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The role of microRNAs (miRNAs) in Mycobacterium fortuitum pathogenesis is not well illustrated. Using zebrafish kidney macrophages (ZFKM) we observed that M. fortuitum triggers miR-155 expression, and the TLR-2/NF-κB axis plays a key role in initiating the process. We report that mir-155 activates the pro-inflammatory Stat1/TBX21 pathway in M. fortuitum-infected ZFKM. Our results further reveal the role of miR-155 in M1-macrophage polarisation during M. fortuitum infection. We observed that miR-155 inhibits socs1 expression augmenting the expression of tnf-α, il-12 and ifn-γ in infected ZFKM. Additionally, attenuating miR-155 inhibited ZFKM apoptosis and increased the intracellular bacterial load implicating its pro-apoptotic and bactericidal role in M. fortuitum pathogenesis. This is the first report on the role of miRNA in regulating innate immunity to mycobacteria in fish. We propose that the TLR-2/NF-κB axis triggers miR-155 expression, which in turn represses socs1 and promotes the development of M1-macrophages. Thus, the functional miR-155/Stat1/TBX21pathway induces a pro-inflammatory milieu favouring ZFKM apoptosis and M. fortuitum clearance. Therefore, our study unveils the role of miR-155 in the hierarchy of events leading to M. fortuitum-induced apoptosis and bacterial clearance in fish that is still not explored in detail.

Background: IgA nephropathy (IgAN) is one of the most common glomerular diseases worldwide. Approximately 25 percent of IgAN patients reach the kidney failure stage within twenty years of diagnosis. The histopathological examination of kidney biopsy is needed to confirm the diagnosis of IgAN. microRNA (miRNA) is a small RNA that plays an important role at the post-transcriptional level by downregulating mRNAs (messenger RNA). We tried to establish a miRNA-based biomarker for IgAN. Methods: We recruited 30 IgAN patients and 15 healthy controls as study participants after taking their informed written consent. A real-time PCR-based method was used for the absolute quantification of miRNAs. A logistic regression method and receiver operating characteristic analysis were performed to find the diagnostic and prognostic accuracy of miR-148b and let-7b for IgAN in histopathological MEST-C scores. Results: miR-148b and let-7b levels were higher in IgAN patients compared to the healthy controls. miR-148b was positively correlated with glomerular filtration rate (GFR) and negatively correlated with segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis (T), and blood pressure (BP). The sensitivity, specificity, and area under the curve (AUC) of the receiver operating characteristic (ROC) for miR-148b against T were 0.87, 0.77, and 0.85, respectively. The threshold value of the miR-148b copy number was 8479 to differentiate the severe condition of IgAN. Conclusion: miR-148b can be used as a potential biomarker for IgAN.

Early diagnosis is the key to easy, low cost, and effective treatment of breast cancer. Therefore, studies have been accelerated to identify breast cancer diagnostic biomarkers and diagnose cancer before it progresses. The use of miR-155 as a potential biomarker in breast cancer, which has different levels at different stages of the disease, provides a simple serological test for breast cancer prognosis/diagnosis, follow-up, and treatment. Nanopolymers containing different functional groups that are formed by thiol affinity technique were synthesized by mini emulsion polymerization method and advanced characterization studies were carried out in this study to be used as bioactive layers in the nanobiosensor system for miRNA detection. The working conditions of the electrochemical nanobiosensor in which nanopolymers are used as bioactive layers were optimized. Analytical measurement characteristics and validation studies of the nanobiosensor were determined and analysis was performed on commercial blood serum. The potential of the developed electrochemical biosensor to be used as a medical diagnostic kit was explained by comparing it with commercial miRNA kit currently used for the detection of miR-155. This novel nanobiosensor provide sensitive, reliable, and rapid detection of miR-155 and it can provide the potential for breast cancer early diagnosis, prognosis, and follow-up.

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.

Antimicrobial peptides (AMPs) have proven to inhibit a variety of pathogens. Chromogranin A-N12 (CGA-N12) is a kind of AMP, and it is characterized by stable structure, high anti-Candida activity, and good safety. However, it remains unclear whether CGA-N12 could effectively inhibit the growth of Candida albicans (C. albicans). Colony forming assays were used to measure minimal inhibitory concentration (MIC), minimal fungicidal concentration (MFC), and time-kill curve. Disseminated C. albicans rabbit model was established to investigate the influence of CGA-N12 on histological damage. The protein and mRNA levels of suppressor of cytokine signaling 1 (SOCS1) after treatment were investigated. The MIC and MFC of CGA-N12 against C. albicans was 6 mg/mL. CGA-N12 considerably inhibited germ tube formation of C. albicans. The fungal load in the tissues and inflammatory factors in the serum were suppressed by CGA-N12. CGA-N12 significantly reduced the histological changes caused by C. albicans, and the protein and mRNA levels of SOCS1 were markedly inhibited. The inhibition effect of CGA-N12 on C. albicans and significant improvement of histological damage by CGA-N12 through microRNA-155/SOCS1 axis were proved in this study. This study proposes a novel therapeutic strategy for the treatment and prevention of C. albicans. Abbreviations: AMPs: Antimicrobial peptides; MIC: Minimal inhibitory concentration; MFC: Minimal fungicidal concentration; AIDS: Acquired immune deficiency syndrome; PBS: Phosphate buffer saline; FBS: Fetal bovine serum; ROS: Reactive oxygen species; CFU: Colony formation unit; CGA: Chromogranin A; SOCS1: Suppressor of cytokine signaling 1; SDA: Sabouraud Dextrose Agar; GRAVY: Grand average of hydropathicity; C. parapsilosis: Candida parapsilosis; C. albicans: Candida albicans

This stud intends to assess whether exosome miR-155-5p derived from human non-small cell lung cancer cells (Hcc827) activates macrophages in lung cancer. Lung cancer Hcc827 cells were assigned into control group and expeirmental group (cultured with macrophages, THP-1 activated by exosome miR-155-5P derived from Hcc827) followed by analysis of macrophage markers inducible nitric oxide synthase (INOS), recombinant human CD163 (CD163), matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 2 (MMP2), and E-cadherin by real-time fluorescent quantitative PCR (RFQ-PCR), IL-10, IL-6 and IL-8 levels by chemiluminescence, cell invasion by Transwell assay and related protein expression by Western blot. miR-155-5p treatment significantly reduced INOS and TNF-β expressions and increased CD163, TNF-α, IL-8, IL-6 and IL-10 expressions along with enhanced cell invasion. In addition, MMP9 and MMP2 expressions in experimental group were significantly increased and E-cdherin was reduced. In conclusion, exosome miR-155-5p derived from lung cancer Hcc827 cells activates macrophages and enhanced lung cancer cell invasion.

