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Identification of human miRNAs involved in coronavirus-host interplay is important due to the current COVID-19 pandemic. Therefore, this study aimed to measure the circulating plasma miR-155 expression level in COVID-19 patients and healthy controls to investigate its roles in the pathogenesis and severity of COVID-19 disease and to assess its usefulness as a clinical biomarker for the detection of COVID-19 disease and the severity of infection. A total of 150 COVID-19 patients and 50 controls were enrolled into our study. Beside the routine laboratory work and chest computed tomography (CT) scans of COVID-19 patients, plasma miR-155 expression level was measured using reverse transcription quantitative real-time PCR (RT-qPCR) technique. Our results demonstrated increased miR-155 expression level in COVID-19 patients compared to controls, in severe compared to moderate COVID-19 patients, and in non-survival compared to survival COVID-19 patients. miR-155 expression level also had significant correlation with clinicopathological characteristics of COVID-19 patients such as chest CT findings, CRP, ferritin, mortality, D-dimer, WBC count, and lymphocytes and neutrophils percentages. Also, our results showed that the area under the curve (AUC) for miR-155 was 0.986 with 90% sensitivity and 100% specificity when used as a biomarker for the detection of COVID-19 disease; while in detection of severity of COVID-19 disease, AUC for miR-155 was 0.75 with 76% sensitivity and specificity. From these results we can conclude that miR-155 has a crucial role in the pathogenesis and severity of COVID-19; also, it could be a good diagnostic clinical biomarker for the detection of COVID-19 disease and the severity of infection.

Th9 is a subset of CD4+ T cells that mainly secrete IL-9. Th9/IL-9 participates in immune response during Staphylococcus aureus and methicillin-resistant Staphylococcus aureus pneumonia (MRSA) infection. Here, we collected bronchoalveolar lavage fluid (BALF) from 30 children with MRSA pneumonia (MRSA group) and 10 children with bronchial foreign bodies (Control group). RT-PCR, ELISA and flow cytometry were used to detect the expression of miR-155 and IL-9 in BALF and the number of Th9 cells. CD4+ T cells isolated from BALF of MRSA and Control group were transfected with miR-155 mimic or inhibitor, and then induced Th9 cell differentiation. The results showed that the expression of miR-155 and IL-9 were significantly increased in BALF and Th9 cell of MRSA group, as well as the number of Th9 cells. miR-155 mimic upregulated IL-9 mRNA expression, IL-9 secretion and increased number of Th9 cells. On the contrary, miR-155 inhibitor inhibited IL-9 mRNA expression, IL-9 secretion and decreased number of Th9 cells. The dual luciferase assays demonstrated miR-155 can target binding to SIRT1 3'UTR. Moreover, overexpression of SIRT1 could reverse the effect of miR-155 mimic on IL-9 expression level, Th9 cell number and transcription factors PU.1 and IRF4 expression. In conclusion, miR-155 regulates Th9 differentiation in children with MRSA by targeting SIRT1.

Considering the critical roles of hsa-miR-155-5p participated in hematopoietic system, this study aims to clarify the possible pathogenesis of chronic myeloid leukemia (CML) induced by hsa-miR-155-5p.Three different strategies were employed, namely a network-based pipeline, a survival analysis and genetic screening method, and a simulation modeling approach, to assess the oncogenic role of hsa-miR-155-5p in CML. We identified new potential roles of hsa-miR-155-5p in CML, involving the BCR/ABL-mediated leukemogenesis through MAPK signaling. Several promising targets including E2F2, KRAS and FLI1 were screened as candidate diagnostic marker genes. The survival analysis revealed that mRNA expression of E2F2, KRAS and FLI1 was negatively correlated with hsa-miR-155-5p and these targets were significantly associated with poor overall survival. Furthermore, an overlap between CML-related genes and hsa-miR-155-5p target genes was revealed using competing endogenous RNA (ceRNA) networks analysis. Taken together, our results reveal the dynamic regulatory aspect of hsa-miR-155-5p as potential player in CML pathogenesis.

s Background/purpose Mycobacterium tuberculosis is a successful intracellular pathogen that uses multiple proteins to survive within macrophages, one of the most remarkable is the virulence factor EsxA. In this study, we evaluate the participation of EsxA in the miRNAs expression profile of human monocyte-derived macrophages (hMDM), to mapping out the contribution of this virulence factor in the miRNA profile and how these changes can influence and alter immune-related processes and pathways. Methods The cytotoxic effect of rEsxA on hMDM was evaluated by the neutral red assay. The evaluation of miRNA expression profile in infected and rEsxA-stimulated hMDM was done using TaqMan Low Density Assays, and in silico analyses was carried on to construct Protein–Protein Interaction network of miRNAs targets. Results miR-155 was the only miRNA upregulated consistently in hMDM infected with M. tuberculosis H37Rv or stimulated with rEsxA. In hMDM stimulated with rEsxA, we found 25 miRNA's dysregulated (8 up-regulated and 17 down-regulated). The most significant were the miR-155 and miR-622 that has been observed in the analysis carried out with two different endogenous controls (U6 snRNA and RNU44) for the normalization of expression analysis. This result suggests that rEsxA induces the deregulation of miRNAs that potentially target genes in key pathways for the infection control, like the MAPK signaling pathway, cytokines, and chemokine signaling pathways, and several connected pathways involved in mycobacterial uptake, vesicular traffic, and endosome maturation. Conclusion Higher expression levels of miR-155 suggest potential roles of these miRNA in EsxA-dependent immune subversion.

MicroRNA-155 (miRNA-155) is known to play an important role in the regulation of innate and adaptive immune responses in mammals. However, no information is available on the role of miRNA-155 in relation to type I interferon (IFN) responses in fish cells. In the present study, we found that the protein inhibitor of activated STAT 4a (PIAS4a) gene of fathead minnow (Pimephales promelas) was a target of miR-155, which was verified by the inhibitory activity of miR-155 in the expression of reporter gene harboring 3'UTR of PIAS4a of EPC cells. Furthermore, cells over-expressing miR-155 showed a significantly higher type I IFN response after polyinosinic-polycytidylic acid (poly I:C) stimulation, suggesting the targeting of PIAS4a in EPC cells by miR-155 can be a cause of the up-regulation of type I IFN, and miR-155 can act as an antiviral factor. However, as the targeting PIAS4a might not be the sole cause of the type I IFN up-regulation by miR-155, further studies on the uncovering of miR-155 target genes that are involved in type I IFN responses in fish are required.

The antimicrobial peptide APKGVQGPNG (named YD), a natural peptide originating from Bacillus amyloliquefaciens CBSYD1, exhibited excellent antibacterial and antioxidant properties in vitro. These characteristics are closely related to inflammatory responses which is the central trigger for liver fibrosis. However, the therapeutic effects of YD against hepatic fibrosis and the underlying mechanisms are rarely studied. In this study, we show that YD improved liver function and inhibited the progression of liver fibrosis by measuring the serum transaminase activity and the expression of α-smooth muscle actin and collagen I in carbon tetrachloride-induced mice. Then we found that YD inhibited the level of miR-155, which plays an important role in inflammation and liver fibrosis. Bioinformatics analysis and luciferase reporter assay indicate that Casp12 is a new target of miR-155. We demonstrate that YD significantly decreases the contents of inflammatory cytokines and suppresses the NF-κB signaling pathway. Further studies show that transfection of the miR-155 mimic in RAW264.7 cells partially reversed the YD-mediated CASP12 upregulation, the downregulated levels of inflammatory cytokines, and the inactivation of the NF-κB pathways. Collectively, our study indicates that YD reduces inflammation through the miR-155–Casp12–NF-κB axis during liver fibrosis and provides a promising therapeutic candidate for hepatic fibrosis., Graphical abstract The antimicrobial peptide YD is beneficial for alleviating liver fibrosis. The inhibitory role of YD in inflammatory responses is mediated by the miR-155–Casp12–NF-κB axis.Image 1

Noncoding RNAs (ncRNAs), including long noncoding RNAs and microRNAs, play an important role in coronary artery disease onset and progression. The ability of ncRNAs to simultaneously regulate many target genes allows them to modulate various key processes involved in atherosclerosis, including lipid metabolism, smooth muscle cell proliferation, autophagy, and foam cell formation. This review focuses on the therapeutic potential of the most important ncRNAs in coronary artery disease. Moreover, various other promising microRNAs and long noncoding RNAs that attract substantial scientific interest as potential therapeutic targets in coronary artery disease and merit further investigation are presented.

