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Traumatic brain injury (TBI) is a serious public health problem worldwide, which could lead to an extremely high percentage of mortality and disability. Current treatment strategies mainly concentrate on neuronal protection and reconstruction, among them, exogenous neural stem cell (NSC) transplantation has long been regarded as the most effective curative treatment. However, due to secondary trauma, transplant rejection, and increased incidence of brain malignant tumor, a non-invasive therapy that enhanced endogenous neurogenesis was more suitable for TBI treatment. Our previous work has shown that miR-132 overexpression could improve neuronal differentiation of NSCs in vitro and in vivo. So, we engineered a new kind of AAV vector named AAV-PHP.eB which can transfect brain parenchyma through intravenous injection to overexpress miR-132 in brain after TBI. We found that miR-132 overexpression could reduce impact volume, promote neurogenesis in the dentate gyrus (DG), accelerate neuroblast migrating into the impact cortex, ameliorate microglia-mediated inflammatory reaction, and ultimately restore learning memory function. Our results revealed that AAV-PHP.eB-based miR-132 overexpression could improve endogenous tissue repairment and release clinical symptoms after traumatic brain injury. This work would provide a new therapeutic strategy for TBI treatment and other neurological disorders characterized by markable neuronal loss and memory impairment. miR-132 overexpression accelerates endogenous neurogenesis and releases TBI-induced tissue repairment and memory impairment. Controlled cortical impact onto the cortex would induce serious cortical injury and microglia accumulation in both cortex and hippocampus. Moreover, endogenous neuroblast could migrate around the injury core. miR-132 overexpression could accelerate neuroblast migration toward the injury core and decreased microglia accumulation in the ipsilateral cortex and hippocampus. miR-132 could be a suitable target on neuroprotective therapy after TBI., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The rapid increase in urbanization is altering the natural composition of the day-night light ratio. The light/dark cycle regulates animal learning, memory, and mood swings. A study was conducted to examine the effect of different quantity and quality of light at night on the daily clock, learning, memory, cognition, and expression of transcripts in key learning centers. Treatment was similar for experiments one to three. Rats were exposed for 30 days to 12 h light and 12 h dark with a night light of 2 lx (dLAN group), 250 lx (LL), or without night light (LD). In experiment one, after 28 days, blood samples were collected and 2 days later, animals were exposed to constant darkness. In experiment two, after 30 days of treatment, animals were subjected to various tests involving learning, memory, and cognition. In experiment three, after 30 days of treatment, animals were sampled, and transcript levels of brain-derived neurotrophic factor, tyrosine kinase, Growth-Associated Protein 43, Neurogranin, microRNA-132, cAMP Response Element-Binding Protein, Glycogen synthase kinase-3β, and Tumor necrosis factor α were measured in hippocampus, thalamus, and cortex tissues. In experiment four, animals were exposed to night light of 0.019 W/m 2 but of either red (640 nm), green (540 nm), or blue (450 nm) wavelength for 30 days, and similar tests were performed as mentioned in experiment 2. While in experiment five, after 30 days of respective wavelength treatments, all animals were sampled for gene expression studies. Our results show that exposure to dLAN and LL affects the daily clock as reflected by altered melatonin secretion and locomotor activity, compromises the learning, memory, and cognitive ability, and alterations in the expression levels of transcripts in the hypothalamus, cortex, and thalamus. The effect is night light intensity dependent. Further, blue light at night has less drastic effects than green and red light. These results could be of the potential use of framing the policies for the use of light at night., (© 2023. The Author(s), under exclusive licence to European Photochemistry Association, European Society for Photobiology.)

Aging causes substantial molecular to morphological changes in the brain. The brain cells are more susceptible towards oxidative damage due to impaired antioxidant defense system. Sirtuin1 (SIRT1) is a crucial cellular survival protein, which its gene has been identified as a direct target of microRNA 132 (miR-132). Trehalose contributes to preventing neuronal damage through several mechanisms. However, little is known about the interactive effects of aging and trehalose on the expression pattern of miR-132 and SIRT1 in the hippocampus. Male Wistar rats were divided into four groups. Two groups of aged (24 months) and young (4 months) rats were administered 2% trehalose solution for 30 days. Two other groups of aged and young rats received regular tap water. At the end of treatment, the levels of Sirt1 mRNA and its protein, malondialdehyde, protein carbonyl content, total antioxidant capacity, tumor necrosis factor α (TNF-α), as well as the expression of miR-132 were measured in the hippocampus. We found that trehalose treatment upregulated the expression of SIRT1 and miR-132. Moreover, administration of trehalose enhanced the level of total antioxidant activity whereas reduced the levels of lipid peroxidation, protein carbonyl content, and TNF-α. In conclusion, our data indicated that trehalose restored antioxidant status and alleviated inflammation in the hippocampus which was probably associated with the upregulation of SIRT1 and miR-132., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Obesity has now surpassed malnutrition and infectious diseases as the most significant contributor to health problems worldwide. In particular, obesity is associated with several metabolic disorders, including hyperlipidemia, hepatic steatosis, and subfertility. Genipin (GNP), the aglycone of geniposide, is isolated from the extract of the traditional Chinese medicine Gardenia jasminoides Ellis and has been used in traditional oriental medicine against several inflammation-driven diseases. However, the effect and molecular mechanism of GNP on obesity-associated dyslipidemia and sperm dysfunction still need to be explored. In this study, we detect the effects of GNP on hyperlipidemia, hepatic lipid accumulation and sperm function using a high-fat diet (HFD)-induced obese mouse model. We find that obese mice treated with GNP show an improvement in body weight, serum triglyceride levels, serum hormone levels, serum inflammatory cytokines, hepatic steatosis and sperm function. At the molecular level, HFD/GNP diversely regulates the expression of miR-132 in a tissue-specific manner. miR-132 further targets and regulates the expression of SREBP-1c in liver cells, as well as the expressions of SREBP-1c and StAR in Leydig cells in the testis, thus modifying lipogenesis and steroidogenesis, respectively. Collectively, our data demonstrate that GNP shows a broad effect on the improvement of HFD-induced metabolic disorder and sperm dysfunction in male mice by tissue-specific regulation of miR-132. Our findings reveal the function GNP in ameliorating hepatic lipid metabolism and sperm function and suggest that this compound is a versatile drug to treat metabolic disorders.