Background Gastric diffuse large B‐cell lymphoma (DLBCL) is often associated with Helicobacter pylori (H. pylori) infection. Those in the early stage could be treated with H. pylori eradication therapy, and are classified into a sensitive group and a resistant group. Methods Genome‐wide miRNA and miRNA expression profiles were obtained from biopsy specimens of gastric DLBCL. MiRNAs and their targets as predictors of responses to H. pylori eradication therapy were identified through differential expression and pathway enrichment analysis, and further confirmed with transfection experiments in lymphoma cell lines of B‐cell origin. Results Genome‐wide miRNA and mRNA profiles showed miR‐200 was associated with the sensitive group, and that the resistant group had higher levels of miR‐155 and lower levels of DEPTOR (an inhibitor of mTOR) than the sensitive group. BJAB cells transfected with miR‐155 also had lower DEPTOR and higher mTOR levels. Therefore, miR‐155‐mediated inhibition of DEPTOR with secondary activation of mTOR was a potential marker for resistance to H. pylori eradication therapy. In contrast, pathway enrichment analysis showed that Toll‐like receptor 5 (TLR5), the receptor for bacterial flagellin, was a potential marker for sensitivity to H. pylori eradication therapy. In an independent series, stronger expression of pS6K1 (a direct target of mTOR) was associated with the resistant group and morphologic evidence of active gastritis was associated with the sensitive group. Conclusions These findings showed that activation of the miR‐155‐DEPTOR pathway is a marker for resistance to H. pylori eradication therapy, and that histological evaluation of active gastritis might be used as a surrogate marker to predict responses to H. pylori eradication therapy in gastric DLBCL.

Purpose: To explore the protective effects of artemisinin (Art) against diabetic retinopathy (DR) and the probable mechanism of action.Methods: MIO-M1 cells were treated with high glucose (HG) and Art, and the cells’ proliferative ability was determined using cell counting kit-8 (CCK-8) and 5-ethynyl-2’-deoxyuridine (EdU) assay. The relative levels of inflammatory factors in the culture medium of MIO-M1 cells were determined by enzyme-linked immunosorbent assay (ELISA). while the expression levels of CASC2, miR-155 and Sirtuin1 (SIRT1) in MIO-M1 cells were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Interaction of Art with the cell target was assessed using dual-luciferase reporter assay. The role of the CASC2/miR-155/SIRT1 axis in Art-induced protection against the proliferation and inflammation of MIO-M1 cells was evaluated.Results: HG induced elevated proliferation of MIO-M1 cells and production of inflammatory factors, but these effects were countered by Art treatment (p < 0.05). CASC2 and SIRT1 were upregulated, while miR-155 was downregulated in HG-treated MIO-M1 cells; changes in their expressions remained the same following Art treatment. CASC2/miR-155/SIRT1 axis was responsible for the ameliorative effect of Art on HG-treated MIO-M1 cells.Conclusion: Artemisinin treatment inhibits cell activation and production of pro-inflammatory cytokines in HG-induced MIO-M1 cells via CASC2/miR-155/SIRT1 axis. Thus, artemisinin has potentials for development into a therapeutic agent for the management of diabetic retinopathy.

Acute lung injury (ALI) is a common and critical disease encountered in clinical practice. When the disease progresses to a more serious stage, it is called acute respiratory distress syndrome and is associated with a high mortality rate. However, there is a lack of specific drugs for treating this disease; therefore, it is very important to find safe and effective drugs for treatment. Piper kadsura (P. kadsura), part of the of the vin family Piperaceae, has a capability to dispel wind and dampness and its n-butanol extract can provide protection against inflammatory responses, such as inflammatory infiltration and hyperplasia of synovial tissue of joints. In order to explore the therapeutic effect of P. kadsura extract on ALI, we treated HPAEpiC cells with different doses of its extract. We found that after treatment using low-medium and high-dose P. kadsura extract, the optical density value was decreased in HPAEpiC cells as induced by lipopolysaccharide (LPS). In addition, the following were statistically and significantly decreased in a dose-dependent (P < 0.05): the apoptosis rate, cleaved-caspase3 expression, the expression levels of TNF-α, IL-6, and miR-155. However, procaspase 3 increased the expression of miR-155, which can promote LPS-induced apoptosis and the release of inflammatory factors in HPAEpiC cells. The overexpressed miR-155 can weaken the protection conferred by P. kadsura extract on ALI. These results suggest that P. kadsura extract may play a protective role against ALI induced by LPS by decreasing the expression of miR-155.

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.

Purpose Helminths and their products can regulate immune response and offer new strategies to control and alleviate inflammation, including asthma. We previously found that a peptide named as SJMHE1 from Schistosoma japonicum can suppress asthma in mice. This study mainly investigated the molecular mechanism of SJMHE1 in inhibiting asthma inflammation. Methods SJMHE1 was administered to mice with OVA-induced asthma via subcutaneous injection, and its effects were detected by testing the airway inflammation of mice. The Th cell distribution was analyzed by flow cytometry. Th-related transcription factor and cytokine expression in the lungs of mice were analyzed using quantitative real-time PCR (qRT-PCR). The expression of miR-155 and levels of phosphorylated STAT3 and STAT5 were also determined after SJMHE1 treatment in mice by qRT-PCR and Western blot analysis. The in vitro mouse CD4+ T cells were transfected with lentivirus containing overexpressed or inhibited miR-155, and the proportion of Th17, Treg cells, CD4+p-STAT3+, and CD4+p-STAT5+ cells were analyzed by flow cytometry. Results SJMHE1 ameliorated the airway inflammation of asthmatic mice, upregulated the proportion of Th1 and Treg cells, and the expression of Th1 and Treg-related transcription factor and cytokines. Simultaneously, SJMHE1 treatment reduced the percentage of Th2 and Th17 cells and the expression of Th2 and Th17-related transcription factor and cytokines. SJMHE1 treatment decreased the expression of miR-155 and p-STAT3 but increased p-STAT5 expression. In vitro, the percentage of Th17 and CD4+p-STAT3+ cells increased in CD4+ T cells transfected over-expression of miR-155, but SJMHE1 inhibited the miR-155-mediated increase of Th17 cells. Furthermore, SJMHE1 increased the proportion of Treg and CD4+p-STAT5+ cells after transfected over-expression or inhibition of miR-155. Conclusion SJMHE1 regulated the balance of Th17 and Treg cells by modulating the activation of STAT3 and STAT5 via miR-155 in asthma. SJMHE1 might be a promising treatment for asthma.

BACKGROUND Literature regarding exosomes as mediators in intercellular communication to promote progression in mycosis fungoides (MF) is lacking. OBJECTIVES To characterize MF-derived exosomes and their involvement in the disease. METHODS Exosomes were isolated by ultracentrifugation from cutaneous T-cell lymphoma (CTCL) cell lines, and from plasma of patients with MF and controls (healthy individuals). Exosomes were confirmed by electron microscopy, NanoSight and CD81 staining. Cell-line exosomes were profiled for microRNA array. Exosomal microRNA (exomiRNA) expression and uptake, and plasma-cell-free microRNA (cfmiRNA) were analysed by reverse-transcriptase quantitative polymerase chain reaction. Exosome uptake was monitored by fluorescent labelling and CD81 immunostaining. Migration was analysed by transwell migration assay. RESULTS MyLa- and MJ-derived exosomes had a distinctive microRNA signature with abundant microRNA (miR)-155 and miR-1246. Both microRNAs were delivered into target cells, but only exomiR-155 was tested, demonstrating a migratory effect on target cells. Plasma levels of cfmiR-1246 were significantly highest in combined plaque/tumour MF, followed by patch MF, and were lowest in controls (plaque/tumour > patch > healthy), while cfmiR-155 was upregulated only in plaque/tumour MF vs. controls. Specifically, exomiR-1246 (and not exomiR-155) was higher in plasma of plaque/tumour MF than in healthy controls. Plasma exosomes from MF but not from controls increased cell migration. CONCLUSIONS Our findings show that MF-derived exosomes promote cell motility and are enriched with miR-155, a well-known microRNA in MF, and miR-1246, not previously reported in MF. Based on their plasma expression we suggest that they may serve as potential biomarkers for tumour burden.

