The role and significance of magnetic resonance imaging and miRNA-125b expression level in diagnosis of head and neck squamous cell carcinoma.

Introduction: Diagnosis of head and neck squamous cell carcinoma (SCC) is an important challenge for clinicians, and finding new approaches to better diagnosis is the basis of a new area of cancer research. Aim: To investigate the diagnostic value and significance of MRI combined with miRNA-125 expression in head and neck SCC. Material and methods: Sixty patients with head and neck SCC were selected as the tumour group, and 20 healthy volunteers as the control group. All subjects were examined by magnetic resonance imaging (MRI) perfusion imaging. Peripheral venous blood was collected from all patients and healthy volunteers. The expression level of miRNA-125 in serum was detected by RT-qPCR, and the levels of interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor ß1 (TGF-ß1) in serum were detected. Meanwhile, tumour tissues and adjacent non-tumour tissues of patients were collected to detect the mRNA expression level of ERBB2. Results: Compared with the control group, the expression level of miRNA-125b in serum of patients decreased with a statistically significant difference (p < 0.05). Compared with adjacent non-tumour tissues, the expression level of ERBB2 mRNA in tumour tissues of patients was significantly increased, with a statistically significant difference (p < 0.05). MiRNA-125b in serum was negatively correlated with tumour size and number of metastatic foci (p < 0.05). The results of enzyme-linked immunosorbent assay showed that the levels of IL-2, TNF-α, and TGF-ß1 in the patient's serum increased while the levels of IFN-γ decreased significantly, with a statistically significant difference (p < 0.05). Conclusions: Detection of miRNA-125b expression level is complementary to MRI diagnosis of head and neck SCC.

miRNA-125b Regulates Osteogenic Differentiation of Periodontal Ligament Cells Through NKIRAS2/NF-κB Pathway.

BACKGROUND/AIMS: Osteogenesis of periodontal ligament cells (PDLCS) is essential for alveolar bone repair. Varieties of factors have been found involved in the regulation of PDLCs osteoblast differentiation. Aim of this study was to identify microRNA as a regulator of the os-teogenic differentiation of PDLCs. METHODS: The CD markers were analyzed by flow cytometry analysis. Osteoblast differentiation of PDLCs was induced by treatment with dexamethasone, ß-glycerol phosphate and α-ascorbic acid. The expression of osteoblastic phenotype was evaluated after the induction by simultaneous monitoring of alkaline phosphatase activity, the expression of genes involved in osteoblastic differentiation by RT-qPCR and Western Blot, and mineralization at the same time. MicroRNA and NKIRAS2 expression was determined by RT-qPCR. Luciferase reporter assays were performed to test whether miR-125b is capable of interacting with the 3'UTR sequence of NKIRAS2. The possible signaling pathway was determined by Western Blot. RESULTS: In this study, we found that the expression of miR-125b was down regulated during the process of ostoblast differentiation of PDLCs. When the expression of miR-125b was up regulated, the osteogenic differentiation of PDLCs was inhibited. During this process, the over-expressed miR-125b led to the activation of NF-κB. NF-κB inhibitor interacting RAS-like 2 (NKIRAS2) is one of target gene of miR-125b, and it is a regulator of NF-κB signaling that plays various roles in osteoblastic differentiation. We demonstrate thatmiR-125b is involved in osteogenic differentiation of PDLCs. CONCLUSION: Our data support the hypothesis that that miR-125b attenuates PDLCs osteoblastic differentiation by targeting NKIRAS2 and enhancing NF-κB signaling.

Inhibition of MiRNA-125b Decreases Cerebral Ischemia/Reperfusion Injury by Targeting CK2α/NADPH Oxidase Signaling.

