR results displayed high expression levels of that miR-146a and FEN-1 in the sEVs derived from HepG2.2.15 cells (P < 0.01). RT -qPCR and WB analysis showed that these sEVs enhanced the expression of FEN-1 or miR-146a in the M1 macrophages through miR-146a or FEN-1 (P < 0.05), while simultaneously reducing the expression of TLR4, NLRP3, caspase-1p20, IL-1β and IL-18 in the M1 macrophages (P < 0.05). In summary, our findings indicate that sEVs loaded with HBV inhibit the inflammatory function of M1 macrophages and promote immune escape. Additionally, miR-146a and FEN-1 present in the sEVs play a crucial role in this process.

MiR-146a (rs2910164) Gene Polymorphism and Its Impact on Circulating MiR-146a Levels in Patients with Inflammatory Bowel Diseases.

MicroRNA-146a (miR-146a) has been involved in the pathophysiology of inflammatory bowel disease (IBD). However, the precise processes are still not entirely understood. Contradictory studies suggest that miR-146a expression could be influenced by the miR-146a rs2910164 C > G polymorphism. This case-control study aimed to investigate the association ofmiR-146a rs2910164 C > G gene polymorphism and its impact on circulating miR-146a expression levels in Egyptian IBD patients. We included 40 IBD patients and 30 matched healthy controls. Genotyping of miR-146a rs2910164 polymorphism and assessment of miR-146a expression level were done using quantitative real-time PCR in all participants. MiR-146a rs2910164 GG genotype and the G allele were reported in 47% and 70% of the IBD patient group, respectively. And they were associated with increased IBD risk. All the IBD patients with the CC genotype (100%) and most of those with the CG genotype (66.67%) had an inactive disease, while most IBD patients with the GG genotype (73.68%) had an active disease. The miR-146a expression level was the highest with the CC genotype and the lowest with the GG genotype. Also, miR-146a expression level decreased significantly in IBD patients than controls and with disease activity. Combined detection of fecal calprotectin with miR-146a expression level improved the diagnostic sensitivity and the negative predictive value in differentiating IBD patients with active disease from those inactive.Our study identified a strong association of miR-146a rs2910164 GG genotype and G allele with IBD-increased susceptibility and activity in the Egyptian population. The miR-146a rs2910164 polymorphism can reduce miR-146a expression levels in these patients as well. Further research on a larger sample size and different ethnic populations can be the key to progress in establishing this genetic association.