Polyphenols are capable of decreasing cancer risk. We examined the chemopreventive effects of a green tea ( Camellia sinensis ) extract, polyphenol extract (a mixture of blackberry ( Rubus fruticosus ), blackcurrants ( Ribes nigrum ), and added resveratrol phytoalexin), Chinese bayberry ( Myrica rubra ) extract, and a coffee ( Coffea arabica ) extract on 7,12-dimethylbenz[a]anthracene (DMBA) carcinogen-increased miR-134, miR-132, miR-124-1, miR-9-3, and mTOR gene expressions in the liver, spleen, and kidneys of CBA/Ca mice. The elevation was quenched significantly in the organs, except for miR-132 in the liver of the Chinese bayberry extract-consuming group, and miR-132 in the kidneys of the polyphenol-fed group. In the coffee extract-consuming group, only miR-9-3 and mTOR decreased significantly in the liver; also, miR-134 decreased significantly in the spleen, and, additionally, miR-124-1 decreased significantly in the kidney. Our results are supported by literature data, particularly the DMBA generated ROS-induced inflammatory and proliferative signal transducers, such as TNF, IL1, IL6, and NF-κB; as well as oncogenes, namely RAS and MYC . The examined chemopreventive agents, besides the obvious antioxidant and anti-inflammatory effects, mainly blocked the mentioned DMBA-activated factors and the mitogen-activated protein kinase (MAPK) as well, and, at the same time, induced PTEN as well as SIRT tumor suppressor genes.

Specific gene and miRNA expression patterns are potential early biomarkers of harmful environmental carcinogen exposures. The aim of our research was to develop an assay panel by using several miRNAs for the rapid screening of potential carcinogens. The expression changes of miR-124-1, miR-212, miR-132, miR-134, and miR-155 were examined in the spleen, liver, and kidneys of CBA/Ca mice, following the 20 mg/bwkg intraperitoneal 7,12-dimethylbenz(a)anthracene (DMBA) treatment. After 24 h RNA was isolated, the miRNA expressions were analyzed by a real-time polymerase chain reaction and compared to a non-treated control. DMBA induced significant changes in the expression of miR-134, miR-132, and miR-124-1 in all examined organs in female mice. Thus, miR-134, miR-132, and miR-124-1 were found to be suitable biomarkers for the rapid screening of potential chemical carcinogens and presumably to monitor the protective effects of chemopreventive agents.

We aimed to explore the relationships between the plasma expression levels of microRNA (miR)-146a and miR-132 in epileptic patients and cognitive, mental and psychological disorders. Eighty epileptic patients and seventy healthy subjects as controls were evaluated with Montreal Cognitive Assessment (MoCA), Hamilton Anxiety Rating (HAMA) and Hamilton Depression Rating (HAMD) scales, and plasma samples were collected. MiR-146a and miR-132 levels were detected by real-time quantitative PCR. The total incidence rate of cognitive dysfunction, anxiety and depression in epilepsy group was 62.5%. Cognitive dysfunction was correlated positively with educational level, but negatively with disease course, duration and type of administration. The frequency and duration of seizures were positively correlated with anxiety. Depression was correlated negatively with educational level, whereas positively with course of disease and number of used drugs. Epileptic patients had significantly higher miR-146a and miR-132 levels than those of healthy controls. The miR-146a and miR-132 levels of patients with complications were significantly higher than those of cases without complications. Their expressions were correlated negatively with total MoCA scale score, but positively with type of complications. MiR-132 expression was positively correlated with the total scores of HAMA and HAMD scales. Plasma miR-146a and miR-132 expressions increased in epileptic patients, and miR-132 expression reflected the severity of epilepsy and predicted the risks of complications.

Parkinson's disease (PD) is an age-related neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. LncRNA MIAT has been shown to be critical in Alzheimer's disease, but its role and mechanism in PD are still unknown. Differentiated PC12 cells were treated with 1-methyl-4-phenylpyridinium (MPP + ) to establish in vitro cell injury model of PD. MTT, Annexin V-PI double staining test and Western blot were used to detect cell viability and apoptosis. Reactive oxygen species (ROS), superoxide dismutase (SOD) and phospholipid hydroperoxide glutathione peroxidase (GSH-PX) kits were used to evaluate oxidative stress in cells. These results showed that LncRNA MIAT was down-regulated in MPP + -induced PC12 cells. Overexpression of LncRNA MIAT remarkably increased cell viability, inhibited cell apoptosis and oxidative stress in MPP + -treated cells. In addition, we proved that miR-132 is a target of LncRNA MIAT. Overexpression of miR-132 could reverse the positive effect of LncRNA MIAT overexpression on MPP + -induced cell oxidative stress injury. SIRT1 is a target of miR-132 and silencing of SIRT1 attunated the positive effect of LncRNA MIAT overexpression on oxidative stress injury in MPP + -induced PC12 cells. In conclusion, this study indicated that LncRNA MIAT suppressed MPP + -induced oxidative stress injury by regulating miR-132/SIRT1 axis in PC12 cells., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neural stem cells residing in the hippocampal neurogenic niche sustain lifelong neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. In Alzheimer's disease (AD), the process of generating new neurons at the hippocampal neurogenic niche is impeded, yet the mechanisms involved are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a potent regulator of AHN, exerting cell-autonomous proneurogenic effects in adult neural stem cells and their progeny. Using distinct AD mouse models, cultured human primary and established neural stem cells, and human patient material, we demonstrate that AHN is directly affected by AD pathology. miR-132 replacement in adult mouse AD hippocampus restores AHN and relevant memory deficits. Our findings corroborate the significance of AHN in mouse models of AD and reveal the possible therapeutic potential of targeting miR-132 in neurodegeneration., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Focal segmental glomerulosclerosis (FSGS) is the common cause of chronic renal disease worldwide. Although there are many etiologic factors which have common theme of podocyte injury conclusive etiology is not clearly understood. In this study, we aimed to explore the role of autophagy in the pathogenesis of podocyte injury, which is the key point in disease progression, and the roles of intrarenal microRNAs and the prorenin receptor (PRR) in the 5/6 nephrectomy and adriamycin nephropathy models of FSGS., Main Methods: For experimental FSGS model, 5/6 nephrectomy and adriamycin nephropathy models were created and characterized in adult Sprague Dawley rats. Microarray analysis was performed on FSGS and control groups that was confirmed by q-RT-PCR. Beclin1, LC3B, PRR, ATG7 and ATG5 expression were evaluated by western blotting and immunohistochemistry. Also, Beclin1 and PRR expression were measured by ELISA. Glomerular podocyte isolation was performed and autophagic activity was evaluated in podocytes before and after transfection with miRNA mimic and antagonists., Key Findings: Glomerular expression of Beclin1, LC3B, PRR, ATG7 and ATG5 were significantly lower in the 5/6 nephrectomy than adriamycin nephropathy group and in both groups lower when compared to control groups. Western blot results were consistent with immunohistochemical data. Electron microscopy revealed signs of impaired autophagy in FSGS. Autophagic activity decreased significantly after miR-214, miR-132 and miR-34c mimics and increased after transfection with antagonists., Significance: These results showed that the role of autophagic activity and decreased expression of PRR in FSGS pathogenesis and miR-34c, miR-132 and miR-214 could be a potential treatment strategy by regulating autophagy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