BACKGROUND/AIMS: Cerebral ischemia-reperfusion (I/R) injury involves multiple independently fatal terminal pathways. CK2α/NADPH oxidase is an important signaling pathway associated with ischemia-reperfusion injury, and miR-125b can regulate oxidative stress-related injury. In this study, we investigated whether the effect of miR-125b in rat brain I/R injury occurs through its modulation of the CK2α/NADPH oxidase pathway. METHODS: Rats were subjected to 2 h of cerebral ischemia followed by 24 h of reperfusion to establish an I/R injury model. Neurological deficit was evaluated using a five-point score. Infarct volume was evaluated with 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, and RT-PCR was used to detect expressions of miR125b and CK2α. We then examined the association between miR-125b expression and the CK2α/NADPH oxidative signaling pathway in a PC-12 cell oxygen-glucose deprivation and reoxygenation (OGD/R) injury model. Transfection with miR-125b mimics, an miR-125b inhibitor, and luciferase reporter gene plasmid was accomplished using commercial kits. In these cells, Western blots were used to detect the levels of expression of CK2α, cleaved caspase-3, NOX2, and NOX4. RT-PCR was used to detect the expressions of CK2α, miR125b, NOX2, and NOX4. We evaluated Lactate Dehydrogenase (LDH) level, NADPH oxidase activity, and caspase-3 activity using commercial kits. Mitochondrial reactive oxygen species (ROS) were measured by fluorescence microscopy. For both PC-12 cells and rat brains, histological analyses were conducted to observe morphological changes, and apoptosis was measured using a commercial kit. RESULTS: I/R rats exhibited an increase in neurological deficit score, infarct volume, and cellular apoptosis, along with miR-125b elevation and CK2α downregulation. OGD/R treatment increased PC-12 cells' injuries, cellular apoptosis, and ROS levels. These changes were associated with miR-125b elevation, CK2α downregulation and activations of NOX2 and NOX4, mimicking our in vivo findings. All of these effects were reversed by the inhibition of miR-125b, confirming a strong correlation between miR-125b activity and the CK2α/NADPH oxidase signaling pathway. CONCLUSIONS: Based on these observations, we conclude that inhibition of miR-125b protects the rat brain from I/R injury by regulating the CK2α/NADPH oxidative signaling pathway.

MicroRNAs miR-125b and miR-100 suppress metastasis of hepatocellular carcinoma by disrupting the formation of vessels that encapsulate tumour clusters.

We have previously shown that vessels that encapsulated tumour cluster (VETC), a prevalent vascular pattern in hepatocellular carcinoma (HCC), facilitates the entry of the whole tumour cluster into the bloodstream in an invasion-independent manner, and that angiopoietin 2 (Angpt2), the levels of which are increased in HCC cells, is essential for VETC formation. However, the mechanisms underlying VETC formation remains unclear. Herein, we characterized miR-125b and miR-100 as novel VETC suppressors by using human HCC specimens, and cell and animal models. We showed that reduced expression of either miR-125b or miR-100 in human HCC tissues was significantly associated with the presence of VETC, venous invasion of tumour cells, and the occurrence of endothelium-coated microemboli. To confirm the role of miR-125b and miR-100 in VETC formation and HCC metastasis, cell lines with stable miR-125b and miR-100 expression were established by using human VETC-2 cells and mouse Hepa1-6 cells, the hepatoma cells that developed xenografts with VETC patterns. Our results showed that expression of miR-125b or miR-100 in VETC-2 and Hepa1-6 cells dramatically reduced VETC formation in xenografts, and consequently inhibited in vivo metastasis, suggesting that miR-125b and miR-100 may attenuate metastasis by repressing VETC formation. Further investigation revealed that miR-125b directly suppressed the expression of Angpt2 by binding to its 3'-untranslated region, whereas miR-100 reduced the protein level of Angpt2 by targeting mechanistic target of rapamycin (MTOR) and blocking the MTOR-p70S6K signalling pathway. Moreover, the suppressive effect of miR-125b and miR-100 on VETC formation was abrogated by injecting Angpt2-expressing viruses into xenografts. Taken together, our findings imply that miR-125b and miR-100 negatively regulate Angpt2 expression through different mechanisms, in turn inhibit VETC formation, and consequently abrogate the VETC-dependent metastasis of hepatoma cells. This study uncovers new regulatory mechanisms of VETC formation, identifies novel functions of miR-125b and miR-100, and provides new targets for antimetastasis therapy of HCC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

MicroRNA (miRNA) Signaling in the Human CNS in Sporadic Alzheimer's Disease (AD)-Novel and Unique Pathological Features.

Of the approximately ~2.65 × 10³ mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset-about 35-40-are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs) for productive miRNA-mRNA interactions and the down-regulation of gene expression. In this article we will: (i) consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer's disease (AD) and related forms of chronic neurodegeneration; and (ii) highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS.