Our laboratory has investigated the role of an evolutionarily conserved RNA species called microRNAs (miRs) in regulation of anti-chlamydial protective immunity. MiRs including miR-155 expressed in specific immune effector cells are critical for antigen specific protective immunity and IFN-γ production. Using miR-155 deficient mice, and a murine pulmonary model for chlamydial infection, we report here 1) the effect of host miR-155 on bacterial burden, and 2) identify probable immune genes regulated by miR-155.

Atherosclerosis (AS) is a lipid-driven chronic inflammatory disease occurring at the arterial subendothelial space. Macrophages play a critical role in the initiation and development of AS. Herein, targeted codelivery of anti-miR 155 and anti-inflammatory baicalein is exploited to polarize macrophages toward M2 phenotype, inhibit inflammation and treat AS. The codelivery system consists of a carrier-free strategy (drug-delivering-drug, DDD), fabricated by loading anti-miR155 on baicalein nanocrystals, named as baicalein nanorods (BNRs), followed by sialic acid coating to target macrophages. The codelivery system, with a diameter of 150 nm, enables efficient intracellular delivery of anti-miR155 and polarizes M1 to M2, while markedly lowers the level of inflammatory factors in vitro and in vivo. In particular, intracellular fate assay reveals that the codelivery system allows for sustained drug release over time after internalization. Moreover, due to prolonged blood circulation and improved accumulation at the AS plaque, the codelivery system significantly alleviates AS in animal model by increasing the artery lumen diameter, reducing blood pressure, promoting M2 polarization, inhibiting secretion of inflammatory factors and decreasing blood lipids. Taken together, the codelivery could potentially be used to treat vascular inflammation., Graphical abstract Image 1Targeted codelivery of anti-miR 155 and anti-inflammatory drug, baicalein, by using a carrier-free strategy effectively promotes polarization of macrophages from M1 toward M2 in vitro and in vivo. The codelivery system has prolonged blood-circulation time and can accumulate in the plaque after intravenous injection. The platform is potent to combat vascular inflammation.

MicroRNAs (miRNAs) are a class of short noncoding RNAs that regulate the translation of target messenger RNA (mRNA) and consequently participate in a variety of biological processes at the posttranscriptional level. miR-155, encoded within a region known as the B cell integration cluster (BIC), plays multifunctional roles in shaping lymphocytes ranging from biological development to adaptive immunity. It has been revealed that miR-155 plays a key role in fine-tuning the regulation of lymphocyte subsets, including dendritic cells (DCs), macrophages, B cells, and CD8+ and CD4+ T cells. Antigen-specific CD4+ T lymphocytes are critical for host defense against pathogens and prevention of damage resulting from excessive inflammation. Over the past years, various studies have shown that miR-155 plays a critical role in CD4+ T cells function. Therefore, we summarize multiple target genes of miR-155 that regulate aspects of CD4+ T cells immunity, particularly CD4+ T cells differentiation, in this review. In addition, we also focus on the role of miR-155 in the regulation of immunological diseases, suggesting it as a potential disease biomarker and therapeutic target.

The immune-regulatory microRNA miR-155 is reduced in recurrent miscarriage, suggesting that miR-155 contributes to immune tolerance in pregnancy. Here we show miR-155 is induced in the uterine mucosa and draining lymph nodes (dLN) during the female immune response to male seminal fluid alloantigens. Mice with null mutation in miR-155 (miR-155-/-) exhibited a reduced CD4+ T cell response after mating, with a disproportionate loss of CD25+FOXP3+ Treg cells. miR-155 deficiency impaired expansion of both peripheral and thymic Treg cells, distinguished by neuropilin-1 (NRP1), and fewer Treg cells expressed Ki67 proliferation marker and suppressive function marker CTLA4. Altered Treg phenotype distribution in miR-155-/- mice was confirmed by t-distributed neighbor embedding (tSNE) analysis. Fewer dendritic cells (DCs) and macrophages trafficked to the dLN of miR-155-/- mice, associated with lower CCR7 on DCs, and reduced uterine Ccl19 expression, implicating compromised antigen presentation in the stunted Treg cell response. miR-155-/- mice exhibited elevated susceptibility to inflammation-induced fetal loss and fetal growth restriction compared with miR-155+/+ controls, but outcomes were restored by transfer of wild-type Tregs. Thus miR-155 is a key regulator of immune adaptation to pregnancy and is necessary for sufficient Tregs to achieve robust pregnancy tolerance and protect against fetal loss.

Background Nicotine, the major component of cigarette smoke, has been reported to promote pancreatic ductal adenocarcinoma (PDAC) growth and invasion. Deregulation of microRNA (miRNA) expression is found in many cancers, including PDAC. The effects of nicotine on miRNAs change in PDAC progression remain unknown. Methods The effects of cigarette smoking/nicotine exposure on PDAC cell lines and tissues were evaluated. Quantitative real-time PCR and in situ hybridization assays were used to determine miR-155-5p expression in human PDAC tissue and cell lines upon cigarette smoking/nicotine exposure. Bioinformatics, loss-of-function experiments, luciferase reporter assay were performed to validate Nedd4 family interacting protein 1 (NDFIP1) as a direct target of miR-155-5p. The potentials of systemic miR-155-5p inhibitor-based therapy in overcoming nicotine exposure were evaluated in tumor xenograft model. Results Nicotine promoted PDAC cells proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in a dose-response manner. MiR-155-5p was found to be highly expressed in PDAC cell lines and tissues upon cigarette smoking/nicotine exposure. Functional studies showed that miR-155-5p knockdown could override the enhancement of oncogenic activity due to nicotine exposure in vitro and in vivo by directly interacting with the 3′ untranslated regions (UTRs) of NDFIP1. Conclusions These data demonstrate that nicotine-regulated miR-155-5p/NDFIP1 promotes tumor progression and EMT of PDAC.

miR-155 is associated with the promotion of tumorigenesis. Herein, we indicate that abnormal miR-155 was negatively correlated with the expression of P21WAF1/Cip1. Our results suggest that miR-155 alters the transcriptome and inhibits the expression of H3F3A in liver cancer cells. Therefore, miR-155 inhibits the methylation modification of histone H3 on the 27th lysine. Notably, on the one hand, miR-155-dependent CTCF loops cause the CDK2 interacting with cyclin E in liver cancer cells; on the other hand, miR-155 promotes the phosphorylation modification of CDK2 by inhibiting H3F3A. Subsequently, miR-155 competitively blocks the binding of RNA polymerase II (RNA Pol II) to the P21WAF1/CIP1 promoter by increasing the phosphorylation of CDK2, inhibiting the transcription and translation of P21WAF1/CIP1. Strikingly, excessive P21WAF1/CIP1 abolishes the cancerous function of miR-155. In conclusion, miR-155 can play a positive role in the development of liver cancer and influence a series of gene expression through epigenetic regulation., Graphical Abstract, miR-155 promotes the phosphorylation modification of CDK2 and inhibits P21WAF1/CIP1 by inhibiting H3F3A. Therefore, miR-155 can play a positive role in the development of liver cancer and influence a series of gene expression through epigenetic regulation.