MicroRNAs are a group of short non-coding RNAs (miRNAs), which are epigenetically involved in gene expression and other cellular biological processes and can be considered as potential biomarkers for cancer detection and support for treatment management. This review aims to amass the evidence to reach the molecular mechanism and clinical significance of miR-132 in different types of cancer. Dysregulation of miR-132 level in various types of malignancies, including hepatocellular carcinoma, breast cancer, colorectal cancer, gastric cancer, lung cancer, prostate cancer, osteosarcoma, pancreatic cancer, and ovarian cancer have reported, significantly decrease in its level, which can be indicated to its function as a tumor suppressor. miR-132 is involved in cell proliferation, migration, and invasion through cell cycle pathways, such as PI3K, TGFβ or hippo signaling pathways, or on oncogenes such as Ras, AKT, mTOR, glycolysis. miR-132 could be potentially a candidate as a valuable biomarker for prognosis in various cancers. Through this study, we proposed that miR-132 can potentially be a candidate as a prognostic marker for early detection of tumor development, progression, as well as metastasis.

Background and Purpose: In subarachnoid hemorrhage (SAH), impairments in motor and cognitive functions may occur and continue in later periods. MicroRNAs (miRNAs) are small non-coding RNAs that can directly or indirectly affect synaptic reconstruction. mir-132, mir-134, and mir-138 are the leading miRNAs that can be effective on some neurological functions through its effects on synaptic plasticity in the relevant brain areas. In our study, it was aimed to determine the levels of miRNAs in the hippocampus and frontal lobe of rats exposed to different environmental conditions after the experimental SAH., Methods: SAH was created using the cisterna magna double blood-injection method. Brain tissues were collected at different times after the last blood injection. Rats were grouped according to the different environmental conditions in which they were kept. Expression levels of miRNAs were performed by qPCR and ultrastructural changes in samples were determined by transmission electron microscopy (TEM)., Results: After SAH, miR-132, miR-134, and miR-138 expressions in the frontal lobes of rats increased in impoverished environment on the 7th day and in the enriched environment on the 14th day. It was observed that the myelin and microtubule structures in the axons that were disrupted after SAH were more organized and stable in the enriched environment., Conclusions: After SAH, different environmental conditions may affect the miRNA levels associated with synaptic plasticity and microtubule organization in the frontal lobe, and this might have some effects especially on cognitive and motor functions related to this brain area., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chemo-resistance and metastasis are the most common causes of breast cancer recurrence and death. Thidiazuron (TDZ) is a plant growth regulator (phytohormone) whose biological effects on humans and animals has not yet been determined. In this study, we investigated the anticancer activity of this phytohormone on the drug resistant-triple negative breast cancer cell line MDA-MB-231. Treatment of the breast cancer cells with TDZ (1-50 μmol/L) caused more stressful environment and induced a significant increase in active caspase-positive cells. In addition, TDZ treatment (5 and 10 μmol/L) significantly attenuated the migration and the invasiveness of these highly metastatic cancer cells. Mechanistically, TDZ reduces cancer progression and invasiveness by targeting miR-202-5p, which stimulates the expression of phosphatase and tensin homolog (PTEN), the tumor suppressor that downregulates the PI3K-Akt signaling pathway. Treatment with TDZ significantly upregulates miRNA-132, the suppressor of breast cancer proliferation, which is also implicated in dysregulation of the TEN-Akt-NFκB signaling pathway. Interestingly, our molecular docking analysis revealed a potential non-covalent interaction between TDZ and Akt, PTEN, and PI3K. These findings suggest that TDZ suppresses breast cancer metastasis by targeting miRNA-132, the miR-202-5p-PTEN axis, and the PI3K-Akt signaling pathway downstream.

Objective: To study the relationship between the circular RNA vesicle-associated membrane protein-associated protein A (circVAPA) and the pathogenesis of oral squamous cell carcinoma., Methods: The expression of circVAPA was detected by RT-qPCR. In vitro loss-of-function experiments were performed in Cal-27 cells. The malignant phenotype of cells was evaluated by cell counting kit-8, clone formation and transwell assays. Luciferase reporter assays were used to assess the circVAPA/miR-132/homeobox A (HOXA) regulatory axis., Results: circVAPA expression was significantly increased in oral cancer tissues and cells. The overall survival and progression-free survival of patients with oral cancer who exhibited high circVAPA expression were significantly shorter compared with those with low expression. circVAPA expression was closely related to tumor size, TNM stage and distant metastasis. circVAPA knockdown reduced the proliferation, invasion and migration of Cal-27 cells. MiR-132 was identified as a target of circVAPA in Cal-27 cells. Cotransfection with si-circVAPA and miR-132 inhibitor reversed the inhibitory effect of circVAPA knockdown on cell malignant phenotypes. HOXA7 was further identified as a downstream target of miR-132., Conclusion: circVAPA is highly expressed in oral cancer, and its abnormal expression might affect the proliferation, invasion and migration of oral cancer cells by modulating the miR-132/HOXA7 signaling axis.