Oral squamous cell carcinoma (OSCC) had the poor prognosis. miR-155 was involved in some diseases. However, whether BMSCs with high expression miR-155 affect the proliferation and metastasis of OSCC is unclear. Our study aims to assess BMSCs’ effect on OSCC cells. miR-155 level in OSCC tumor tissues was analyzed. BMSCs were transfected with miR-155 followed by analysis of cell proliferation by MTT assay, cell apoptosis and migration, and MMP-9 level by ELISA and PTEN12 level. In the tumor tissue, miR-155 level was significantly increased (P P

Aim: This study aimed to investigate the effects of LINC00240/miR-155/Nrf2 axis on trophoblast function and macrophage polarization in the pathogenesis of preeclampsia. Methods: Bindings between LINC00240, miR-155 and Nrf2 were validated by dual luciferase reporter assay or RNA-immunoprecipitation method. Cell proliferation, migration, invasion, and pyroptosis were detected by CCK-8, clone formation, wound healing, Transwell system and flow cytometry, respectively. Macrophage polarization was tested by flow cytometry. LINC00240, miR-155 and Nrf2 levels, and oxidative stress and pyroptosis related-protein levels in in vitro and in vivo preeclampsia model were analyzed by qPCR, western blot or ELISA assays. Blood pressure, urine protein level, liver and kidney damages, and trophoblast marker in placenta tissues were further studied in vivo. Results: Placenta tissues from preeclampsia patients and animals showed decreased LINC00240 and Nrf2 expressions and increased miR-155 expression. LINC00240 directly bound and inhibited expression of miR-155, which then inhibited oxidative stress-induced pyroptosis, promoting proliferation, migration and invasion abilities of trophoblasts, and M2 macrophage polarization. Inhibition of miR-155 led to the increased Nrf2 expression and similar changes as LINC00240 in trophoblast function and macrophages polarization. Overexpression of LINC00240 in an in vivo preeclampsia model decreased blood pressure, urine protein, liver and kidney damages, increased fetal weight and length, and also induced trophoblast function and M2 macrophage polarization. Conclusion: LINC00240 inhibited symptoms of preeclampsia through regulation on miR-155/Nrf2 axis, which suppressed oxidative stress-induced pyroptosis to improve trophoblast functions and polarization of M2 macrophages. LINC00240 could be a potential therapeutic target for preeclampsia. Funding Statement: This work was supported by A study on serum proteomics and clinical application of pregnancy induced hypertension based on iTRAQ technology（ SB201901087） and Relationship between fibronectin and hypertensive disorder complicating pregnancy and its clinical application (192102310335). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: Written informed consent was collected from all participants before the procedure. The research protocol was approved by the Ethical Committee of the Henan Provincial People’s Hospital (Zhengzhou, Henan, China). All the animal experiment procedures were approved by the Animal Ethics Committee of Henan Provincial People’s Hospital (Zhengzhou, Henan, China).

Background Due to their role in fine-tuning cellular protein expression, microRNAs both promote viral replication and contribute to antiviral responses, for a range of viruses. The interactions between norovirus and the microRNA machinery have not yet been studied. Here, we investigated the changes that occur in microRNA expression during murine norovirus (MNV) infection. Methods Using RT-qPCR-based arrays, we analysed changes in miRNA expression during infection with the acute strain MNV-1 in two permissive cell lines, a murine macrophage cell line, RAW264.7, and a murine microglial cell line, BV-2. By RT-qPCR, we further confirmed and analysed the changes in miR-155 expression in the infected cell lines, bone-marrow derived macrophage, and tissues harvested from mice infected with the persistent strain MNV-3. Using miR-155 knockout (KO) mice, we investigated whether loss of miR-155 affected viral replication and pathogenesis during persistent MNV-3 infection in vivo and monitored development of a serum IgG response by ELISA. Results We identified cell-specific panels of miRNAs whose expression were increased or decreased during infection. Only two miRNAs, miR-687 and miR-155, were induced in both cell lines. miR-155, implicated in innate immunity, was also upregulated in bone-marrow derived macrophage and infected tissues. MNV-3 established a persistent infection in miR-155 knockout (KO) mice, with comparable levels of secreted virus and tissue replication observed as for wildtype mice. However, serum anti-MNV IgG levels were significantly reduced in miR-155 KO mice compared to wildtype mice. Conclusions We have identified a panel of miRNAs whose expression changes with MNV infection. miR-155 induction is a marker of MNV infection in vitro and in vivo, however it does not contribute to the control of persistent infections in vivo. This finding suggests that the immune defects associated with miR-155 deletion, such as lower serum IgG levels, are also not important for control of persistent MNV-3 infection.

Background: The innate immune response is a tightly regulated process that reacts rapidly in response to pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS). Evidence is accumulating that microRNAs contribute to this, although few studies have examined the early events that constitute the “primary” response. Methods: LPS-dependent changes to miRNA expression were studied in primary human monocyte-derived macrophages (1°MDMs). An unbiased screen by microarray was validated by qPCR and a method for the absolute quantitation of miRNAs was also developed, utilising 5’ phosphorylated RNA oligonucleotide templates. RNA immunoprecipitation was performed to explore incorporation of miRNAs into the RNA-induced silencing complex (RISC). The effect of miRNA functional inhibition on TNF expression (mRNA and secretion) was investigated. Results: Of the 197 miRNAs expressed in 1°MDMs, only five were induced >1.5-fold. The most strongly induced was miR-155-3p, the partner strand to miR-155-5p, which are both derived from the MIR155HG/BIC gene (pri-miR-155). The abundance of miR-155-3p was induced transiently ~250-fold at 2-4hrs and then returned towards baseline, mirroring pri-miR-155. Other PAMPs, IL-1β, and TNF caused similar responses. IL-10, NF-κB, and JNK inhibition reduced these responses, unlike cytokine-suppressing mycolactone. Absolute quantitation revealed that miRNA abundance varies widely from donor-to-donor, and showed that miR-155-3p abundance is substantially less than miR-155-5p in unstimulated cells. However, at its peak there were 446-1,113 copies/cell, and miR-155-3p was incorporated into the RISC with an efficiency similar to miR-16-5p and miR-155-5p. Inhibition of neither miRNA affected TNF secretion after 2hrs in 1°MDMs, but technical challenges here are noted. Conclusions: Dynamic regulation of miRNAs during the primary response is rare, with the exception of miR-155-3p. Further work is required to establish whether its low abundance, even at the transient peak, is sufficient for biological activity and to determine whether there are specific mechanisms determining its biogenesis from miR-155 precursors