Silicosis is a fatal profession-related disease linked to long-term inhalation of silica. The present study aimed to determine whether meprin α, a master regulator of anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), is diminished by miR-155-5p in silicotic and control lung macrophages and fibroblasts upon activation. NR8383 macrophages, primary lung fibroblasts, and mouse embryonic fibroblasts were used to evaluate the expression and function of meprin α and miR-155-5p. In vitro meprin α manipulation was performed by recombinant mouse meprin α protein, actinonin (its inhibitor), and small interfering RNA knockdown. Macrophage and fibroblast activation was assessed by western blotting, real-time PCR, matrix deposition, and immunohistochemical staining. The roles of meprin α and miR-155-5p were also investigated in mice exposed to silica. We found that the meprin α level was stably repressed in silicotic rats. In vitro, silica decreased meprin α, and exogenous meprin α reduced activation of macrophages and fibroblasts induced by profibrotic factors. miR-155-5p negatively regulated Mep1a by binding to the 3′ untranslated region. Treatment with anti-miR-155-5p elevated meprin α, ameliorated macrophage and fibroblast activation, and attenuated lung fibrosis in mice induced by silica. The sustained repression of meprin α and beneficial effects of its rescue by inhibition of miR-155-5p during silicosis indicate that miR-155-5p/meprin α are two of the major regulators of silicosis.

Removal of dysfunctional mitochondria is essential step to maintain normal cell physiology, and selective autophagy in mitochondria, called mitophagy, plays a critical role in quality control of mitochondria. While in several diseases and aging, disturbed mitophagy has been observed. In stem cells, accumulation of damaged mitochondria can lead to deterioration of stem cell properties. Here, we focused on miR-155-5p (miR-155), one of the most prominent miRNAs in inflammatory and aged tissues, and found that miR-155 disturbed mitophagy in mesenchymal stem cells (MSCs). As a molecular mechanism of miR-155-mediated mitophagy suppression, we found that BCL2 associated athanogene 5 (BAG5) is a direct target of miR-155. Reduction of BAG5 resulted in destabilization of PTEN-induced kinase (PINK1) and consequently disrupted mitophagy. Our study suggests a novel mechanism connecting aging and aging-associated inflammation with mitochondrial dysfunction in stem cells through a miRNA-mediated mechanism.

Gastric cancer (GC) has a poor prognosis due to its relentless proliferation and metastasis. One of the reasons for this plight is the formidable angiogenesis ability of GC. Considering the important role of cancer exosomes as carriers and communicators in the tumor microenvironment, we explored the role of exosome-microRNA (miRNA) in regulating angiogenesis. Western blotting and quantitative real-time PCR were used to measure the protein and mRNA levels of the miRNA target gene. To detect changes in cellular biological functions, we pretreated human umbilical vein endothelial cells (HUVECs) that were severally cocultured with GC-derived exosomes and transfected them with different miRNAs directly. Also, we used the mouse xenograft model to verify the effect of miR-155 on angiogenesis of GC tissues in vivo. Our study confirmed that miR-155, as a driver of angiogenesis, encapsulated by exosomes from GC can enhance the generation of new vessels for GC in vitro through inhibiting the expression of Forkhead box O3 (FOXO3a) protein, which led to the progression of GC. Therefore, miR-155 is probable to become a potential biomarker for the detection of migration and angiogenesis of GC, and serves as a novel target for anti-angiogenesis therapy. Keywords: gastric cancer, GC, exosomes, miR-155, FOXO3a, angiogenesis

MiR-155 regulates the development of germinal-center and the generation of immunoglobulin class-switched plasma cells. However, whether miR-155 is involved in immune response in fish is still unclear. Here, CIK cells transfected with miR-155 overexpressed plasmid inhibited mRNA expression of mIg and Rag2 (P

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors and the Editor-in-Chief as the validity of the data cannot be guaranteed. The journal was initially contacted by the corresponding author to report that, when the authors verified post publication PTEN as their former target of miR-140-3p, they found that treatment with miR-140-3p or miR-155-5p antagomir increased PTEN protein levels in patient-derived chordoma cells without having a significant effect on the malignancy of the tumor cells. The journal further requested the author to provide more information about their post publication findings with regard to this article. However, the author was not able to fulfil this request.

High expression levels of miR-155 are involved in the pathogenesis of inflammatory bowel disease (IBD). We observed an increase in miR-155 in peripheral regulatory T (Treg) cells from IBD patients. Mice that specifically overexpress miR-155 in Foxp3+ Treg cells exhibit spontaneous autoimmunity and more severe dextran sulfate sodium (DSS)-induced intestinal injury. MiR-155 overexpression can lead to a lack of follicular Treg (Tfr) cells and central Treg (cTreg), whereas DSS treatment further depletes the Tfr cells. Furthermore, miR-155 can target the expression of CTLA-4 in cTreg and Tfr, directly inhibiting Tfr cell production and promoting enhanced germinal center (GC) B cell activation and autoantibody overproduction. This outcome may be the cause of severe intestinal injury in patients with autoimmune IBD.

Introduction and aims Interferon-α (IFN) has shown potential benefits in patients with hepatocellular carcinoma (HCC), and these effects may be mediated by inhibiting cancer cell proliferation. However, the detailed mechanisms underlying the anti-proliferative effects of IFN remain obscure. In this study, we evaluate the role of the novel oncogenic microRNA (miRNA) miR-155 in the anti-proliferative effects of pegylated interferon-α (PEG-IFN) on HCC cells. Methods The effects of PEG-IFN on HepG2 cell proliferation, migration and invasion were determined using the MTT assay, flow cytometry analysis and the Transwell assay, respectively. Reverse transcription quantitative polymerase chain reaction was used to analyze miR-155 expression. The levels of proteins involved in Wnt/β-catenin signal transduction were determined by western blot analysis and immunofluorescence staining. Mimics of miR-155 were transfected into HepG2 cells to assess the role of miR-155 in the PEG-IFN-induced anti-proliferative effect. Results PEG-IFN significantly inhibited the proliferation, migration and invasion of HepG2 cells in a dose-dependent manner by inhibiting cell cycle progression. In parallel with reduced cell proliferation, migration and invasion, miR-155 was efficiently downregulated by PEG-IFN in a dose-dependent manner. Moreover, the transfection of miR-155 decreased the inhibitory effect of PEG-IFN on HepG2cell proliferation, migration and invasion, as well as the downregulation of proteins in the Wnt/β-catenin pathway. Conclusions The anti-proliferative effects of PEG-IFN on HCC are at least partially attributable to the downregulation of miR-155.

Background Immunotherapy is a promising method for the treatment of hepatocellular carcinoma (HCC), in which CD8+T cells play a key role. The influence of long noncoding RNA (lncRNA) nuclear-enriched autosomal transcript 1(NEAT1) on the antitumor activity of CD8+T cells was clarified in this study. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from HCC patients, and the expressions of NEAT1 and Tim-3 were determined by qRT-PCR and western blot, respectively. CD8+T cell apoptosis and cell percentage were analyzed via flow cytometry. The cytolysis activity of CD8+T cells against HCC cells was examined. RNA immunoprecipitation (RIP) and RNA pull-down assay were performed to explore the interaction between NEAT1 and miR-155. Results NEAT1 and Tim-3 were up-regulated in the PBMCs of patients with HCC (n = 20) compared with healthy subjects (n = 20). Down-regulation of NEAT1 restrained CD8+T cell apoptosis and enhanced the cytolysis activity, while interference of miR-155 showed the opposite effects by up-regulating Tim-3. Binding and interaction between NEAT1 and miR-155 were validated in CD8+T cells. Down-regulation of NEAT1 restrained CD8+T cell apoptosis and enhanced the cytolysis activity through the miR-155/Tim-3 pathway. Repression of NEAT1 suppressed tumor growth in HCC mice. Conclusion Via modulating the miR-155/Tim-3 pathway, repression of NEAT1 restrained CD8+T cell apoptosis and enhanced the cytolysis activity against HCC, implying an effective target for improving the outcome of immunotherapy.