Investigation of the potential of miRNA candidates as non-invasive biomarkers for the diagnosis and follow-up of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide, and despite advances in treatment, molecular biomarkers are needed for both early diagnosis and prognosis monitoring. It is known that microRNAs (miRNA), one of the epigenetic mechanisms, are effective in the initiation and development of cancer by regulating the activity of tumor suppressors and/or oncogenes. In this study, the potential of the molecules let-7, miRNA125b, and miRNA30a, which are known to play a role in cellular processes, as biomarkers for colorectal cancer and their molecular mechanisms were investigated in this model. The aim was to evaluate the diagnostic, prognostic, and predictive utility of the target miRNAs in colorectal cancer patients. MATERIAL AND METHODS: The expression changes of miRNAs let-7, miRNA125b, and miRNA30a were investigated by miRNAs isolation and cDNA synthesis from the serum samples of 60 patients diagnosed with CRC or from the serum samples of 20 healthy individuals. The calculation was performed using the quantitative real-time polymerase chain reaction method to determine the expression level. The results were compared with clinical parameters. RESULT: An 8-fold decrease in the expression of let-7 and miRNA125b and a 60-fold decrease in the expression of miRNA30a were found in the serum samples of patients diagnosed with colorectal cancer (CRC) compared to the healthy group. A decrease in let-7 was observed in 53.3%, miRNA125b in 58.3%, and miRNA30a in 55% of patients. A significant correlation was found between the reduced expression status and the stage, lymph nodes, local recurrence, and metastasis (p < 0.05). The ROC analysis showed that the miRNA30a level could be a diagnostic biomarker for CRC (p < 0.001). No significant impact of target miRNA expression changes on overall disease survival was observed. CONCLUSION: It is thought that the target miRNA30a can be used for early diagnosis and screening and that the target miRNA let-7, miRNA125b, and miRNA30a can be used as non-invasive biomarkers for disease follow-up, with larger patient studies being conducted on CRC patients.

Flavonoid Rutin Presented Anti-Glioblastoma Activity Related to the Modulation of Onco miRNA-125b Expression and STAT3 Signaling and Impact on Microglia Inflammatory Profile.

Glioblastoma (GBM) is the most aggressive and treatment-resistant brain tumor. In the GBM microenvironment, interaction with microglia is associated with the dysregulation of cytokines, chemokines, and miRNAs, contributing to angiogenesis, proliferation, anti-apoptosis, and chemoresistance. The flavonoid rutin can inhibit glioma cell growth associated with microglial activation and production of pro-inflammatory mediators by mechanisms that are still poorly understood. The present study investigated the effect of rutin on viability, regulation of miRNA-125b, and the STAT3 expression in GBM cells, as well as the effects on the modulation of the inflammatory profile and STAT3 expression in microglia during indirect interaction with GBM cells. Human GL15-GBM cells and human C20 microglia were treated or not with rutin for 24 h. Rutin (30-50 µM) significantly reduced the viability of GL15 cells; however, it did not affect the viability of microglia. Rutin (30 µM) significantly reduced the expression of miRNA-125b in the cells and secretome and STAT3 expression. Microglia submitted to the conditioned medium from GBM cells treated with rutin showed reactive morphology associated with reduced expression of IL-6, TNF, and STAT3. These results reiterate the anti-glioma effects of the flavonoid, which may also modulate microglia towards a more responsive anti-tumor phenotype, constituting a promising molecule for adjuvant therapy to GBM.

Topical Delivery of microRNA-125b by Framework Nucleic Acids for Psoriasis Treatment.

Purpose: Psoriasis is a chronic and recurrent inflammatory dermatitis characterized by T cell imbalance and abnormal keratinocyte proliferation. MicroRNAs (miRNAs) hold promise as therapeutic agents for this disease; however, their clinical application is hindered by poor stability and limited skin penetration. This study demonstrates the utilization of Framework Nucleic Acid (FNA) for the topical delivery of miRNAs in psoriasis treatment. Methods: By utilizing miRNA-125b as the model drug, FNA-miR-125b was synthesized via self-assembly. The successful synthesis and stability of FNA-miR-125b in bovine fetal serum (FBS) were verified through gel electrophoresis. Subsequently, flow cytometry was employed to investigate the cell internalization on HaCaT cells, while qPCR determined the effects of FNA-miR-125b on cellular functions. Additionally, the skin penetration ability of FNA-miR-125b was assessed. Finally, a topical administration study involving FNA-miR-125b cream on imiquimod (IMQ)-induced psoriasis mice was conducted to evaluate its therapeutic efficacy. Results: The FNA-miR-125b exhibited excellent stability, efficient cellular internalization, and potent inhibition of keratinocyte proliferation. In the psoriasis mouse model, FNA-miR-125b effectively penetrated the skin tissue, resulting in reduced epidermal thickness and PASI score, as well as decreased levels of inflammatory cytokines.