Extracellular vesicles (EVs) are nanosized vesicles that act as snapshots of cellular components and mediate cellular communications, but they may contain cargo contents with undesired effects. We developed a model to improve the effects of endometrium-derived EVs (Endo-EVs) on the porcine embryo attachment in feeder-free culture conditions. Endo-EVs cargo contents were analyzed using conventional and real-time PCR for micro-RNAs, messenger RNAs, and proteomics. Porcine embryos were generated by parthenogenetic electric activation in feeder-free culture conditions supplemented with or without Endo-EVs. The cellular uptake of Endo-EVs was confirmed using the lipophilic dye PKH26. Endo-EVs cargo contained miR-100, miR-132, and miR-155, together with the mRNAs of porcine endogenous retrovirus (PERV) and β-catenin. Targeting PERV with CRISPR/Cas9 resulted in reduced expression of PERV mRNA transcripts and increased miR-155 in the Endo-EVs, and supplementing these in embryos reduced embryo attachment. Supplementing the medium containing Endo-EVs with miR-155 inhibitor significantly improved the embryo attachment with a few outgrowths, while supplementing with Rho-kinase inhibitor (RI, Y-27632) dramatically improved both embryo attachment and outgrowths. Moreover, the expression of miR-100, miR-132, and the mRNA transcripts of BCL2, zinc finger E-box-binding homeobox 1, β-catenin, interferon-γ, protein tyrosine phosphatase non-receptor type 1, PERV, and cyclin-dependent kinase 2 were all increased in embryos supplemented with Endo-EVs + RI compared to those in the control group. Endo-EVs + RI reduced apoptosis and increased the expression of OCT4 and CDX2 and the cell number of embryonic outgrowths. We examined the individual and combined effects of RI compared to those of the miR-155 mimic and found that RI can alleviate the negative effects of the miR-155 mimic on embryo attachment and outgrowths. EVs can improve embryo attachment and the unwanted effects of the de trop cargo contents (miR-155) can be alleviated through anti-apoptotic molecules such as the ROCK inhibitor.

Previous studies assessed the involvement and impact of periodontal bacteria in preeclamptic women with chronic periodontitis. To explore further, the current study aimed to associate periodontal viruses and bacteria with mir155 levels in placental tissues of preeclamptic women with generalized chronic periodontitis. Four-hundred 45 pregnant women, 18–35 years of age, were selected and divided into four groups (controls, A, B, and C) where the Controls included 145 systemically and periodontally healthy pregnant women Group A-100 systemically healthy pregnant women with chronic periodontitis, Group B- 100 preeclamptic women with chronic periodontitis, Group C- 100 preeclamptic women without chronic periodontitis. Age, BMI, SES, and periodontal parameters such as PI, BOP, PPD, and CAL were noted. Periodontal pathogens such as Tf, Td, Pg, Pi, Fn, HSV, EBV, and HCMV were tested in subgingival plaque, placental tissues, and mir155. We observed that PI, BOP, PPD, CAL, Tf, and EBV were highly significant in Group B. We found a higher number of periodontal bacteria, viruses, and mir 155 in Group B showing a higher risk of preeclampsia. More genetic studies in this field are advised to ascertain the role of periodontopathogens and mir 155 in preeclampsia and periodontal inflammation. What is already known on this subject? Periodontal diseases pose an increased risk of developing preeclampsia and delivering preterm and/or low-birth-weight babies. What do the results of this study add? Periodontal variables such as PI, pocket depth, BOP, and clinical attachment levels, were found to be increased in the preeclamptic women with chronic periodontitis. The significant difference was seen in the relative fold expression of mir155 with higher gene expression of mir155 in groups B and A as compared to group C and controls. What are the implications of these findings for clinical practice and/or further research? In our study, mir155 correlation with the periodontal parameters and periodontal pathogens further strengthen the evidence of periodontal inflammation as a risk of preeclampsia in pregnant women especially when associated with chronic periodontitis. mir155 can be considered to be one of the genetic biomarkers and can be used as a diagnostic tool for the early detection of PE.

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.

Although microRNA-155 (miR-155) is considered a pro-inflammatory mediator, cumulative evidence indicates that it also has anti-inflammatory effects in macrophages and dendritic cells. In this study, we identified the dramatic expression changes of more than half of potential miR-155-targeted genes upon lipopolysaccharide (LPS) stimulation; 223 genes were down-regulated and 85 genes were up-regulated, including suppressor of cytokine signaling 1 (SOCS1) and transforming growth factor-β-activated kinase 1-binding protein 2 (TAB2), two well-known genes involved in miR-155-mediated regulation of the Toll-like receptor 4 (TLR4) signaling pathway. We also found that miR-155 acted as an anti-inflammatory mediator in the initial stage of LPS-induced inflammatory response mainly through repressing TAB2 protein translation, and as a pro-inflammatory mediator by down-regulating SOCS1 in the later stage. Meanwhile, overexpression of TAB2 3' untranslated region (UTR) in macrophages promoted the development of endotoxin tolerance by competing for binding with miR-155, which resulted in an elevated expression level of SOCS1 protein. These findings provide new insights for understanding the regulatory mechanisms in fine-tuning of LPS-induced innate immune response.

Cisplatin resistance is one of the major concerns in the treatment of oral squamous cell carcinoma (OSCC). Accumulating evidence suggests microRNA (miRNA) dysregulation as one of the mediators of chemoresistance. Toward this, our previous study revealed the role of exosomal microRNA-155 (miR-155) in cisplatin resistance via downregulation of FOXO3a, a direct target of miR-155, and induction of epithelial-to-mesenchymal transition in OSCC. In the present study, we demonstrate the therapeutic potential of miR-155 inhibitor-laden exosomes in the sensitization of a cisplatin-resistant (cisRes) OSCC 3D tumor spheroid and xenograft mouse model. The cisRes OSSC 3D tumor spheroid model recapitulated the hallmarks of solid tumors such as enhanced hypoxia, reactive oxygen species, and secretory vascular endothelial growth factor. Further treatment with miR-155 inhibitor-loaded exosomes showed the upregulation of FOXO3a and induction of the mesenchymal-to-epithelial transition with improved sensitization to cisplatin in cisRes tumor spheroids and xenograft mouse model. Moreover, the exosomal miR-155 inhibitor suppressed the stem-cell-like property as well as drug efflux transporter protein expression in cisplatin-resistant tumors. Taken together, our findings, for the first time, established that the miR-155 inhibitor-loaded exosomes reverse chemoresistance in oral cancer, thereby providing an alternative therapeutic strategy for the management of refractory oral cancer patients.

Allergic rhinitis (AR) is a familiar respiratory allergic inflammatory disease with higher incidence. The pathogenesis of AR is particularly complex. Therefore, a lot of work is acquired to excavate deep mechanisms, thereby providing effective strategies for AR diagnose and treatment. AR mice model was induced by recombinant murine IL-33 (0.05 µg/µl) on days 1, 3, and 5. The lentiviral vectors carrying si-circ_0067835, miR-155 mimic, si-NC or miR-NC were injected into AR mice. Thus, mice were divided into control, AR, AR + si-NC, AR + si-circ_0067835, AR + si-circ_0067835 + miR-NC, and AR + si-circ_0067835 + miR-155 mimic groups. qRT-PCR experiment was used to measure the expression of circ_0067835 and miR-155. Behavioral test result was quantified to assess AR mice model. Hematoxylin and eosin (HE) staining was performed to analyze histopathological changes. Helper T cell 2 (Th2) cytokines (IL-4, IL-5, IL-9 and IL-13) and percentage of type-2 innate lymphoid cells (ILC2s) in nasal mucosa tissues in AR mice model were evaluated needing western blot, ELISA, and flow cytometry. Besides, the targeting relationship between circ_0067835 and miR-155, or between miR-155 and GATA3, was investigated via luciferase report assay. Circ_0067835 expression levels were raised in the nasal mucosa tissues of AR mice. Inhibiting circ_0067835 could reduce Type2 cytokines and ILC2s levels in AR mice model. Furthermore, circ_0067835 targeted and positively regulated miR-155 expression, and GATA3 was a downstream target of miR-155 and adjusted by circ_0067835/miR-155 axis. In addition, silencing circ_0067835 inhibited cytokines and ILC2s levels by down-regulating miR-155. Circ_0067835 effectively inhibited AR response in ILC2s through participation of miR-155/GATA3 axis.