Methamphetamine (METH) is a highly addictive stimulant and METH exposure can induce a series of neuroinflammatory effects. Peli1 is a novel and important E3 ubiquitin-protein ligase contributing to neuroinflammation; targeting Peli1 may thus provide promising therapeutic strategies for neuroinflammation. In addition to the classic MyD88-dependent or MyD88-independent pathways, miRNAs may also be involved in Peli1 modulation. In the present study, two novel miRNAs, miR-142a-3p and miR-155-5p, that were predicted to target Peli1 using bioinformatics were chosen, and their unique roles in METH-induced neuroinflammation via regulating Peli1 expression were identified. Our results showed that miR-142a-3p was significantly reduced in METH-induced neuroinflammation and was negatively associated with Peli1 expression both in BV2 cells and in the brain of mouse. MiR-155-5p was significantly reduced by METH in vitro but increased in vivo. A luciferase reporter assay was performed to reveal that miR-142a-3p and miR-155-5p bound specifically to Peli1, an effect that was completely abolished by the Peli1 binding site mutation. Reciprocally, the overexpression of miR-142a-3p and miR-155-5p could directly suppress Peli1 expression and could protect against the inflammatory effects of METH treatment partially through activating p38 MAPK and NF-κB inflammatory pathways. In conclusion, the present study reveals a novel signaling pathway, the miR-142a-3p/miR-155-5p/Peli1 axis in METH-mediated neuroinflammation, and this pathway could be a potential therapeutic target for METH-mediated neurotoxicity.

Background Type 1 diabetes (T1D) is a multifactorial disease identified by a deficiency in the production of insulin. MicroRNAs (miRNAs) are identified as important epigenetic regulators in T1D. Many studies highlight the differential expression of these small non-coding molecules in the pathogenesis of T1D. Aim of the study In the present study, the expression pattern of miR-21, miR-155 and miR-338 were analyzed in the peripheral blood mononuclear cells (PBMCs) of T1D patients compared to healthy controls. Methods The expression levels of miR-21, miR-155 and miR-338 were measured in the PBMCs of 30 T1D patients and 11 healthy controls by real time PCR method. The final results were statistically analyzed and ROC curves were created for miRNAs with significant differential expression. Results Both miR-155 (p value: 0.021) and miR-21 (p value: 0.05) were upregulated in the PBMCs of T1D patients compared to healthy controls. There was no significant difference in the expression level of miR-338 between patients and controls. Furthermore, ROC curve analysis was performed for miR-21 (AUC: 0.65) and miR-155 (AUC: 0.73) which suggests the potential role of miR-155 as a biomarker in T1D patients. Using integrative computational analysis, a number of dysregulated miR155-mRNA and miR21-mRNA interactions were also suggested. Conclusion Our findings suggest the significant association between the expression levels of miR-21 and miR-155 with T1D. In addition, miR-155 (AUC: 0.73) could be considered as a possible biomarker to track disease in T1D patients.

Macrophages play a major role in the control and elimination of invading Mycobacterium tuberculosis (Mtb). Emerging studies have demonstrated that long non-coding RNAs (lncRNAs) are involved in resident macrophages in Mtb. However, the regulatory mechanism between lncRNAs and macrophages in tuberculosis (TB) remains unclear. In this study, we sought to investigate the effect of Mtb-associated lncRNA PCED1B-AS1 on macrophage apoptosis and autophagy. Our study first evaluated PCED1B-AS1 expression in the CD14+ monocytes from patients with active tuberculosis and from healthy individuals. It was found that PCED1B-AS1 expression was down-regulated in patients with active tuberculosis, accompanied by significant attenuated monocyte apoptosis and enhanced autophagy. In vitro, knockdown of PCED1B-AS1 reduced macrophage apoptosis and promoted autophagy. PCED1B-AS1 serves as an endogenous sponge to block miR-155 expression in macrophages by directly binding to miR-155. Furthermore, we demonstrated that overexpression of FOXO3/Rheb, target genes of miR-155, reversed the PCED1B-AS1-mediated effects on macrophage apoptosis and autophagy. Altogether, our data indicate that PCED1B-AS1 modulates macrophage apoptosis and autophagy by targeting the miR-155 axis in active TB.

Background Atherosclerosis is a chronic inflammatory disease. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) and microRNAs have emerged as critical regulators of atherosclerosis; however, whether they have crosstalk on this issue remains elusive. Here, we investigated the potential associations between lncRNA-MALAT1 and miR-155 on the regulation of atherosclerosis. Methods Quantitative real-time PCR was employed to assess the expression of MALAT1, IL-6 and IL-8. ELISA was performed to measure the secretion of IL-6 and IL-8. MTT assay was used to determine the proliferation of Human Coronary Artery Endothelial Cells (HCAECs). Flow cytometry was used to measure the cell apoptosis. Western blot was used to assess the expression of apoptosis-related proteins and the phosphorylation of STAT1 and STAT3. Results We found that the pro-inflammatory cytokine release and the apoptosis of HCAECs were elevated upon ox-LDL treatment, while MALAT1 expression was also up regulated. Knocking down of MALAT1 boosted ox-LDL-induced cytokine release and apoptosis of HCAECs. The binding site of miR-155 in MALAT1 sequence was confirmed by dual luciferase assay. Furthermore, miR-155 inhibition significantly repressed ox-LDL mediated inflammation and apoptosis of HCAECs via SOCS1. At last, we found that MALAT1 could suppress the inflammatory cytokine release and cell apoptosis via sponging miR-155 to increase SOCS1 level, which in turn restrained JAK-STAT pathway. Conclusion In summary, this study revealed the mechanisms by which MALAT1 worked as a putative atherosclerosis suppressor via miR-155 and SOCS1. Therefore, modulation of MALAT1/miR-155/SOCS1 axis might alleviate the inflammation persisted in atherosclerosis.

MiR-155 can inhibit the formation of atherosclerosis by interfering with the transformation of macrophages into foam cells that plays a critical role in the pathogenesis of atherosclerosis, but the precise mechanisms of miR-155 are still unknown. Herein, we observed that mRNA and protein expression levels of CEH were significantly upregulated in a dose- and time-dependent manner by transfected with miR-155 mimics in THP-1 macrophages. Further studies showed that overexpression of miR-155 can significantly inhibit foam cells formation, reduce intracellular CE accumulation and enhance the efflux of FC and cholesterol, result in a decrease of intracellular lipid accumulation; while this effect was significantly reversed by siCEH. Meanwhile, we found that Tim-3 is associated with miR-155-mediated CEH expression in THP-1 macrophage-derived foam cells. Overexpression of Tim-3 can attenuate miR-155-mediated CEH induction. Taken together, our findings demonstrated that miR-155 can inhibit the transformation of macrophages into foam cells by enhancing CEH signaling pathway in macrophages, this effect is likely to be achieved by inhibiting the expression of Tim-3.