Heavy metal levels are positively associated with serum periostin and miRNA-125b levels, but inversely associated with miRNA-26a levels in pediatric asthma cases. A case-control study.

BACKGROUND: The study investigated heavy metals levels [urinary cadmium (U-Cd), erythrocytic cadmium (E-Cd), urinary arsenic (U-As), and whole blood lead (WB-Pb)] in children with bronchial asthma (BA) and tested their associations with serum periostin, miRNA-125b and miRNA-26a levels, and with asthma severity clinically and laboratory [blood eosinophils count (BEC) and serum total immunoglobin E (IgE)]. Also, we tested cut-off points, for the studied parameters, to distinguish BA cases from healthy children. METHODS: This case-control study included 158 children divided into control group; n = 72 and BA group; n = 86. Heavy metals were measured by an inductively coupled plasma-optical emission spectrophotometer. Serum periostin and IgE levels were measured by their corresponding ELISA kits. miRNAs relative expressions were estimated by RT-qPCR using the 2-ΔΔCT method. RESULTS: Heavy metals, serum periostin, and miR-125b levels were significantly high in BA group (p < 0.001). Heavy metals levels correlated positively with serum periostin, miR-125b and IgE levels, BEC, and asthma severity. The reverse was observed regarding serum miR-26a levels. Receiver operating characteristics (ROC) curve analysis showed good to excellent abilities of U-Cd, E-Cd, U-As, WB-Pb, serum periostin, miRNA-125b, and miRNA - 26a, and total IgE levels to distinguish BA cases from healthy children. CONCLUSIONS: Heavy metal toxicity in children is associated with BA severity, increased serum periostin and miRNA-125b levels, and decreased miRNA-26a levels. Specific measures to reduce children's exposure to heavy metals should be taken. Future research should consider blocking miRNA-125b action or enhancing miRNA-26a action to manage BA cases.

Tumor-targeted miRNA nanomedicine for overcoming challenges in immunity and therapeutic resistance.

miRNA are critical messengers in the tumor microenvironment (TME) that influence various processes leading to immune suppression, tumor progression, metastasis and resistance. Strategies to modulate miRNAs in the TME have important implications in overcoming these challenges. However, miR delivery to specific cells in the TME has been challenging. This review discusses nanomedicine strategies to achieve cell-specific delivery of miRNAs. The key goal of delivery is to activate the tumor immune landscape as well as to prevent chemotherapy resistance. Specifically, the use of hyaluronic acid-based nanoparticle miRNA delivery to the TME is discussed. The discussion is focused on miRNA-125b for reprogramming tumor-associated macrophages to overcome immunosuppression and miRNA-let-7b to overcome resistance to anticancer chemotherapeutics because both these miRNAs have been extensively evaluated for delivery with hyaluronic acid-based delivery systems.

miRNAs are the messenger molecules with the tumor that have significant influence on the cancer growth and progression. Many strategies have been evaluated to modulate these messengers artificially to obstruct cancer growth and destroy cancer cells. This review discusses one such strategy to deliver these messenger miRNAs using hyaluronic acid-based nanoparticles that harness the body's own immune system to fight cancer. The two miRNAs that this review discusses are miRNA-125b and miRNA-let7b.

The role of miRNA125b in the progression of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common tumours worldwide, and identifying markers related to HCC is an important area of research. As a microRNA (miRNA), miRNA125b (miR-125b) plays an important role in the prediction and prognosis of HCC. In the past 10 years, with increasing research on miR-125b and HCC, the molecular mechanism of its relationship with the development of HCC has been elucidated. MiR-125b inhibits the development of HCC and is highly accurate in predicting HCC and is therefore a valuable predictive marker of HCC. This article summarizes the clinical application of miR-125b in HCC and the potential mechanism of its involvement in the progression of HCC.

Cochlioquinone derivative CoB1 induces cytostatic autophagy in lung cancer through miRNA-125b and Foxp3.