This study investigated the effects and mechanisms of miR-132 related to the permeability and mobility of human retinal pigment epithelium ARPE-19 cells in high-glucose (HG) condition. ARPE-19 cells were cultured in normal and HG condition and identified by immunofluorescence staining. Cell viability was assessed by the MTT assay, cell permeability was assessed by the FITC-dextran assay and cell mobility was assessed by the wound healing assay. Different miRNA and mRNA expression levels were determined by quantitative real-time polymerase chain reaction (RT-qPCR). The expression of tight junction-related proteins was determined by Western blot assay and immunofluorescence. The interaction between occludin and miR-132 was confirmed by a dual-luciferase reporter assay. We revealed that HG-treated ARPE-19 cells exhibited significantly increased miR-132 expression, decreased expression of the tight-junction markers including occludin and E-cadherin, and increased cell mobility and permeability. Occludin is a direct target of miR-132, which could regulate cell viability, mobility and permeability under HG condition through the JAK/STAT3 signaling pathway. These are the first data to suggest that miR-132 may contribute to the progression of diabetic retinopathy (DR) and that targeting the effect of miR-132 on occudin and the JAK/STAT3 pathway could represent a novel effective DR-treatment strategy.

MicroRNAs play an important role in the modulation of the immune system. T helper 17 (Th17) cells are involved in the modulation of the tumour microenvironment. However, the function of miRNA in Th17 cells in the tumour microenvironment is unclear. In this study, we analysed miR-132 expression in Th17 cells and assessed the function of miR-132 on Th17 cell differentiation. In addition, the effect of miR-132 on Th17 cells in the tumour microenvironment, especially hepatic stellate cells (HSCs), was confirmed. CD4 + IL-17 ∓ cells were isolated from hepatocellular carcinoma (HCC) tumour tissues. The expression of miR-132 was higher in CD4 + IL-17 + cells than in CD4 + IL-17- cells. Human primary CD4 + T cells were used for Th17 cell differentiation. Compared with primary CD4 + T cells, Th17 cells expressed high levels of miR-132. During Th17 cell differentiation, a miR-132 mimic and inhibition were applied. After treatment with the miR-132 mimic, the differentiation of Th17 cells accelerated, showing a a higher percentage of Th17 cells and the expression and secretion of IL-17 and IL-22. Smad nuclear interacting protein 1 (SNIP1), as one of the targets of miR-132, decreased during Th17 cell differentiation-related Th17 differentiation and IL-17 expression. The conditioned medium of miR-132-overexpressing Th17 cells could increase the activation of the HSCs, which strongly promoted HCC cell migration and epithelial-mesenchymal transition (EMT). In summary, miR-132 positively regulates Th17 cell differentiation and improves the function of Th17 on HSCs for their tumour-promoting effects., (© 2020 The Scandinavian Foundation for Immunology.)

Background: Osteoarthritis (OA) is a commonly known prevalent joint disease, with limited therapeutic methods. This study aimed to investigate the functions of miRNA-132 (miR-132) in the modulation of PTEN/PI3K/AKT signaling pathway in the development and progression of osteoarthritis., Methods: Eight male osteoarthritic patients and eight healthy males were recruited. Male Sprague Dawley (SD) rats were used for cellular experiments. QRT-PCR was performed to detect the expression levels of miR-132, PTEN, PI3K and AKT. MTT assay and apoptosis assay were carried out to measure the cell proliferation rate and cell apoptosis rate, respectively. Western blotting was employed to detect the protein expression of related RNAs and inflammatory factors., Results: In osteoarthritic patients, the expression level of miR-132 was decreased, compared with that in the normal group. Over-expression of miR-132 elevated cell proliferation and decreased apoptosis of chondrocytes. Down-regulation of miR-132 decreased cell proliferation and induced apoptosis in chondrocytes. In addition, down-regulation of miR-132 promoted the expression of Bax protein and activated caspase-3/9, increased inflammation divisors. PTEN inhibitor antagonized the destructive effect of the miR-132 inhibitor on cell proliferation of chondrocytes. PI3K inhibitor increased the destructive effect of the miR-132 inhibitor on osteoarthritis., Conclusion: In conclusion, miR-132 is an important regulator of osteoarthritis in chondrocytes through the PTEN/PI3K/AKT signaling pathway.

Fragile X-related protein 1 (FXR1) is a member of the fragile X family of RNA-binding proteins, which regulates a number of neurological and neuropsychiatric disorders such as fragile X syndrome, and is expected as a novel therapeutic target for some psychiatric diseases. However, it is unknown how FXR1 changes and functions in post-traumatic stress disorder (PTSD), a common mental disorder related to trauma and stressor. In this study, we characterized the expression pattern of FXR1 in the pathophysiological process of PTSD and further investigated the possible mechanism underlying these changes by finding an upstream regulator, namely miRNA-132 (miR-132). Furthermore, we verified whether miR-132 silence had an effect on the PTSD-like behaviors of single prolonged stress (SPS) rats through open field test, forced swimming test, and water maze test. At last, we examined the expression levels of PSD95 and synapsin I in the hippocampus, which was one of the key brain regions associated with PTSD. We showed that the levels of FXR1 and fragile X mental retardation protein (FMRP), an autosomal homolog of FXR1, were decreased in the hippocampus of PTSD rats, but the levels of PSD95 and synapsin I were increased, which could be reversed by downregulation of miR-132. The results revealed that miR-132 could modulate PTSD-like behaviors in rats following SPS through regulating FXR1 and FMRP.