Depression is a mental illness comorbid risk factor for glucose intolerance worldwide. Chaihu-shugan san, a ‘Shu-Gan’ formula in traditional Chinese medicine, is clinically used in the treatment of depression. The aim of this study was to investigate whether Chaihu-shugan san improved glucose tolerance with its antidepressant activity in rat model of depression and explore the mechanisms underlying its action on liver-brain inflammation axis. After 6 weeks of chronic unpredictable mild stress (CUMS) procedure, male Wistar rats were given Chaihu-shugan san water extract (925 and 1850 mg/kg) by gavage for the next 6 consecutive weeks. Sucrose consumption test was used to assess animal depressive-like behaviors. Oral glucose tolerance test (OGTT) was employed to define the status of glucose tolerance in rats. Serum alanine aminotransferase (ALT) and interleukin-1 beta (IL-1β) were measured by commercial kits, respectively. Western blot was used to detect the expression of key proteins in inflammatory signaling cascades including toll-like receptor 4 (TLR4), myeloid differentiation protein 88 (MyD88), nuclear factor-kappa B (NF-κB), Nod-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), cysteinyl aspartate specific proteinase-1 (Caspase-1) and IL-1β, as well as insulin signaling in liver and prefrontal cortex of rats. Immunohistochemical staining or immunofluorescence staining of NF-κB, and nuclear/cytoplasmic ratio of NF-κB by Western blot were used to describe its nuclear entry in liver and prefrontal cortex of rats. RT-qPCR and Western blot analysis, as well as microRNA-155 (miR-155) mimic or inhibitor transfection were used to explore possible association of MyD88 and miR-155. In this study, Chaihu-shugan san increased sucrose consumption and reduced serum glucose levels in CUMS rats, showing its antidepressant activity with glucose tolerance improvement. Chaihu-shugan san reduced serum levels of ALT and IL-1β in this animal model. Furthermore, this formula inhibited hepatic and prefrontal cortical inflammatory response by suppressing TLR4/MyD88/NF-κB pathway and NLRP3 inflammasome activation, and improved insulin signaling in CUMS rats. More importantly, Chaihu-shugan san up-regulated miR-155 expression in liver and prefrontal cortex of CUMS rats. These results provide direct evidence that Chaihushugan San can ameliorate depressive-like behaviors by inhibiting liver-brain inflammation axis.

Cervical cancer is one of the most common malignant tumors and the leading cause of cancer-related mortality in women. Persistent cervical infection by high-risk human papillomavirus (hrHPV) is related to cervical cancer. MicroRNAs could regulate autophagy caused by viral infection. The aim of the present study was to investigate the regulation of autophagy by miR-155-5p in cervical cancer. In HPV+ human cervical lesion tissues, miR-155-5p expression was found to be markedly decreased. Compared to C33A cancer cells (HPV-), the miR-155-5p expression was significantly lower in Siha and HeLa cells (HPV+), which are both hrHPV positive. The level of autophagy was higher in C33A cells than in Siha and HeLa cells. In addition, in C33A, Siha and HeLa cervical cancer cells, miR-155-5p overexpression promoted autophagy, whereas miR-155-5p downregulation had the opposite effects. Furthermore, miR-155-5p downregulation suppressed LC3 and promoted P62 protein expression in C33A cells through promoting the PDK1/mTOR pathway, whereas miR-155-5p overexpression recovered LC3 and suppressed P62 protein expression by suppressing PDK1/mTOR signaling. Taken together, our results indicate the importance of miR-155-5p in cervical cancer cells and suggest a novel mechanism of hrHPV in promoting cervical lesions.

Osteolysis is a major complication of total joint arthroplasty, and tanshinone IIA (TAN) can attenuate the disorder. The current study aimed to verify the anti-osteolysis potential of TAN and explore the associated mechanism. Osteolysis was induced in mice and in human hFoB 1.19 osteoblasts using ultrahigh molecular weight polyethylene (UHMWPE). The effects of TAN on joint tissue structure and inflammation and osteoblast viability, apoptosis, and inflammation were detected. The miR-155-5p level was modulated in osteoblasts to explain its role in the function of TAN. TAN attenuated UHMWPE-induced tissue destruction and suppressed inflammation. In the in vitro system, TAN increased cell viability, reduced cell apoptosis, and inhibited proinflammatory cytokines. TAN upregulated miR-155-5p and osteoprotegerin (OPG) and downregulated FOXO3 and RANKL. Once miR-155-5p was inhibited, the effects of TAN were counteracted. TAN exerted its anti-osteolysis effects by inducing miR-155-5p, which inhibited FOXO3 and balanced the levels of OPG and RANKL.

Background Increasing evidences have proved that long noncoding RNAs (lncRNAs) regulate the occurrence of bladder cancer (BC) and participate in various pathophysiology processes. However, little is unknown about the role of lncRNAs in drug resistance of BC cells. In this study, we explored the role of non-coding RNA activated by DNA damage (NORAD) in the gemcitabine (GEM) resistant of BC cells and explored its potential mechanism. Methods Real-time quantitative PCR (RT-qPCR) was used to detect the expression of NORAD and miR-155-5p of BC cells. Cell counting kit-8 (CCK-8) and Western blot were used to detect cell inhibition rate and the expression of WEE1 G2 checkpoint kinase (WEE1), P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). Flow cytometry detected cell cycle and apoptosis. Dual luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay were used to confirm the targeting relationship between miR-155-5p, NORAD and WEE1. The xenograft model was used to observe the function of NORAD in vivo. immunohistochemistry (IHC) assay was used to detect the expression of WEE1, caspase-3 and Ki67 in tumor tissues. Results NORAD highly expressed in GEM-resistant BC cell lines. Knockdown of NORAD significantly inhibited the proliferation of T24/GEM cells, the expression of drug-resistant proteins P-gp and MRP1, inhibit the G0/G1 phase of cells, and induce cell apoptosis. Knockdown of NORAD reversed the promotion effect of miR-155-5p on WEE1 expression and promoted the sensitivity of T24/GEM cells to GEM. In vivo, knockdown of NORAD inhibited the tumor growth, and enhanced the GEM-sensitivity in mice. Conclusion These data highlight the potential of NORAD acts as a therapeutic target for BC GEM resistance. It revealed the vital roles of NORAD/miR-155-5p/WEE1 axis in GEM resistant BC cells, providing a novel therapeutic strategy for BC.

Introduction: Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphomas presents with a broad spectrum of clinical and histopathologic manifestations. Diagnosis is often delayed, especially at the early stages. Clinicopathologic correlation and integration of molecular data is essential for a timely diagnosis and treatment. The use of microRNAs as biomarkers in biopsies and/or biological fluids has gained great interest over the last years. The aim of the present study was to analyze the expression levels of microRNAs (mir)-146a and -155 in the plasma of MF patients and healthy volunteers and to detect the presence of single nucleotide polymorphisms (SNPs) in their genes. Patients and methods: The appropriate sample size for statistical power equal to 0.94 (1–β=94%) and significance level at 0.05 (α=5%) was determined by a pilot study, using G.Power 3.1.9.2. The optimal sample size was calculated at n=82, with a ratio of MF patients/healthy individuals equal to 1:1. All samples were derived from consenting individuals. The mirs’ plasma expression was evaluated with real-time quantitative reverse transcription PCR, and the relative quantity was calculated by the 2–ΔCt method using cel-mir-39 as reference gene. In a subset of patients, the promoter region and/or the pre-microRNA genomic region of these mirs were scanned for the presence of SNPs in DNA extracted from white blood cells, by Sanger sequencing. Statistical analysis was performed with the statistical package IBM SPSS 25. Results: Plasma levels of mir-146a and mir-155 were significantly higher in patients with MF as compared to healthy volunteers (p=0.001 and p=0.028 respectively). Moreover, plasma levels were higher in patients with early MF vs healthy individuals (p=0.001 and p Discussion: The presence of SNPs regulating mirs’ function may need to be evaluated in larger cohorts, while the detection of increased mir-146a and mir-155 plasma levels in MF patients is an important finding in the attempt to establish putative non-invasive biomarkers for prompt diagnosis, prognosis, and adequate therapy of these patients.