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide, yet no effective medication for this disease is available. Cochlioquinone B derivative (CoB1), purified from Salvia miltiorrhiza endophytic Bipolaris sorokiniana, affects the defense against pulmonary pathogens by regulating inflammatory responses. However, the effect of CoB1 on lung cancer and the underlying molecular mechanisms remain unknown. In the present study, we investigate the protective effects of CoB1 on lung cancer and explore its underlying mechanism. METHOD: We examined the inhibitory effect of CoB1 on lung cancer cells (A549 cells) by MTT and colony formation assay. The effect of CoB1 on cytostatic autophagy in lung cancer cells was verified by Western blot, transmission electron microscopy, and confocal microscopy. The differentially expressed miRNAs were identified using quantitative RT-PCR. Luciferase assay and Northern blot were performed to verify the correlation between miRNA-125b and Foxp3. Protein expression in autophagy-related pathways was detected by Western blot. Xenograft tumor models were constructed to explore the inhibitory effect of CoB1 and the role of miRNA-125b as a suppressor in lung cancer in vivo. RESULT: CoB1 inhibited lung cancer cell proliferation by inducing cytostatic autophagy both in vitro and in vivo. CoB1-induced autophagy was related to blocking of the PI3K/Akt1/mTOR signaling pathway. In addition, CoB1 induced miR-125b expression via activating the TAK1/MKK4/JNK/Smad axis, thereby reducing Foxp3 expression and further inducing autophagy. CONCLUSION: This study is the first to report the specific inhibitory function of CoB1 purified from Salvia miltiorrhiza endophytic Bipolaris sorokiniana in lung cancer, which may be due to the induction of autophagy. This study provides evidence and novel insights into the anticancer efficacy of CoB1.

MicroRNA-125b-5p Correlates With Prognosis and Lung Adenocarcinoma Progression.

A growing number of studies have focused on investigating microRNAs as crucial regulators in the progression of multiple cancer types. Nevertheless, the biological effects and immunological role of miR-125b-5p in non-small cell lung cancer (lung adenocarcinoma, LUAD) have not been determined. The present study aimed to examine the function of miR-125b-5p on cell proliferation and the outcomes of LUAD patients. We utilized diverse public databases in the analysis of the expression, prognosis, diagnostic value, and immune role of miR-125b-5p in non-small cell lung cancer. The growth curve, colony formation, flow cytometry, and Transwell and invasion assays were utilized to determine the function of miR-125b-5p in LUAD progression. In this study, we found that miR-125b-5p was decreased in LUAD and correlated with poor prognosis. Pathway analyses revealed that miR-125b-5p was mainly involved in cell proliferation and immune regulation. Moreover, in vitro experiments indicated that the overexpression of miR-125b-5p significantly inhibited cell proliferation, migration, and invasion and induced cell apoptosis of LUAD. Finally, we discovered that miR-125b-5p correlated with immune cell infiltration. In summary, these results demonstrated that miR-125b-5p serves as a prognostic marker and a therapeutic target for LUAD.

lncRNA-XIST protects the hypoxia-induced cardiomyocyte injury through regulating the miR-125b-hexokianse 2 axis.

Ischemic injury in the heart is associated with low oxygen, leading to the damage of cardiomyocytes. The lncRNA-XIST is known to involve in post-ischemia myocardial remodeling. However, the roles and mechanism of XIST in the hypoxia-induced cardiomyocyte are still under investigation. Moreover, studies that elucidated the impaired glucose metabolism present new hallmark of ischemic cardiovascular injury. The objective of this study is to investigate the effects of lncRNA-XIST on cardiomyocyte injury under hypoxia. Here, we demonstrate that the XIST expressions of cardiomyocyte line, H9c2 were apparently suppressed by long-time hypoxia exposure under low glucose supply. On the contrary, miRNA-125b showed reverse expression pattern to XIST. We identified that XIST functioned as a ceRNA of miR-125b to downregulate its expression in both cell line and rat primary cardiomyocyte. Under low glucose supply, H9c2 cells exhibited increased susceptibility to hypoxia. We observed overexpression of XIST significantly elevated glycose metabolism rate under hypoxia, but overexpression of miR-125b inhibited glycose metabolism rate of cardiomyocyte under hypoxia. The glycolysis enzyme, hexokinase 2 (HK2) was validated as a direct target of miR-125b, which binds to the 3'-UTR region of HK2 mRNA in cardiomyocytes. Moreover, inhibition of miR-125b significantly protected the hypoxia-induced cardiomyocyte injury through restoration of glucose metabolism. Finally, we demonstrated that transfection of miR-125b in lncRNA-XIST overexpressed H9c2 cells effectively abolished the XIST-activated glucose metabolism and cardiomyocyte protection under hypoxia. The present study illustrates roles of the XIST-miR-125b-HK2 axis in the hypoxia-induced cardiomyocyte injury and proposes that maintaining glucose metabolism might be an effective approach for protection of cardiomyocyte injury.