Background: The long non-coding RNA (lncRNA) small nucleolar RNA host gene 5 (SNHG5) has been verified as a crucial regulator in many types of tumours but not clear in cervical cancer (CC). This study aims to investigate the effect and further mechanisms of lncRNA SNHG5 in CC., Methods: The expression of SNHG5 and miR-132, as well as SOX4 (sex-determining region Y-box 4) mRNA expression were determined by quantitative real-time PCR (qRT-PCR). The protein level of SOX4 and epithelial-mesenchymal transition (EMT)-related proteins were evaluated by western blot. Then, Edu and Transwell assay were performed to assess the proliferation, migration and invasion of CC cells. RNA immunoprecipitation (RIP) and RNA pull-down assay were conducted to explore the relationship between SNHG5 and miR-132., Results: SNHG5 and SOX4 were upregulated, and miR-132 was downregulated in CC tissues and cell lines. SNHG5 was positively correlated with FIGO stage ( p  = .003) and lymph node metastasis ( p  = .001). Pearson's correlation analysis conveyed that SNHG5 was positively correlated with SOX4, and miR-132 was negatively correlated with SOX4 and SNHG5. Knockdown of SNHG5 in vitro reduced CC cell proliferation, migration and invasion through regulating miR-132. Moreover, overexpression of miR-132 restrained CC cell proliferation, migration, and invasion through targeting SOX4, and SNHG5 enhanced SOX4 expression via negatively regulating miR-132., Conclusion: SNHG5 promotes SOX4 expression to accelerate CC cell proliferation, migration and invasion through negatively regulating miR-132.

Aryl hydrocarbon receptor (AhR), is a transcription factor and an environmental sensor that has been shown to regulate T cell differentiation. Interestingly, AhR ligands exert varying effects from suppression to exacerbation of inflammation through induction of Tregs and Th-17 cells, respectively. In the current study, we investigated whether the differential effects of AhR ligands on T cell differentiation are mediated by miRNA during delayed-type hypersensitivity (DTH) reaction against methylated Bovine Serum Albumin (mBSA). Treatment of C57BL/6 mice with TCDD attenuated mBSA-mediated DTH response, induced Tregs, decreased Th-17 cells, and caused upregulation of miRNA-132. TCDD caused an increase in several Treg subsets including inducible peripheral, natural thymic, and Th3 cells. Also, TCDD increased TGF-β and Foxp3 expression. In contrast, treating mice with FICZ exacerbated the DTH response, induced inflammatory Th17 cells, induced IL-17, and RORγ. Analysis of miRNA profiles from draining lymph nodes showed that miR-132 was upregulated in the TCDD group and downregulated in the FICZ group. Transfection studies revealed that miRNA-132 targeted High Mobility Group Box 1 (HMGB1). Downregulation of HMGB1 caused an increase in FoxP3+ Treg differentiation and suppression of Th-17 cells while upregulation of HMGB1 caused opposite effects. Moreover, TCDD was less effective in suppressing DTH response and induction of Tregs in mice that were deficient in miR-132. In summary, this study demonstrates that TCDD and FICZ have divergent effects on DTH response and T cell differentiation, which is mediated through, at least in part, regulation of miRNA-132 that targets HMGB1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Abdulla, Neamah, Sultan, Chatterjee, Singh, Nagarkatti and Nagarkatti.)

Background: Myocardial fibrosis is a hallmark of the failing heart, contributing to the most common causes of deaths worldwide. Several microRNAs (miRNAs, miRs) controlling cardiac fibrosis were identified in recent years; however, a more global approach to identify miRNAs involved in fibrosis is missing., Methods and Results: Functional miRNA mimic library screens were applied in human cardiac fibroblasts (HCFs) to identify annotated miRNAs inducing proliferation. In parallel, miRNA deep sequencing was performed after subjecting HCFs to proliferating and resting stimuli, additionally enabling discovery of novel miRNAs. In-depth in vitro analysis confirmed the pro-fibrotic nature of selected, highly conserved miRNAs miR-20a-5p and miR-132-3p. To determine downstream cellular pathways and their role in the fibrotic response, targets of the annotated miRNA candidates were modulated by synthetic siRNA. We here provide evidence that repression of autophagy and detoxification of reactive oxygen species by miR-20a-5p and miR-132-3p explain some of their pro-fibrotic nature on a mechanistic level., Conclusion: We here identified both miR-20a-5p and miR-132-3p as crucial regulators of fibrotic pathways in an in vitro model of human cardiac fibroblast biology., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Numerous findings have demonstrated that MicroRNAs dysregulation plays a key role in many neoplasms, including oral squamous cell carcinoma (OSCC), yet the potential mechanisms of microRNAs in chemo-resistance remain elusive. Here, we analyzed the miR-132 expression in OSCC tissues and OSCC cell lines, and explored it role and mechanisms on invasion and migration and cisplatin (CDDP)-induced cell death. The clinical tissues of 37 patients with OSCCs and paired normal tissues were collected. The miR-132 expression in OSCC tissues and cell lines were detected by reverse transcription-quantitative polymerase chain reation (RT-qPCR). The in vitro repopulation models were established to mimic the biological processes of OSCC. The results showed that miR-132 expression was significantly decreased in the OSCC tissues and CDDP resistant OSCC cell line (CAL-27/CDDP). miR-132 mimic inhibited cell proliferation, invasion, migration and enhanced the pro-apoptotic ability of CDDP. On the contrary, downregulation of miR-132 promoted proliferation, invasion, migration and conferred OSCC cell resistance to CDDP-induced apoptosis in vitro . The TGF-β1 expression in OSCC tissues and CAL-27/CDDP cells was significantly higher. miR-132 significantly inhibited the TGF-β1/Smad2/3 signals. TGF-β1 upregulation significantly promoted OSCC cell proliferation and resumed OSCC cell chemo-resistance in the miR-132 overexpressing cells, which is contrary to the function of miR-132. In summary, miR-132 acts as a tumor suppressor and exerts a substantial role in inhibiting the proliferation, invasion, and enhanced the chemosensitivity to CDDP of OSCC via regulating TGF-β1/Smad2/3 signals in vitro . These observations indicate that miR-132 may be a suitable therapeutic target for the treatment of OSCC.