Using bis(tridentate)polypyridyl ligands, two new 2 D (two-dimensional) coordination polymers (CPs), {Cu2(tpbn)(2,6-NDC)2}n (1) and {[Cu2(tphn)(2,6-NDC)2]·4H2O}n (2), where tpbn = N,N′,N″,N‴-tetrak...

Noha Adly Sadik,1 Laila Ahmed Rashed,2 Mai Ahmed Abd-El Mawla3 1Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt; 2Department of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt; 3Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, EgyptCorrespondence: Noha Adly SadikDepartment of Internal Medicine, Faculty of Medicine, Cairo University, Dyar City, Middle Hill El Mokattam, Cairo, 11571, EgyptTel +201278444526Email noha_adly@yahoo.comBackground: “Micro RNAs and their target genes recently have been identified to play a crucial role in the molecular pathogenesis of post-stroke ischemic cellular injury, which elucidates their new role in ischemic stroke diagnosis and therapy”. Thus, we evaluated the relative serum expression of miR-155, an inflammatory micro RNA, and the mRNAs (JAK2/STAT3) in acute ischemic stroke patients and its associations with the inflammatory cytokine TNF-α and different stroke risk factors.Subjects and Methods: The relative expression of serum miR-155 and mRNAs (JAK2/STAT3) was assessed using RT-PCR, serum TNF-α was measured using ELIZA in 46 acute ischemic stroke patients and 50 control subjects. Receiver operating characteristic (ROC) curve was constructed to assess the specificity and sensitivity of circulating miR-155, JAK2/STAT3 as biomarkers for acute ischemic stroke.Results: Circulating miR-155, JAK2/STAT3 were significantly up-regulated among stroke patients (8.5, 2.9, 4.2 fold respectively, P< 0.001) with significant increase in TNF-α (263.8 ± 10.7 pg/mL, P < 0.001). MiR-155, JAK2/STAT3 were positively correlated with TNF-α. MiR-155, JAK2/STAT3 were significantly increased in stroke patients and associated with risk factors such as hypertension, carotid atherosclerosis, and atrial fibrillation. Our study revealed that miR-155 has diagnostic accuracy for acute ischemic stroke where AUC=0.9, (P< 0.001).Conclusion: The elevated expressions of circulating miR-155, JAK2/STAT3, and TNF-α in acute ischemic stroke patients could trigger post-stroke cellular inflammation. MiR-155 could be used as potential inflammatory biomarker for acute ischemic stroke. However, further clinical studies are still needed to determine the exact role of miRNAs and different signal transduction expressions in the stage of acute ischemic stroke.Keywords: ischemic stroke, miR-155, Janus kinases, signal transduction, post stroke ischemic injury

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.

Chronic inflammation can induce proliferative events and posttranslational DNA modifications in prostate tissues through oxidative stress. The miR-155 expression is abnormally increased in tumors. Therefore, this study aims to explore the clinical significance of serum TNF-α and IL-1α as well as miR-155 expression in prostate cancer (PC) patients. A total of 50 blood samples from patients diagnosed with prostate cancer were collected from the Oncology Department, Baghdad Teaching Hospital, along with samples from 50 healthy volunteers. Serum TNF-α and IL-1α levels in Iraqi males with prostate cancer were estimated by using enzyme-linked immunosorbent assay (ELISA). The total RNA was extracted from all subjects and converted to cDNA using Stem-Loop technique and the expression was measured by real-time PCR (RT-PCR) using SYBR Green with specific primers. The results showed that serum TNF-α and IL-1α levels were significantly higher in the clinical stage of tumor node metastasis (TNM) as compared to those in the control (p

Intestinal fibrosis is the most common complication of Crohn's disease (CD) that is one major disorder of inflammatory bowel disease (IBD), but the precise mechanism remains unclear. MiR‐155 has been involved in fibrotic diseases. Here, we determined the role of miR‐155 in regulating intestinal fibrosis. MiR‐155 levels were significantly up‐regulated in CD patients with intestinal stricture CD. The overexpression of miR‐155 significantly aggravated TNBS‐induced CD‐associated intestinal fibrosis. Mechanistically, we identified that HBP1, a negative regulator of the Wnt/β‐catenin signalling pathway, is a direct target of miR‐155. Moreover, in vitro and in vivo experiments suggested that the miR‐155/HBP1 axis activates Wnt/β‐catenin signalling pathway to induce intestinal fibrosis. Taken together, we demonstrated that miR‐155 directly targets HBP1 to induce CD‐associated intestinal fibrosis via Wnt/β‐catenin signalling pathway.

Introduction Clear cell papillary renal cell carcinoma often develops in the context of the dialyzed kidney (end-stage renal disease). However, the relationship between clear cell papillary renal cell carcinoma and microRNA expression in patients with end-stage renal disease remains unclear. Case presentation A left renal tumor measuring 22 mm was detected and a radical nephrectomy was performed on a 50-year-old man who had received hemodialysis for the past 6 years. A pathological diagnosis of pT1aNxMx, clear cell papillary renal cell carcinoma was made. We studied the expression of miR-155 in this case and compared it to the expression in nondialysis kidney tissue. The expression level of miR-155 was upregulated in tumor tissue compared with expression levels in the renal cortex for the present case. The expression level of miR-155 in the renal cortex was lower in the present case than in nondialysis kidney tissues. Conclusion We demonstrated upregulation of miR-155 in a case of clear cell papillary renal cell carcinoma arising from end-stage renal disease.

Microglia are the innate immune cells of the central nervous system that adopt rapid functional changes in response to Damage Associated Molecular Patterns, including aggregated β-Amyloid (Aβ) found in Alzheimer's disease (AD). microRNAs (miRNAs) are post-transcriptional modulators that influence the timing and magnitude of microglia inflammatory responses by downregulating the expression of inflammatory effectors. Recent studies implicate miR-155, a miRNA known to regulate inflammatory responses, in the pathogenesis of neurodegenerative disorders including multiple sclerosis, ALS, familial Parkinson's disease, and AD. In this work, we asked if miR-155 expression in microglia modifies cellular behaviors in response to fibrillar Aβ1-42 (fAβ1-42 ), in vitro. We hypothesized that in microglia, miR-155 expression would impact the internalization and catabolism of extracellular fAβ1-42 . Primary microglia stimulated with lipopolysaccharide demonstrate fast upregulation of miR-155 followed by delayed upregulation of miR-146a, an anti-inflammatory miRNA. Conditional overexpression of miR-155 in microglia resulted in significant upregulation of miR-146a. Conditional deletion of miR-155 promoted transit of fAβ1-42 to low-pH compartments where catabolism occurs, while miR-155 overexpression decreases fAβ1-42 catabolism. Uptake of fAβ1-42 across the plasma membrane increased with both up and downregulation of miR-155 expression. Taken together, our results support the hypothesis that inflammatory signaling influences the ability of microglia to catabolize fAβ1-42 through interconnected mechanisms modulated by miR-155. Understanding how miRNAs modulate the ability of microglia to catabolize fAβ1-42 will further elucidate the role of cellular players and molecular crosstalk in AD pathophysiology.