Mastiha is a natural nutritional supplement with known anti-inflammatory properties. Non-alcoholic fatty liver disease (NAFLD) and Inflammatory bowel disease (IBD) are immune mediated inflammatory diseases that share common pathophysiological features. Mastiha has shown beneficial effects in both diseases. MicroRNAs have emerged as key regulators of inflammation and their modulation by phytochemicals have been extensively studied over the last years. Therefore, the aim of this study was to investigate whether a common route exists in the anti-inflammatory activity of Mastiha, specifically through the regulation of miRNA levels. Plasma miR-16, miR-21 and miR-155 were measured by Real-Time PCR before and after two double blinded and placebo-controlled randomized clinical trials with Mastiha. In IBD and particularly in ulcerative colitis patients in relapse, miR-155 increased in the placebo group (p = 0.054) whereas this increase was prevented by Mastiha. The mean changes were different in the two groups even after adjusting for age, sex and BMI (p = 0.024 for IBD and p = 0.042). Although the results were not so prominent in NAFLD, miR-155 displayed a downward trend in the placebo group (p = 0.054) whereas the levels did not changed significantly in the Mastiha group in patients with less advanced fibrosis. Our results propose a regulatory role for Mastiha in circulating levels of miR-155, a critical player in T helper-17 (Th17) differentiation and function.

Background Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that results in neurological deficits in patients leading to disabilities which are evaluated on a scale known as the Expanded Disability Status Scale (EDSS). The most prevalent subtype of the disease is Relapsing-Remitting Multiple sclerosis (RRMS). One of the key players in MS pathogenesis is CD8+ T cells present in abundance in MS lesions expressing surface receptors, intracellular adhesion molecule (ICAM1) and integrin Subunit Beta 2 (ITGB2). These proteins are crucial for migration through the blood-brain barrier (BBB) and secondary stimulatory signal, along with the cytotoxic proteins perforin and granzymeB that attack oligodendrocytes. MicroRNAs (miRNAs) are small non-coding RNAs that play a substantial regulatory role in various disease pathogeneses through post-transcriptional modifications, and miR-155 shows potential for its use as a biomarker of the disease. The study aims at investigating the expression of miR-155, ICAM1, ITGB2, perforin and GranzymeB in CD8+ T cells of RRMS patients receiving different treatment regimens and how these genes correlate with patients' EDSS and miR-155 expression. Methods Gene expression of miR-155, ICAM1, ITGB2, perforin and granzymeB was evaluated using RT-qPCR in CD8+ T cells isolated from blood samples of RRMS patients and compared to healthy controls. Results Results showed downregulation of miR-155 and upregulation of surface receptors and cytotoxic proteins in CD8+T cells with significant correlation with each other and patients' EDSS. Conclusion This study helps pave the road for the discussed genes for their use as potential biomarkers of disease disability and future investigations on their regulatory roles in disease pathogenesis.

Cystic echinococcosis, an important zoonotic disease, is caused by Echinococcus granulosus. MicroRNAs are a small group of single-stranded noncoding RNAs, which play an effective role in biological processes. This study aimed at comparing the expression levels of miR-146a and miR-155 in the plasma of patients with hydatidosis and healthy individuals. A group of 20 patients with hydatid cyst formed a study group and 20 healthy individuals with no known chronic diseases formed a control group. Plasma samples were collected from hydatidosis patients as well as sex- and age-matched healthy volunteers. After that, RNA extraction and cDNA synthesis were done and the expression levels of miR-146a and miR-155 were determined by quantitative real-time polymerase chain reaction (PCR) for both groups. The results indicated that the level of miR-146a increased in all patients with hydatidosis compared to the control group. Also, the level of miR-155 increased in all hydatidosis patients, but no correlation was observed in the level of miR-155 between the two groups. The results also revealed that miR-146a and miR-155 upregulation in the plasma leads to the development of novel biomarkers for echinococcosis. One of the reasons for the increase of miRNAs in hydatidosis may be their role in modulating the immune system. These miRNAs are likely to be considered as one of the most important biomarkers in determining the severity of hydatidosis.

MicroRNAs (miRNAs) play important roles in the tumorigenesis of glioma. Recent studies showed that miR-155 expression was increased in types of cancer, including glioma. However, the underlying mechanism of miR-155 on glioma is still unclear. In the present study, expression of miR-155 and caudal-type homeobox 1 (CDX1) was determined in glioma tissues by qRT-PCR, and the regulatory axis was further studied in glioma cells. We showed that miR-155 expression was significantly increased in glioma tissues while CDX1 expression was decreased. Correlation analysis revealed that miR-155 was negatively correlated with CDX1 expression in glioma tissues. Moreover, Kaplan-Meier analysis indicated that patients with high miR-155 expression had a poor overall survival. In addition, our results showed that the translation of CDX1 expression could be suppressed by miR-155 mimics. And miR-155 mimics promoted glioma cell proliferation could be reversed by CDX1 overexpression. In vivo assay, we showed that miR-155 overexpression promoted the progress of tumor formation. Therefore, we suggested that miR-155 might promote glioma cell growth partially by targeting CDX1, which provided a novel therapeutic strategy for glioma patients.

During the last decades, basic and translational research has enabled great improvements in the clinical management of cancer. However, scarcity of complete remission and many drug-induced toxicities are still a major problem in the clinics. Recently, microRNAs (miRNAs) have emerged as promising therapeutic targets due to their involvement in cancer development and progression. Their extraordinary regulatory potential, which enables regulation of entire signalling networks within the cells, makes them an interesting tool for the development of cancer therapeutics. In this review we will focus on miRNAs with experimentally proven therapeutic potential, and discuss recent advances in the technical development and clinical evaluation of miRNA-based therapeutic agents.

MicroRNAs (miRNAs) are involved in regulation of epithelial-mesenchymal transition (EMT) during breast cancer progression. The purpose of this study was to analyze the clinicopathologic significance of expression of EMT-related miRNAs, miR-9 and miR-155, in triple-negative breast cancers (TNBCs). We analyzed relative expression levels of miR-9 and miR-155 in 190 surgically resected TNBC specimens using quantitative real-time polymerase chain reaction. Then we analyzed the relationship between these miRNA expression levels and EMT marker expression (vimentin, smooth muscle actin [SMA], osteonectin, N-cadherin, E-cadherin, CD146, and ZEB1) assessed by immunohistochemistry. We also evaluated the prognostic significance of these miRNA expression levels. While miR-9 expression level showed a positive correlation with pT category, miR-155 expression level did not correlate with any clinicopathologic features of TNBCs. In relation to EMT phenotype, miR-9 expression was not associated with EMT marker expression except for SMA. However, miR-155 expression level correlated inversely with the expression of several EMT markers including SMA, osteonectin, and CD146. We observed that both miR-9 and miR-155 could be prognostic markers in TNBC in opposite ways; high level of miR-9 expression showed significant association with poor disease-free survival and distant metastasis-free survival (DMFS) in TNBC, while high level of miR-155 expression was associated with better DMFS. Our study suggests that expression levels of both miR-9 and miR-155 can serve as candidates for prognostic biomarkers in TNBCs.

Changes in the neuro-immune balance play a major role in the induction and maintenance of neuropathic pain. We recently reported pathophysiologically relevant alterations in skin and sural nerve cytokine expression in peripheral neuropathies of different etiologies. Immune processes and cytokine expression are under tight control of microRNAs (miRNAs). To identify potential master switches in the neuro-immune balance, we aimed at characterizing inflammation-regulating miRNA profiles in patients with peripheral neuropathies. In an unselected patient cohort with polyneuropathies of different etiologies seen at our neuromuscular center between 2014 and 2015, we determined the systemic and local relative expression of miR-21-5p, miR-146a, and miR-155. In white blood cells we found higher miR-21 (p

Marek’s disease virus type 1 (MDV-1) is a representative oncogenic Alpha herpesvirus that causes an immunosuppressive and neoplastic lymphoproliferative avian disease, namely Marek’s disease (MD). The rapid-onset T-cell lymphoma in chickens induced by MDV-1 has been historically regarded as an ideal natural model for herpesvirus-related cancer research. As a viral analog of cellular miR-155, the MDV-1-encoded miR-M4-5p has been shown to be crucial for the virally-induced MD tumorigenesis. Our previous studies demonstrated that miR-M4-5p induces an over-expression of oncogene c-Myc by targeting LTBP1 and suppressing the TGF-β signaling pathway during MDV-1 infection. We have now further identified the chicken heterogeneous nuclear ribonucleoprotein AB (hnRNPAB) as a new cellular biological target for miR-M4-5p. Suppression of hnRNPAB expression mediated by miR-M4-5p promotes the proliferation, but not the apoptosis, of both primary chicken embryo fibroblasts (CEFs) and transformed chicken fibroblast DF-1 cell line. HnRNPAB is a member of the hnRNP family of proteins that play important roles in normal biological processes as well as cancer development. Our data suggests that the recognition and down-regulation of hnRNPAB by miR-M4-5p may be one of the important strategies for MDV-1 to trigger the development of MD lymphomas.