Melanoma, which originates from the transformation of normal melanocytes, is one of the three main types of skin cancer. We aimed to explore the functions of SNHG16 and miR-132 in melanoma. CCK-8, Transwell assays were used to measure the viability and migration, respectively. Spearman's correlation analysis was performed to analyze the relationship between the expression of SNHG16, miR-132 and LAPTM4B in melanoma tissues. SNHG16 was overexpressed, and miR-132 was low expressed in melanoma tissues and cell lines. Moreover, overexpression of SNHG16 was associated with poor prognosis of melanoma patients. The expression of SNHG16 had a negative connection with the expression of miR-132, and it had a positive relationship with the expression of LAPTM4B in melanoma tissues. Knockdown of SNHG16 or overexpression of miR-132 inhibited SK-MEL-2 cell proliferation and migration. In addition, we confirmed that SNHG16 directly binding to miR-132 promotes the expression of LAPTM4B, facilitating the tumorigenesis of melanoma. SNHG16 promotes the expression of LAPTM4B by sponging miR-132, thereby acting as an oncogene in melanoma. This study demonstrated that the lncRNA-miRNA-mRNA signal cascade existed in melanoma, which may help elucidate the tumorigenesis and development mechanism of melanoma., (Copyright 2020 Biolife Sas. www.biolifesas.org.)

Long non-coding RNAs small nucleolar RNA host gene 5 (lncRNA SNHG5) plays well-defined roles in the malignant progression. However, the roles of SNHG5 in chronic obstructive pulmonary disease (COPD) progression remain unclear. In the present study, SNHG5 expression was low expressed in COPD tissues and positively correlated with low forced expiratory volume in one second (FEV1)% in patients. Subsequently, cigarette smoke extract (CSE) decreased SNHG5 expression in 16HBE cells, and SNHG5 overexpression in 16HBE cells mitigated the effects of CSE on the proliferation, apoptosis and inflammation (IL-1β, IL-6 and TNF-a). Mechanistically, SNHG5 functioned as a competing endogenous RNA (ceRNA) for miR-132 in COPD, thereby increasing the expression of the miR-132 target PTEN. Moreover, rescue assays demonstrated that PTEN suppression (or miR-132 overexpression) attenuated the effects of SNHG5 upregulation on COPD progression. In conclusion, the SNHG5-miR-132-PTEN axis might play critical roles in COPD development, providing an effective target for the treatment of COPD., Competing Interests: Declaration of Competing Interest This article has not been published elsewhere in whole or in part. All authors have read and approved the content and agree to submit for consideration for publication in the journal. The authors declared no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Non-invasive diagnostic markers are of great importance for early screening nonalcoholic fatty liver disease (NAFLD). MicroRNAs (miRNAs) play significant roles in many metabolic disease, including NAFLD. Therefore, this study focusd on a Chinese population to explore the possible correlation between circulating miR-132 and NAFLD., Results: Serum miR-132 was positively associated with NAFLD in non-type 2 diabetes mellitus (T2DM) groups by logistic regression (OR = 3.082 [1.057, 8.988], P = 0.039) after adjusting age, sex, and body mass index (BMI). Additionally, in non-T2DM subgroup, after adjusting age, sex, bmi, serum miR-132 was significantly associated with ALT (β ± SE = 0.005 ± 0.002, P = 0.018), TG (β ± SE = 0.072 ± 0.029, P = 0.015), FPG (β ± SE = 0.123 ± 0.058, P = 0.036), γ-GT (β ± SE = 0.002 ± 0.001, P = 0.047), apoE (β ± SE = 0.038 ± 0.002, P = 0.017) ., Conclusions: Serum miR-132 was found to be associated with NAFLD risk in a Chinese cross-section study. This finding provides a prospective research direction for early screening and diagnosing NAFLD.

Objective: MicroRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. Deciphering their targets and precise role, however, remains challenging. In this study, we aimed to identify miRNAs and their downstream targets involved in the regeneration of islet beta cells following partial pancreatectomy in mice., Methods: RNA from laser capture microdissected (LCM) islets of partially pancreatectomized and sham-operated mice were profiled with microarrays to identify putative miRNAs implicated in beta cell regeneration. Altered expression of the selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA, protein expression levels, and signaling upon miR-132 knockdown and/or overexpression in mouse MIN6 and human EndoC-βH1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pancreatectomized miR-132 -/- and control mice., Results: Partial pancreatectomy significantly increased the number of BrdU + /insulin + islet cells. Microarray profiling revealed that 14 miRNAs, including miR-132 and -141, were significantly upregulated in the LCM islets of the partially pancreatectomized mice compared to the LCM islets of the control mice. In the same comparison, miR-760 was the only downregulated miRNA. The changed expression of these miRNAs in the islets of the partially pancreatectomized mice was confirmed by RT-PCR only in the case of miR-132 and -141. Based on previous knowledge of its function, we focused our attention on miR-132. Downregulation of miR-132 reduced the proliferation of MIN6 cells while enhancing the levels of pro-apoptotic cleaved caspase-9. The opposite was observed in miR-132 overexpressing MIN6 cells. Microarray profiling, RT-PCR, and immunoblotting of the latter cells demonstrated their downregulated expression of Pten with concomitant increased levels of pro-proliferative factors phospho-Akt and phospho-Creb and inactivation of pro-apoptotic Foxo3a via its phosphorylation. Downregulation of Pten was further confirmed in the LCM islets of pancreatectomized mice compared to the sham-operated mice. Moreover, overexpression of miR-132 correlated with increased proliferation of EndoC-βH1 cells. The regeneration of beta cells following partial pancreatectomy was lower in the miR-132/212 -/- mice than the control littermates., Conclusions: This study provides compelling evidence about the critical role of miR-132 for the regeneration of mouse islet beta cells through the downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell mass., (Copyright © 2019 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Emerging evidence shows that the long noncoding RNA taurine-upregulated gene 1 (TUG1) plays pivotal roles in regulating biological properties and functions of parenchyma cells in various types of disease processes. However, the mechanism underlying the effects of TUG1 on cell proliferation and apoptosis of human periodontal ligament cells (PDLCs) in periodontitis is undefined. In this study, we explored the functions of TUG1 and its underlying mechanisms in the inflammatory process induced by Porphyromonas gingivalis-derived lipopolysaccharide (LPS) in PDLCs. Our results showed that TUG1 had a decreased expression in both periodontal ligament (PDL) tissues with periodontitis and PDLCs under a LPS-induced inflammatory condition, and TUG1 expression was negatively correlated with miR-132 expression in periodontitis-affected PDL tissues. Furthermore, we found that TUG1 overexpression in PDLCs alleviated LPS-induced proliferative inhibition and apoptosis promotion, while TUG1 knockdown had the opposite effect. In addition, miR-132 inhibitor alleviated TUG1 knockdown-induced inhibition of proliferation and increase of apoptosis in PDLCs under inflammatory conditions induced by LPS. These findings indicated that TUG1 has an enormous potential in regulating cell proliferation and apoptosis of PDLCs during periodontitis and may provide an effective therapeutic target for periodontitis to reduce the damage caused by inflammatory reactions., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