Background Understanding the molecular basis underlying metastasis of non-small cell lung cancer (NSCLC) may provide a new therapeutic modality for the treatment of NSCLC. However, the mechanisms by which tumor-associated macrophages (TAMs) affect NSCLC metastasis remain undefined. In this study, we aimed to discover a novel regulatory pathway involved in NSCLC metastasis. Methods Cell Counting Kit-8 (CCK-8), Transwell, western blot assays were used to assess cell viability, migration, invasion and epithelial-mesenchymal transition (EMT). Exosomes from macrophages medium were characterized, and in vitro cell coculture was further conducted to investigate M2 derived exosomes mediated crosstalk between TAMs and tumor cells. Besides, miRNA microarray was used to analyze miRNA expression profiles of M0 and M2 derived exosomes. Luciferase reporter assay was used to verify the potential binding between miRNA and mRNA. Moreover, 6-week-old male BALB/c nude mice were performed to establish transplantation tumor model using tail vein injection. Hematoxylin & eosin staining was used to detect the metastasis of tumor tissues. Results We found that M2 TAMs were the main TAMs in metastatic tissues of NSCLC patients and exosomes derived from M2 TAMs were able to promote cell viability, cell migration, cell invasion and EMT in NSCLC. We demonstrated that miR-155 and miR-196a-5p were abundant in M2 TAMs and exosomes secreted by M2 TAMs. Functional experiments demonstrated that the deletion of miR-155 and miR-196a-5p in M2 TAMs significantly prevented NSCLC metastasis in vitro and in vivo. To clarify the mechanism governing miR-155 and miR-196a-5p from M2 TAMs, we carried out bioinformatics analysis to predict potential target genes. Mechanistically, miR-155 and miR-196a-5p directly bound to the 3'-UTR of Ras association domain family member 4 (RASSF4), and negatively regulating RASSF4 expression. At last, rescue assays demonstrated that miR-155 and miR-196a-5p exerted its performance by RASSF4. Conclusions Overall, we revealed a new regulatory pathway that was M2 TAMs secreted exosomal miR-155 and miR-196a-5p to promote NSCLC metastasis. This dynamic and reciprocal cross-talk between NSCLC and macrophages innovatively provided a potential opportunity for diagnosis and treatment of NSCLC.

Bronchopneumonia is a disease of the respiratory tract. It leads to other complications and endangers life and health. Long non-coding RNA (lncRNA) participates in the occurrence and development of bronchopneumonia. Nuclear paraspeckle assembly transcript 1 (NEAT1) plays a key role in inflammatory diseases, but the function of NEAT1 in bronchopneumonia remains unclear.RT-qPCR and Western blotting were performed to determine genes and proteins expressions. MTT was applied to test cell viability. Cell apoptosis was detected by flow cytometry. RIP was used to investigate the correlation between NEAT1 and miR-155-5p. The interaction between miR-155-5p and NEAT1 or MyD88 was evaluated by the dual-luciferase reporter gene.NEAT1 and MyD88 were upregulated in BEAS-2B cells by LPS, while miR-155-5p was downregulated. Knockdown of NEAT1 inhibited LPS-induced BEAS-2B cells growth inhibition by inhibiting the apoptosis. In addition, NEAT1 silencing suppressed LPS-induced inflammatory responses in BEAS-2B cells via suppression of TNF-α, IL-1β, IL-6, and IL-18. Meanwhile, NEAT1 is directly bound to miR-155-5p to regulate MyD88/NF-κB axis, and overexpression of miR-155-5p increased cell proliferation and suppressed inflammatory factors expression levels and cell apoptosis. Furthermore, sh-NEAT1-induced inhibition of BEAS-2B cells injury was partially reversed by miR-155-5p inhibitor or MyD88 overexpression.NEAT1 silencing suppressed LPS-induced BEAS-2B cells injury and inflammation by the mediation of miR-155-5p/MyD88/NF-κB axis. Thus, our study might shed new light on exploring the new strategies for the treatment of bronchopneumonia.

Purpose: miRNA-155 is an oncogenic miRNA highly expressed in B-cell malignancies, particularly in the non–germinal center B-cell or activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL), where it is considered a potential diagnostic and prognostic biomarker. Thus, miR-155 inhibition represents an important therapeutic strategy for B-cell lymphomas. In this study, we tested the efficacy and pharmacodynamic activity of an oligonucleotide inhibitor of miR-155, cobomarsen, in ABC-DLBCL cell lines and in corresponding xenograft mouse models. In addition, we assessed the therapeutic efficacy and safety of cobomarsen in a patient diagnosed with aggressive ABC-DLBCL. Experimental Design: Preclinical studies included the delivery of cobomarsen to highly miR-155–expressing ABC-DLBCL cell lines to assess any phenotypic changes, as well as intravenous injections of cobomarsen in NSG mice carrying ABC-DLBCL xenografts, to study tumor growth and pharmacodynamics of the compound over time. To begin to test its safety and therapeutic efficacy, a patient was recruited who underwent five cycles of cobomarsen treatment. Results: Cobomarsen decreased cell proliferation and induced apoptosis in ABC-DLBCL cell lines. Intravenous administration of cobomarsen in a xenograft NSG mouse model of ABC-DLBCL reduced tumor volume, triggered apoptosis, and derepressed direct miR-155 target genes. Finally, the compound reduced and stabilized tumor growth without any toxic effects for the patient. Conclusions: Our findings support the potential therapeutic application of cobomarsen in ABC-DLBCL and other types of lymphoma with elevated miR-155 expression.

Depression is one of most common psychiatric disorders, and the detailed molecular mechanism remains to be fully elucidated. Brain-derived neurotrophic factor (BDNF) is a critical neurotrophic factor that is decreased and closely involved in the development of depression. Noncoding RNAs are central regulators of cellular activities that modulate target genes. However, the roles of long noncoding RNA (lncRNA) MIR155HG and miRNA-155 (miR-155) in the pathophysiology of depression are unclear. In the present study, we aimed to explore the effects of lncRNA MIR155HG and miR-155 on the development of depression and uncover the underlying molecular mechanism. Real-time quantitative polymerase chain reaction was used to examine the expression of MIR155HG and miR-155. Western blotting was applied to measure the expression of BDNF. A luciferase reporter assay was utilized to determine the regulatory relationship between MIR155HG and miR-155. Our current work found that lncRNA MIR155HG and BDNF levels decreased while miR-155 levels increased in the hippocampal region of CUMS (chronic unpredictable mild stress) mice, a well-accepted mouse model of depression. Moreover, MIR155HG rescued while miR-155 exacerbated the depression-like behaviors of CUMS mice. Through bioinformatics analysis and luciferase reporter assays, we found that MIR155HG directly bound to and negatively modulated the expression of miR-155. Moreover, increased miR-155 was found to repress the expression of BDNF, a critical neurotrophic factor that has been reported to alleviate the depression-like behaviors of CUMS mice. Our present study revealed that lncRNA MIR155HG protected CUMS mice by regulating the miR-155/BDNF axis. Our study aimed to understand the pathophysiology of depression and provided potential therapeutic targets to diagnose and treat depression.