MicroRNAs (miRNAs) play an important role in regulating immune system function by mRNA destabilisation or inhibition of translation. Recently, miR-155 was detected to be significantly up-regulated in colonic tissues of patients with active UC. However, it is unknown whether miR-155 is involved in the pathogenesis of UC and how it influences immune response in dextran sulfate sodium (DSS)-induced colitis mice. Here, we investigated the role of miR-155 in UC. Firstly, through bioinformatics analysis and luciferase report assay, we found Jarid2 was a direct target of miR-155; then, we carried out in situ hybridization, immunofluorescence and flow cytometry, and revealed that miR-155 levels were increased, Jarid2 levels were decreased and the frequency of Th17 cells was elevated in DSS-induced mice; we also used lentiviral vector to deliver miR-155 inhibition sequences to silence miR-155 that was effectively taken up by epithelial cells. MiR-155 inhibition attenuated DSS-induced colonic damage and inhibited Th17 cells differentiation. This study suggests that miR-155 plays a host-damaging role during DSS-induced colitis mice and induces Th17 differentiation by targeting Jarid2.

Allergen-induced airway inflammation is characterized by Th2-mediated eosinophilic inflammation in the lungs. While the molecular mechanisms leading to this abnormal Th2 response remain unclear. Recent studies have demonstrated that MicroRNAs (miRNAs) modulate allergic airway inflammation. In this study, the role of miRNAs in allergic asthma pathogenesis was examined. Differentially expressed miRNAs were identified via miRNA microarray, with miR-155 being among the most highly expressed in asthma mice lungs. Examination of miR-155 overexpression resulted in enhanced inflammation and mucus hypersecretion in the lungs of allergen-challenged mice compared with control animals. Furthermore, CTLA-4, an important negative regulator of T-cell activation, was identified as a direct miR-155 target. Moreover, miR-155 overexpression in CD4+ T cells resulted in decreased CTLA-4 levels and a subsequent increased proliferative response. Collectively, these findings suggest that miR-155 might contribute to allergic asthma by increasing the proliferative response of Th cells via CTLA-4 downregulation and thus may be a potential therapeutic target for allergic asthma.

In the cancer microenvironment, extracellular communication allows various types of cells to coordinate and execute biological functions. Emerging evidence indicates that exosomes, as mediators of cell communication, are involved in tumor progression. Little is known, however, about the mechanism by which exosomal miRNAs regulate inflammatory infiltration in arsenite-induced liver cancer. The present research aimed to determine if miRNAs secreted from arsenite-transformed human hepatic epithelial (L-02) cells are transferred into normal L-02 and THLE-3 cells, which are functionally active in the recipient cells. The results show that the exosomes from arsenite-transformed L-02 cells enhance miR-155 expression and the pro-inflammatory properties of normal L-02 and THLE-3 cells. Transformed cells transfer miR-155 into normal L-02 cells via exosomes. The inhibition of NF-κB by siRNA and inhibitor, which reduces miR-155 levels in exosomes derived from transformed L-02 cells, blocks inflammation. Arsenite-transformed cells secrete exosomes to enhance inflammation, but the inhibition of the synthesis of exosomes fails to stimulate inflammation. miR-155 is involved in exosome-mediated intercellular communication between neoplastic and normal liver cells. In addition, miR-155, IL-6, and IL-8 were over-expressed in the serum of arsenite exposure group. And there was a positive correlation between miR-155 and IL-6 or IL-8 levels. Further, exosomal miR-155 was up-regulated in the serum of arsenite exposure group. Thus, these results show that exosomes derived from transformed L-02 cells transfer miR-155 to surrounding cells, which induces pro-inflammatory activity of normal liver cells. The findings support the concept that exosomal miRNAs are involved in cell-cell communication during carcinogenesis induced by environmental chemicals.

Background MicroRNAs (miRNAs) are integral for maintaining immune homeostasis and self-tolerance. The influence of miRNAs on T-cell differentiation and plasticity are critical in the development of chronic rejection of transplanted hearts. In this study, we sought to determine whether the knockout of miR-155 affects the development of cardiac allograft vasculopathy (CAV) in a murine model. Methods miRNA microarray and quantitative polymerase chain reaction (qPCR) analyses were performed for allograft neointimal lesion samples in chronic rejection. A model of heterotopic murine heart transplantation (bm12 to miR-155 +/+ or miR-155 –/– mice) was then used to analyze allograft survival, histology, mRNA expression and T-cell sub-populations in spleens. The accelerated experiments were performed by intraperitoneal injection of either recombinant interleukin-17A or phosphate-buffered saline (PBS) after heart transplantation. For the competitive transfer experiments, CD4 + splenocytes from wild-type (WT) or miR-155 –/– mice were mixed and injected into Rag1 –/– mice, and cardiac transplantation was performed after 24 hours. The differentiation of T-helper subsets (Th1/Th17/iTreg) was investigated in vitro. Results miR-155 –/– mice showed resistance to cardiac rejection along with weakened T-cell–mediated inflammation, especially for Th17 cells. Recombinant IL-17A could restore this relieved injury. The competitive experiments implied that miR-155 plays a vital role in the stability of the Th17 phenotype. In vitro, we also demonstrated that miR-155 –/– mice exhibit a defect in Th17 differentiation. Conclusions miR-155 regulates Th1/Th17-related inflammation in chronic cardiac rejection and may be a potential therapeutic target to attenuate cardiac allograft rejection. Despite advancements in immunosuppressive therapy, the immunologic mechanisms responsible for allograft rejection remain an important issue for both clinicians and researchers. Allograft rejection is a T-cell–dependent phenomenon and is critically dependent on inflammation mediated by CD4 + Th subsets, including Th1, Th2, Th17, Th9 and regulatory T (Treg) cells.

Chronic immune activation and systemic inflammation during HIV infection despite effective antiretroviral therapy (ART) is associate with non-AIDS co-morbidities in people living with HIV (PLWH). Previous studies have shown that plasma levels of extracellular vesicles (EVs) may be used as immune activation or inflammatory biomarkers of HIV disease progression. Several studies have focused on microRNA and mitochondrial DNA (mtDNA) levels reached concomitantly in immune cells and EVs. We hypothesized that large and small EVs could contain different amounts of microRNA and mtDNA and that could reflect immune activation associated with elevated CD8 T cell count or low CD4/CD8 ratio in PLWH receiving ART. Plasma EVs obtained from PLWH and uninfected control were sized using dynamic light scattering and quantified using flow cytometry. Expression of mature miR-92, miR-155, miR-223 and mtDNA was measured by qRT-PCR. Positive correlation have been observed between CD8+ T cell count and large EV abundance, AChE activity in small EVs and negative correlation with miR-155 levels in small EVs. CD4/CD8 ratio was positively correlated with large EVs abundance and negatively with AChE activity in small EVs and PMN-associated copies of miR-92. MicroRNA-155 level in small EVs were positively correlated with monocyte counts. MiR-155 and mtDNA contents of large EVs were increased more than miR-92 and miR-223 contents in small EVs. A positive correlation was observed between large EVs mtDNA content and CD4 T cell count. These findings suggest that profiling the microRNA and mtDNA contents of EV might provide new functional biomarkers of immune activation and inflammation. Funding Statement: This study was funded through Canadian Institutes of Health Research (CIHR) grants MOP 188726; MOP-267056 (HIV/AIDS initiative) to C.G., MOP-03230 to J.P.R. and to C.T. for the cohort establishment and CIHR Foundation Grant FDN-143218 to M.A. for the studentship awarded to W.W.B., as well as by the Fonds de recherche du Quebec – Sante (FRQ-S) AIDS and infectious diseases network. C.T. is an FRQ-S scholar and holder of the Pfizer/Universite de Montreal chair on HIV translational Research. J-P.R. holds the Louis Lowenstein chair in Hematology & Oncology at McGill University. M-A.J. holds a CIHR Canada Research Chair tier 2 in Immuno-Virology. The infrastructure of the Centre de recherche du CHU de Quebec – Universite Laval is supportes by the FRQ-S. Declaration of Interests: The authors declare that no competing interests exist. Ethics Approval Statement: This study received approval from the ethics review boards of Centre de recherche du CHU de Quebec, Quebec, Canada and the McGill University Health Centre, Montreal, Quebec, Canada. All subjects were anonymous volunteers and provided written informed consent to participate in the study.