MicroRNA (miRNAs) emerges as key oncogene or tumor suppressor in a variety of cancers including pancreatic carcinoma. In this study, we detected the role of miR-132 in development and progression of pancreatic cancer and the underlying mechanism. First, the expression of miR-132 in pancreatic carcinoma and adjacent non-cancerous tissues were detected by qRT-PCR. Then, the role of miR-132 in biological function of pancreatic carcinoma cells was investigated. Our results identified that miR-132 was generally upregulated in pancreatic carcinoma, and phosphatase and tensin homolog (PTEN) was generally downregulated. miR-132 and PTEN were associated with advanced tumor size, lymph node metastasis and Tumor-Nodes-Metastases (TNM) stage of pancreatic carcinoma. Downregulation of miR-132 inhibited proliferation, migration and invasion of pancreatic carcinoma cells. In contrast, overexpression of miR-132 promoted proliferation, migration and invasion of pancreatic carcinoma cells. The luciferase reporter system demonstrated PTEN is a direct target of miR-132. Overexpression of PTEN abrogated the induction of miR-132 on proliferation, migration and invasion of pancreatic carcinoma cells. Taken together, miR-132 promotes the proliferation, invasion and migration of human pancreatic cancer by inhibition of PTEN, and could be a tumor oncogene in development and progression of pancreatic carcinoma, and might be a candidate prognostic biomarker and a promising target for new treatment of human pancreatic cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Extracellular signal-regulated kinase 1 (ERK1) is an important signal transduction molecule in the ERK/mitogen-activated protein kinase pathway. miR-132 downregulation is associated with colorectal cancer (CRC). However, whether it is related to drug resistance remains poorly understood. Bioinformatics analysis demonstrated the targeting relationship between miR-132 and ERK1 3'-UTR. This study investigated the role of miR-132 in regulating ERK1 expression and affecting CRC cell proliferation, apoptosis, and adriamycin (ADM) resistance. Materials and Methods: Dual luciferase reporter gene assay was used to evaluate the targeted relationship between miR-132 and ERK1. ADM-resistant cell lines Lovo/ADM and SW480/ADM were established followed by analysis of miR-132 and ERK1 expression levels, and cell proliferation by cell counting kit-8 assay. The impact of ADM on cell proliferation and apoptosis was assessed by 5-bromodeoxyuridine (EdU) staining and flow cytometry, respectively. Lovo/ADM and SW480/ADM cells were cultured in vitro and divided into two groups, including miR-NC group and miR-132 mimic group. Results: There was a targeted regulatory relationship between miR-132 and ERK1 mRNA. The miR-132 expression was significantly lower, whereas ERK1 mRNA and protein expression levels were significantly higher in Lovo/ADM and SW480/ADM cells than those in Lovo and SW480 cells. Transfection of miR-132 mimic significantly reduced the expression of ERK1 in Lovo/ADM and SW480/ADM cells, enhanced cell apoptosis, and weakened cell proliferation. Conclusions: miR-132 reduction and ERK1 elevation are related to ADM resistance in CRC cells. Upregulation of miR-132 expression inhibits CRC cell proliferation, induces apoptosis, and reduces ADM resistance possibly by targeting ERK1 expression.

Nav1.1 and Nav1.2 are the voltage-gated sodium channel alpha subunit1 and 2, encoded by the genes of SCN1A and SCN2A. Previous studies have shown that chronic cerebral hypoperfusion (CCH) could induce neuropathological and cognitive impairment and increased total Nav1.1 and Nav1.2protein levels, yet the detailed mechanisms are not fully understood. MicroRNAs (miRNAs) are a class of small, non-coding RNAs that are involved in the regulation of dementia. miR-132 is known to play a key role in neurodegenerative disease. Here, we determined that miR-132 regulates Nav1.1 and Nav1.2 under CCH state. In this study, the expression of miR-132 was decreased in both the hippocampus and cortex of ratsfollowing CCH generated by bilateral common carotid artery occlusion (2VO). Lentiviral-mediated overexpression of miR-132 ameliorated dementia vulnerability induced by 2VO. At the molecular level, miR-132 repressed the increased protein expression of Nav1.1 and Nav1.2 in both the hippocampus and cortex induced by 2VO. MiR-132 suppressed, while AMO-miR-132 enhanced, the level of Nav1.1 and Nav1.2 in primary cultured neonatal rat neurons (NRNs) detected by both western blot analysis and immunofluorescence analysis. Results obtained by dual luciferase assay showed that overexpression of miR-132 inhibited the expression of Nav1.1 and Nav1.2 in human embryonic kidney 293 (HEK293T) cells. Additionally, binding-site mutation failed to influence Nav1.1 and Nav1.2, indicating that Nav1.1 and Nav1.2 are potential targets for miR-132. Taken together, our findings demonstrated that miR-132 protects against CCH-induced learning and memory impairments by down-regulating the expression of Nav1.1 and Nav1.2, and SCN1A and SCN2A are the target genes of miR-132., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Tauopathies are a class of neurodegenerative diseases that are characterized by pathological aggregation of tau protein, which is accompanied by synaptic disorders. However, the role of tau in endocytosis, a fundamental process in synaptic transmission, remains elusive. Here, we report that forced expression of human tau (hTau) in mouse cortical neurons impairs endocytosis by decreasing the level of the GTPase dynamin 1 via disruption of the miR-132-MeCP2 pathway; this process can also be detected in the brains of Alzheimer's patients and hTau mice. Our results provide evidence for a novel role of tau in the regulation of presynaptic function., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