Multi-marker diagnosis method for early Hepatocellular Carcinoma based on surface plasmon resonance.

Early diagnosis of Hepatocellular Carcinoma (HCC) is an important means to raise the survival rate of patients. Multi-marker combined detection is a powerful tool of early HCC diagnosis. Traditional detection methods are not effective and accurate because it is difficult to achieve combined detection of multiple markers. In this paper, we selected Alpha Fetoprotein (AFP) and miRNA-125b as the combined detection markers to improve the simultaneously diagnostic sensitivity and specificity. The anti-AFP monoclonal antibody and the DNA probes paired with the miRNA-125b were modified on the surface of surface plasmon resonance (SPR) sensor respectively to specifically recognize AFP and miRNA-125b in serum. In order to enhance the SPR response signal and detection sensitivity, Double Antibody Sandwich Method (DASM) and S9.6 antibody enhanced method were applied to achieve low detection limit of the two markers. Experimental results showed that AFP (25-400 ng/mL) was accurately detected by DASM and the detection limit of miRNA-125b by S9.6 antibody enhanced method reached 123.044 pM. These results verified the feasibility of the multi-marker detection method in early diagnosis of HCC.

Addressing Alzheimer's Disease (AD) Neuropathology Using Anti-microRNA (AM) Strategies.

Disruptions in multiple neurobiological pathways and neuromolecular processes have been widely implicated in the etiopathology of Alzheimer's disease (AD), a complex, progressive, and ultimately lethal neurological disorder whose current incidence, both domestically and globally, is reaching epidemic proportions. While only a few percent of all AD cases appear to have a strong genetic or familial component, the major form of this disease, known as idiopathic or sporadic AD, displays a multi-factorial pathology and represents one of the most complex and perplexing neurological disorders known. More effective and innovative pharmacological strategies for the successful intervention and management of AD might be expected: (i) to arise from strategic-treatments that simultaneously address multiple interrelated AD targets that are directed at the initiation, development, and/or propagation of this disease and (ii) those that target the "neuropathological core" of the AD process at early or upstream stages of AD. This "Perspectives paper" will review current research involving microRNA (miRNA)-mediated, messenger RNA (mRNA)-targeted gene expression pathways in sporadic AD and address the potential implementation of evolving anti-microRNA (AM) strategies in the amelioration and clinical management of AD. This novel-therapeutic approach: (i) incorporates a system involving the restoration of multiple miRNA-regulated mRNA-targets via the use of selectively-stabilized AM species; and (ii) that via implementation of synthetic AMs, the abundance of only relatively small-families of miRNAs need be modulated or neutralized to re-establish neural-homeostasis in the AD-affected brain. In doing so, these strategic approaches will jointly and interactively address multiple AD-associated processes such as the disruption of synaptic communication, defects in amyloid peptide clearance and amyloidogenesis, tau pathology, deficits in neurotrophic support, alterations in the innate immune response, and the proliferation of neuroinflammatory signaling.

microRNA-125b Regulates Apoptosis by Targeting Bone Morphogenetic Protein Receptor 1B in Yak Granulosa Cells.

The intronic microRNA, miR-125b, plays a vital role in promyelocytic and hematopoietic stem cells, and in the development and apoptosis of cancer cells. In this study, we showed that miR-125b regulates granulosa cell (GC) apoptosis in the yak ovary. Bioinformatic analyses and luciferase reporter assays demonstrated that bone morphogenetic protein receptor type 1B (BMPR1B) is an miR-125b target. miR-125b overexpression induced apoptosis in yak GC, and affected the mRNA and protein expression of BMPR1B and the ratio of Bcl2/Bax. Silencing of miR-125b decreased the rate of yak GC apoptosis and increased the ratio of Bcl2/Bax. In addition, the effects of an miR-125b inhibitor were overturned by cotransfection with siRNA-BMPR1B2 (siRNA-299) in yak GC. Together, these results demonstrated that miR-125b regulates GC apoptosis in the yak ovary by targeting BMPR1B.