ObjectivesDirect inhibition of M1 polarization of synovial macrophages may be a useful therapeutic treatment for OA and OA-associated synovitis. Frugoside (FGS) is a cardiac glycoside compound isolated and extracted from Calotropis gigantea. Cardiac glycosides possess interesting anti-inflammatory potential. However, the corresponding activity of FGS has not been reported. Therefore, our aim was to find direct evidence of the effects of FGS on synovial macrophage M1 polarization and OA control.MethodsCollagenase was used to establish an experimental mouse OA model (CIOA) with considerable synovitis. Then, FGS was intra-articular administered. The mRNA and protein levels of iNOS were analysed by real-time PCR and Western blotting in vitro. Immunohistochemical and immunofluorescence staining were used to measure the expression of F4/80, iNOS, Col2α1 and MMP13 in vivo. The levels of pro-inflammatory cytokines in FGS-treated M1 macrophage culture supernatants were analysed by flow cytometry.ResultsFGS attenuates synovial inflammation and delays the development of OA in CIOA mice. Further results demonstrate that FGS inhibits macrophage M1 polarization in vitro and in vivo, which subsequently decreases the secretion of IL-6 and TNF-α, in turn delaying cartilage and extracellular matrix (ECM) degradation and chondrocyte hypertrophy. FGS inhibits macrophage M1 polarization by partially downregulating miR-155 levels.ConclusionThis study demonstrates that intra-articular injection of FGS is a potential strategy for OA prevention and treatment, even at an early stage of disease progression. This is a novel function of FGS and has promising future clinical applications.

MiR-155 plays main roles in several physiological and pathological mechanisms, such as Down syndrome (DS), immunity and inflammation and potential anti-AD therapeutic target. The miR-155 is one of the overexpressed miRNAs in DS patients that contribute directly and indirectly to the onset or progression of the DS. Since the miR-155 can simultaneously reduce the translation of several genes at post-transcriptional levels, targeting the miR-155 might set the stage for the treatment of DS. One of the rational strategies in providing therapeutic interventions in this respect is to design and develop novel small molecules inhibiting the miR-155 function or biogenesis or maturation. In the present study, we aim to introduce small molecule compounds with the potential to inhibit the generation of the selectively miR-155 processing by employing computational drug design approaches, as well as in vitro studies. We designed and synthesized a novel series of imidazo[1,2-a]pyridines derivatives as new nonpeptic candidates for the treatment of DS with AD. The designed compounds were investigated for their BACE1 and miR-155 binder inhibitory potential in vitro and in cell. In addition, we present a systematic computational approach that includes 3 D modeling, docking-based virtual screening, and molecular dynamics simulation to identify Small - molecule inhibitors of pre-miR-155 maturation. To confirm the inhibitory potential of compound 8k on miR-155 maturation, qRT- PCR was performed. All our results confirm that compound 8k, in addition to being a good inhibitor of BACE1, can also be a good inhibitor of miR-155. Communicated by Ramaswamy H. Sarma.

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

Thyrotoxic heart disease (THD) is a common and severe complication of hyperthyroidism and the etiology of this complication remains poorly understood. Activation of the rennin-angiotensin- aldosterone system by excess thyroxin is one of the major factors that contribute to the pathogenesis of THD. Several microRNAs such as miR-21, miR-155, miR-208a, and miR-499 are closely related to the rennin-angiotensin-aldosterone system and therefore should be involved in this process. Our study intends to explore whether these miRNAs are involved in the pathogenesis of THD, and if these miRNAs could be secreted into the circulation and serve as sentinel indicators for THD. Though there is a trend of elevation of miR- 155 in THD than in simple hyperthyroidism patients, we did not find statistically significant differences in the expression of these miRNAs in the blood of THD patients, but we found that miR-155 was significantly up-regulated in patients with Graves' disease with or without THD in comparison with healthy controls. Thus, miR-155 can serve as a novel biomarker for Graves' disease and can play important roles in pathogenesis of Graves' disease.

Background: Osteoarthritis (OA) is the most common joint disorder characterized by degeneration of the articular cartilage and joint destruction with an associated risk of mobility disability in elderly people. Although a lot of achievements have been made, OA is still regarded as an incurable disease. Therefore, the pathological mechanisms and novel therapeutic strategies of OA need more investigation. Methods: MTT assay was conducted to measure the viability of chondrocytes after LPS treatment. Cell apoptosis was analyzed by annexin V/propidium iodide labeling. ELISA was used to determine the concentrations of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the culture supernatant of chondrocytes. The expression level of miR-155, IL-1β, FOXO3, TNF-α, IL-6, caspase-3, and caspase-9 in chondrocytes was analyzed by RT-qPCR or Western blot. Results: We found that LPS led to inflammatory responses, cell apoptosis, and increased miR-155 expression in human articular chondrocytes. Tanshinone IIA could inhibit LPS-induced inflammation and cell apoptosis of chondrocytes via regulating the expression of miR-155 and FOXO3. miR-155 directly targeted the 3′-UTR of FOXO3 to regulate its expression. Conclusions: Taken together, our data suggest tanshinone IIA ameliorates inflammation response in OA via inhibition of the miR-155/FOXO3 axis, and provide some evidences that tanshinone IIA could be designed and developed as a new promising clinical therapeutic drug for OA patients.

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. Our aim was to identify a novel miRNA that can predict prognosis of childhood ALL patients and explore its potential mechanism.The miRNA expression profiles of childhood ALL were analyzed using GEO database and HiSeq instruments. The expression of miR-155 was examined by RT-PCR in 42 ALL patients. To investigate the role of miR-155 in ALL, four ALL cell lines (CEM-C1, Jurkat, MOLT-3 and MOLT-4) were transfected with miR-155 mimics, miR-155 inhibitors or corresponding controls. Dual-luciferase reporter system was applied to confirm the miR-155 target ZNF238. Moreover, proliferation and apoptosis were evaluated by MTT and flow cytometry.Dataset GSE56489 and GSE23024 demonstrated that miR-155 was up-regulated and ZNF238 was down-regulated at diagnosis status of ALL. High miR-155 expression was associated with poor outcome. Overexpressed miR-155 promoted ALL cell proliferation and inhibited apoptosis. Dual-luciferase reporter result showed that miR-155 directly regulated ZNF238. Silencing ZNF238 promoted cell proliferation in ALL cells.Our research indicating that miR-155 might possess potential value as a biomarker for predicting the prognosis of individuals. However, the role of ZNF238 in childhood ALL remain unknown. In the present study, we found the possible role of ZNF238 as a new tumor suppressor in ALL, which might be necessary for the antiproliferative functions of normal cells to counteract ALL formation.Our results propose that miR-155 is in association with poor prognosis of childhood ALL. Furthermore, miR-155 could promote cell proliferation targeting ZNF238.

Background: Although renal cell carcinoma remains one of the most malignant cancers, our understanding of progression and recurrence of this disease is limited. The present study explored the precise role of miR-155-5p in renal cancer metastasis. Methods: The expression of miR-155-5p in renal carcinoma clinical tissues and cells was determined using quantitative real time-polymerase chain reaction. The role of miR-155-5p on tumor cell growth were examined using CCK-8 and colony formation assays. Transwell assay was utilized to identify the role of miR-155-5p on the invasion and migration of renal cancer cells. Markers of epithelial-mesenchymal transition were determined using western blot. The in vivo effects of miR-155-5p on renal cancer cell growth, apoptosis, and metastasis were explored using xenograft mice. Luciferase reporter assay was performed to identify the potential target of miR-155-5p. Results: Levels of miR-155-5p were significantly elevated in renal cancer tissues and cell lines. Suppression of miR-155-5p decreased the growth, colony formation, migration, and invasiveness of renal cancer cells. In contrast, overexpression of miR-155-5p led to opposite effects on renal cancer cells. Mechanically, the apoptosis-inducing factor was identified as the target of miR-155-5p. Interference of miR-155-5p significantly increased mRNA and protein expression of the apoptosis-inducing factor, whereas overexpression of miR-155-5p remarkably suppressed the apoptosis-inducing factor levels in renal cancer cells. The xenograft model identified that suppression of miR-155-5p restrained tumor growth and promoted apoptosis, whereas overexpression of miR-155-5p decreased apoptosis and accelerated tumor growth. Moreover, the number of lung metastasis nodules were decreased following injection with anti-miR-155-5p transfected cells, whereas the nodules were remarkably increased after overexpression of miR-155-5p. In addition, in vitro and in vivo assays both confirmed that suppression of miR-155-5p increased the expression of E-cadherin and decreased levels of N-cadherin and Snail, whereas overexpression of miR-155-5p accelerated epithelial–mesenchymal transition progression in renal cancer cells. Conclusion: These findings demonstrate that miR-155-5p enhances metastasis and epithelial–mesenchymal transition by targeting the apoptosis-inducing factor, suggesting that miR-155-5p represents a novel therapeutic target for renal cancer.