Rat hippocampal neurons were isolated and divided into Normal, oxygen glucose deprivation/reoxygenation (OGD/R), OGD/R + DEX, OGD/R + NC mimic, OGD/R + miR-155 mimic and OGD/R + DEX + miR-155 mimic groups. In OGD/R group, LDH, ROS and MDA levels and apoptosis rate was increased, with up-regulations of miR-155, Cyt c and Bax/Bcl-2 ratio, but decreases of SOD, GSH-Px and MMP levels, as well as down-regulations of p-ERK1/2/ERK1/2. As compared to the OGD/R group, parameters above in the OGD/R + DEX group were ameliorated evidently, while OGD/R + miR-155 mimic group manifested the opposite changes. Besides, miR-155 mimic could abolish the protective effect of DEX on the hippocampal neurons under OGD/R. DEX, via down-regulating the expression of miR-155, could activate the ERK1/2 pathway, thereby mitigating the apoptosis and oxidative stress injury and increasing the MMP, thereby protecting hippocampal cells from OGD/R injury.

Development is an irreversible process of differentiating the undifferentiated cells to functional cells. Brain development involves generation of cells with varied phenotype and functions, which is limited during adulthood, stress, damage/degeneration. Cellular reprogramming makes differentiation reversible process with reprogramming somatic/stem cells to alternative fate with/without stem cells. Exogenously expressed transcription factors or small molecule inhibitors have driven reprogramming of stem/somatic cells to neurons providing alternative approach for pre-clinical/clinical testing and therapeutics. Here in, we report a novel approach of microRNA (miR)- induced trans-differentiation of macrophages (CD11b high) to induced neuronal cells (iNCs) (neuronal markershigh- Nestin, Nurr1, Map2, NSE, Tubb3 and Mash1) without exogenous use of transcription factors. miR 9, 124, 155 and 224 successfully transdifferentiated macrophages to neurons with transient stem cell-like phenotype. We report trans differentiation efficacy 18% and 21% with miR 124 and miR 155. in silico(String 10.0, miR gator, mESAdb, TargetScan 7.0) and experimental analysis indicate that the reprogramming involves alteration of pluripotencygenes like Oct4, Sox2, Klf4, Nanog and pluripotency miR, miR 302. iNCs also shifted to G0 phase indicating manipulation of cell cycle by these miRs. Further, CD133+ intermediate cells obtained during current protocol could be differentiated to iNCs using miRs. The syanpsin+ neurons were functionally active and displayed intracellular Ca+2 evoke on activation. miRs could also transdifferentiate bone marrow-derived macrophages and peripheral blood mononuclear cells to neuronal cells. The current protocol could be employed for direct in vivo reprogramming of macrophages to neurons without teratoma formation for transplantation and clinical studies.

The environmental contamination with lead (Pb) is considered a critical issue worldwide. Therefore, this study aimed to evaluate the expression levels of circulating miRNAs (miR-155, miR-126, and miR-145) in Mexican women exposed to Pb. Blood lead levels (BLL) were assessed in enrolled women (n = 190) using an atomic absorption method. Also, serum miRNAs expression levels were quantified through a real-time PCR assay. A mean BLL of 10.5 ± 4.50 μg/dL was detected. Overexpression of miR-155 was detected in highly exposed women. Besides, a significant simple positive relationship (p < 0.05) was found between BLL and serum miR-155 expression levels. Additionally, a significant inverse correlation (p < 0.05) was determined between BLL and serum miR-126 expression levels, as downregulation of miR-126 expression levels was observed in highly exposed women. The findings in this study are the concern, as epigenetic changes detected may represent a connection between health illnesses and Pb exposure.

Background Tuberculosis (TB) and non-small cell lung cancer (NSCLC) are two of the major contributor to mortality and morbidity worldwide. TB has symptoms identical to malignancy, therefore, sometimes its diagnosis confused with lung cancer. Several biologic pathways have been identified to be involved in these diseases. The miRNAs are biological molecules that were shown to play essential roles in TB and NSCLC through targeting the related genes. Methods In this research paper we evaluated the expression pattern of common miRNAs between TB and NSCLC and compared them with healthy controls. MiR-155 and miR-146a were examined using RT-qPCR and mir-16 were used as a reference gene. Additionally, the bioinformatics analysis was performed to confirm the role of miR-155 and miR-146a in signaling pathways of TB and NSCLC through targeting related genes. Results mir-155 showed higher expression in TB and NSCLC patients than healthy controls (P value = 0.0221 and 0.0214 respectively), whereas mir-146a showed lower expression in TB and NSCLC patients than healthy controls (P value ≤ 0.0001 and 0.0056 respectively). Conclusions The results demonstrated that miR-155 and miR-146a can be used as a biomarker for early detection, screening, treatment strategies and clinical management of TB and NSCLC.

Background Vascular calcification (VC) is associated with the high morbidity and mortality of cardiovascular diseases in dialysis patients and is a process in which vascular smooth muscle cells (VSMCs) actively differentiate into osteoblast-like cells. Reticulocalbin-2 (RCN2) is involved in the process of osteogenic differentiation under diabetic conditions, but its regulatory role under hyperphosphatemic conditions and the related mechanisms remain unclear. In this study, the importance of the interactions among RCN2, STAT3 and miR-155-5p during the osteogenic differentiation and calcification of human aortic VSMCs (HASMCs) were investigated. Methods RCN2 was measured in femoropopliteal artery plaque specimens from 6 peripheral arterial disease (PAD) patients with chronic kidney disease (CKD) and 6 PAD patients without CKD. RCN2 protein and mRNA expression were assessed in the high phosphate-induced aortic rings culture ex vivo model. In vitro calcification assays and molecular mechanism studies were performed in HASMCs. Results Immunohistochemical staining results revealed increased RCN2 expression in the calcified plaques of femoral arteries of patients with CKD and in a high phosphate-induced aortic culture ex vivo model. RCN2 promoted HASMCs osteogenic differentiation and calcification by inducing STAT3 phosphorylation. Furthermore, inhibition of STAT3 activation by cryptotanshinone (CT) promoted miR-155-5p expression in HASMCs. In turn, miR-155-5p inhibited RCN2 mRNA expression, while RCN2 overexpression partially offset the miR-155-5p-mediated inhibition of HASMC calcification, acting as a positive feedback loop. Conclusion These results demonstrate that RCN2 is a crucial regulator of VC under hyperphosphatemic conditions. RCN2/STAT3/miR-155-5p feedback loop is important in VC and targeting each member of this feedback loop could potentially reverse high phosphate-induced VC.