Systemic Inflammation in C57BL/6J Mice Receiving Dietary Aluminum Sulfate; Up-Regulation of the Pro-Inflammatory Cytokines IL-6 and TNFα, C-Reactive Protein (CRP) and miRNA-146a in Blood Serum.

A number of experimental investigations utilizing different murine species have previously reported: (i) that standard mouse-diets supplemented with physiologically realistic amounts of neurotoxic metal salts substantially induce pro-inflammatory signaling in a number of murine tissues; (ii) that these diet-stimulated changes may contribute to a systemic inflammation (SI), a potential precursor to neurodegenerative events in both the central and the peripheral nervous system (CNS, PNS); and (iii) that these events may ultimately contribute to a chronic and progressive inflammatory neurodegeneration, such as that which is observed in Alzheimer's disease (AD) brain. In these experiments we assayed for markers of SI in the blood serum of C57BL/6J mice after 0, 1, 3 and 5 months of exposure to a standard mouse diet that included aluminum-sulfate in the food and drinking water, compared to age-matched controls receiving magnesium-sulfate or no additions. The data indicate that the SI markers that include the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), the acute phase reactive protein C-reactive protein (CRP) production and a triad of pro-inflammatory microRNAs (miRNA-9, miRNA-125b and miRNA-146a) all increase in the serum after aluminum-sulfate exposure. For the first time these results suggest that ad libitum exposure to aluminum-sulfate at physiologically realistic concentrations, as would be found in the human diet over the long term, may predispose to SI and the potential development of chronic, progressive, inflammatory neurodegeneration with downstream pathogenic consequences.

Regulation of human adipogenesis by miR125b-5p.

MicroRNAs (miRNAs) are non-coding RNAs that regulate target gene expression at the post-transcriptional level and are supposed to be implicated in the control of adipogenesis. We aimed to identify miRNAs which are involved in the regulation of human adipogenesis and searched for their molecular targets. Applying microarray-analysis we identified miR125b-5p as upregulated during human adipocyte differentiation, although its role during adipogenesis is unknown. We identified and characterized the matrix metalloproteinase 11 (MMP11) as a direct target of miR125b-5p by showing that miR125b-5p overexpression significantly reduces MMP11 luciferase activity and mutation of any single binding site was sufficient to abolish the miR125b-5p mediated inhibition of luciferase activity. MMP11 overexpression decreased fat accumulation, indicating that MMP11 acts as an anti-adipogenic regulator. In contrast, overexpression of miR125b-5p itself reduced adipogenesis. In summary, we identified miR125b-5p as upregulated during human adipogenesis indicating that miR125b-5p may serve as a regulator of human adipocyte differentiation. We further show that miR125b-5p downregulates the anti-adipogenic MMP11, but directly inhibits adipogenesis itself. Taken together, these data implicate that miR125b-5p can affect human adipogenesis via MMP11 and probably additional targets.

Expression and Its Significance of microRNA-125b and microRNA-133b in Plasma in Children with Asthma / 现代检验医学杂志

Objective To explore the diagnostic value of the quantitative detection of plasma miRNA-125b and miRNA-133b in children with asthma.Methods Thirty asthmatic patients were enrolled in this study and collected the blood specimens during acute phase and stable phase respectively (AP group and SP group).Thirty allergic rhinitis children (AR group) and thirty healthy children were recruited to the control group (NC group).The levels of miRNA in different groups were detected by qRT-PCR.The performance of miRNA-125b and miRNA-133b were evaluated by receiver operating characteristic curves (ROC) and the area under the curve (AUC) (95％CI).Results The relative expression of miRNA-125b in AP group and SP group were significantly higher than A R group (t=3.913,3.120,P＜0.01),miRNA-133b.In AP group and AR group the expression of miRNA-133b were significantly higher than control group (t=4.426,4.720,P＜0.01).The detection of miRNA-125b yielded an area under the curve of ROC of 0.7989,(95 ％ CI:0.7111～ 0.8864) in discriminating asthmatic patients from healthy group.And the miRNA-133b was 0.7274 (95％CI:0.586 5～0.863 0) in discriminating asthmatic patients during the acute phase from healthy group.Conclusion The relative expression of miRNA-125b in children with asthma was significantly higher than that in AR group and NC group,miRNA-125b may prove to be a non-invasive biomarker for the auxiliary diagnosis of asthma especially when the relative expression up to 1.998.