Sepsis-induced lung injury is a lethal complication with no effective treatment options, affecting millions of people worldwide. Oroxylin A (OroA) is a natural flavonoid with potent anticancer effects, but its modulating effect on inflammation through microRNAs (miRs) is not apparent. In this report, we investigated the target genes of the miR pathway mediated by OroA and assessed the potential for novel treatments of septic lung injury. An miR array screening and quantitative polymerase chain reaction identified that miR-155-5p could be a candidate regulated by OroA. Bioinformatics analysis indicated that interferon regulatory factor-2-binding protein-2 (IRF2BP2) might be a target of miR-155-5p, and this hypothesis was verified through reporter assays. In addition, an immunoprecipitation assay demonstrated that OroA increased the binding activity of IRF2BP2 to the nuclear factor of activated T-cells 1 (NFAT1), causing inducible nitric oxide synthase to cause an inflammatory reaction. Finally, the direct injection of short hairpin RNA (shRNA)-miR-155-5p into the bone marrow of mice ameliorated LPS-induced acute lung injury and inflammation in mice. Our results provide new mechanistic insights into the role of the OroA-induced miR-155-5p-IRF2BP2-NFAT1 axis in sepsis, demonstrating that direct bone marrow injection of lentivirus containing shRNA-155-5p could prove to be a potential future clinical application in alleviating sepsis-induced acute lung injury.

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.

Objectives : Oral squamous cell carcinoma (OSCC) is one of the most common types of head and neck cancer. MicroRNAs, as new biomarkers, are recommended for diagnosis and treatment of different types of cancers. Bevacizumab, sold under the trade name Avastin, is a humanized whole monoclonal antibody that targets and blocks VEGF-A (vascular endothelial growth factor A; angiogenesis) and oncogenic signaling pathways. Materials and methods This study comprised 50 cases suffering from OSCC and 50 healthy participants. Peripheral blood samples were collected in glass test tubes, and RNA extraction was started immediately. Expression levels of miR-155, miR-191, and miR-494 biomarkers in the peripheral blood of OSCC-affected individuals and healthy volunteers in vivo were evaluated using real-time PCR. The influence of Avastin on the expression levels of the aforementioned biomarkers in vitro and in the HN5 cell line was also investigated. Results Expression levels of miR-155, miR-191, and miR-494 in the peripheral blood of individuals affected by OSCC were higher than in those who were healthy. Moreover, Avastin at a concentration of 400 μM caused a decrease in the expression levels of the three biomarkers and a 1.5-fold, 3.5-fold, and 4-fold increase in apoptosis in the test samples compared to the controls in the HN5 cell line after 24, 48, and 72 hours, respectively. Conclusion The findings of this study demonstrate that overexpression of miR-155, miR-191, and miR-494 is associated with OSCC, and Avastin is able to regulate and downregulate the expression of those biomarkers and increase apoptosis in cancerous cells in the HN5 cell line.

Encouraging insight into novel underlying mechanisms targeting abnormal biological pathways in colorectal cancer (CRC) are currently under investigation, edging closer and closer to clinical use. Of note, basic leucine zipper ATF-like transcription factor 3 (BATF3) has been implicated with the tumorigenicity of CRC. The current study aimed to elucidate the oncogenic BATF3-mediated S1PR1/p-STAT3/miR-155-3p/WDR82 axis in CRC. Initially, clinical samples of CRC tissues as well as CRC cell lines were collected to evaluate the expression patterns of BATF3/S1PR1/p-STAT3/miR-155-3p/WDR82. Dual luciferase assay was employed to assess the binding affinity between miR-155-3p and WDR82. Artificial modulation of BATF3 (down- and overexpression) was conducted to measure the malignant phenotypes of CRC cells, while tumor-bearing mice were examined to determine the in vivo effects. BATF3 facilitated the proliferative, migratory, and invasive potential of CRC cells by upregulating S1PR1. Besides, the stimulatory effect of S1PR1 was realized via restored p-STAT3 expression. Furthermore, p-STAT3 was evidenced to heighten the expression of miR-155-3p and subsequently restrict the expression of its target gene WDR82. The in vivo assays provided data further substantiating the in vitro findings that inactivation of the BATF3/S1PR1/p-STAT3/miR-155-3p/WDR82 axis suppresses CRC tumor growth. Collectively, the results of the present study emphasize the oncogenic function of BATF3 illustrated by the reinforcement the biological processes of proliferation, invasion, as well as the metastatic capacity of CRC cells through activating the S1PR1/p-STAT3/miR-155-3p/WDR82 axis.

Considering the significance of lncRNA/miRNA axis in explaining atherosclerosis (AS) progression, this investigation was intended to clarify whether lncRNAs XIST/SNHG5 would regulate AS aetiology by sponging miR‐155, an AS‐promoting molecule. We altogether recruited 367 patients who were examined by coronary angiography, and meanwhile, human coronary artery endothelial cells (HCAECs) were purchased to establish cells models via ox‐LDL treatment. The study results indicated that lowly expressed XIST/SNHG5 and highly expressed miR‐155 were frequently detectable among AS patients who showed severe stenosis and possessed high triglyceride (TG), low‐density lipoprotein cholesterol (LDL‐C) and high‐sensitivity C‐reactive protein (hs‐CRP) levels. Besides, HCAECs treated by ox‐LDL released large amounts of inflammatory cytokines, and their apoptosis rate was also raised. Moreover, expressions of XIST and SNHG5 declined markedly within ox‐LDL‐treated HCAECs, whereas miR‐155 expression significantly ascended. Transfection of pcDNA‐XIST and pcDNA‐SNHG5 both reduced the expression of TNF‐α, IL‐6, IL‐8 and IL‐1β within HCAECs and also dampened the apoptotic tendency of HCAECs. Co‐treatment of pcDNA‐XIST and pcDNA‐SNHG5 produced a larger effect on HCAEC activity than pcDNA‐XIST or pcDNA‐SNHG5 alone. Furthermore, miR‐155, modified by XIST and SNHG5, was capable of reversing the impacts of XIST and SNHG5 on HCAEC activity. Eventually, CARHSP1 was activated by XIST and SNHG5, and its overexpression dwindled impacts of miR‐155 mimic on proliferation and inflammation response of HCAECs. In conclusion, targeting XIST and SNHG5 might be an ideal alternative in delaying AS progression, allowing for their repression of downstream miR‐155.