MicroRNA-132 (miR-132), a small RNA that regulates gene expression, is known to promote neurogenesis in the embryonic nervous system and adult brain. Although exposure to psychoactive substances can increase miR-132 expression in cultured neural stem cells (NSCs) and the adult brain of rodents, little is known about its role in opioid addiction. So, we set out to determine the effect of miR-132 on differentiation of the NSCs and whether this effect is involved in opioid addiction using the rat morphine self-administration (MSA) model. We found that miR-132 overexpression enhanced the differentiation of NSCs in vivo and in vitro. Similarly, specific overexpression of miR-132 in NSCs of the adult hippocampal dentate gyrus (DG) during the acquisition stage of MSA potentiated morphine-seeking behavior. These findings indicate that miR-132 is involved in opioid addiction, probably by promoting the differentiation of NSCs in the adult DG.

MicroRNAs (miRNAs) are small and evolutionary conserved noncoding RNAs that are involved in post-transcriptional gene regulation. Differential expression levels of miRNAs can be used as potential biomarkers of disease. Previous animal studies have indicated that the expression level of miR-132 is negatively correlated with its downstream molecule nuclear receptor related 1 protein (Nurr1), which is one of the key factors for the maintenance of dopaminergic function and is particularly vulnerable in Parkinson's disease (PD). However, this correlation has not been confirmed in human patients with PD. Moreover, the possible involvement of miR-132 during the pathogenesis and progression of PD is not fully investigated. Therefore, in the present study, we determined the peripheral circulation levels of miR-132 and Nurr1 in patients with PD, neurological disease controls (NDC) and healthy controls (HC) by reverse transcription real-time quantitative PCR (RT-qPCR). Our data clearly demonstrated that the plasma miR-132 level in PD was significantly higher than those in HC (178%, p < 0.05) and NDC (188%, p < 0.001). When adjusted for gender and age, higher level of miR-132 expression was associated with the significantly increased risk for PD in males and was closely related with the disease stages and disease severity. Furthermore, peripheral Nurr1 was significantly decreased in PD compared with HC (56%, p < 0.001) and NDC (58%, p < 0.001). Much more interestingly, further analysis revealed a negative correlation between the decreased Nurr1 level and the elevated miR-132 level in PD. All these findings indicated that the combination of a high miR-132 level with the low level of its downstream Nurr1 might be a potential biomarker aiding in the diagnosis of PD and monitoring disease progression.

Determining the mechanisms that distinguish protective immunity from pathological chronic inflammation remains a fundamental challenge. miR-132 has been shown to play largely immunoregulatory roles in immunity; however, its role in CD4 + T cell function is poorly understood. Here, we show that CD4 + T cells express high levels of miR-132 and that T cell activation leads to miR-132 up-regulation. The transcriptomic hallmark of splenic CD4 + T cells lacking the miR-132/212 cluster during chronic infection is an increase in mRNA levels of ribosomal protein (RP) genes. BTAF1, a co-factor of B-TFIID and novel miR-132/212-3p target, and p300 contribute towards miR-132/212-mediated regulation of RP transcription. Following infection with Leishmania donovani, miR-132 -/- CD4 + T cells display enhanced expression of IL-10 and decreased IFNγ. This is associated with reduced hepatosplenomegaly and enhanced pathogen load. The enhanced IL-10 expression in miR-132 following treatment with phenylephrine, a drug reported to promote ribosome synthesis. Our results uncover that miR-132/212-mediated regulation of RP expression is critical for optimal CD4 -/- Th1 cells is recapitulated in vitro following treatment with phenylephrine, a drug reported to promote ribosome synthesis. Our results uncover that miR-132/212-mediated regulation of RP expression is critical for optimal CD4 + T cell activation and protective immunity against pathogens., (© 2019 The Authors.)

Dysfunctional insulin secretion is a hallmark of type 2 diabetes (T2D). Interestingly, several islet microRNAs (miRNAs) are upregulated in T2D, including miR-132. We aimed to investigate whether in vivo treatment with antagomir-132 lowers expression of miR-132 in islets thereby improving insulin secretion and lowering blood glucose. Mice injected with antagomir-132 for 24 h, had reduced expression of miR-132 expression in islets, decreased blood glucose, and increased insulin secretion. In isolated human islets treated with antagomir-132, insulin secretion from four of six donors increased. Target prediction coupled with analysis of miRNA-messenger RNA expression in human islets revealed DESI2, ARIH1, SLC25A28, DIAPH1, and FOXA1 to be targets of miR-132 that are conserved in both species. Increased expression of these targets was validated in mouse islets after antagomir-132 treatment. In conclusion, we identified a post-transcriptional role for miR-132 in insulin secretion, and demonstrated that systemic antagomir-132 treatment in mice can be used to improve insulin secretion and reduce blood glucose in vivo. Our study is a first step towards utilizing antagomirs as therapeutic agents to modulate islet miRNA levels to improve beta cell function.

Brain damage is a complex dysfunction that involves a variety of conditions whose pathogenesis involves a number of mediators that lead to clinical sequelae. For this reason, the identification of specific circulating and/or tissue biomarkers which could indicate brain injury is challenging. This experimental study focused on microRNAs (miRNAs), a well-known diagnostic tool both in the clinical setting and in medico-legal investigation. Previous studies demonstrated that specific miRNAs (miR-21, miR-34, miR-124, miR-132, and miR-200b) control important target genes involved in neuronal apoptosis and neuronal stress-induced adaptation. Thus, in this experimental setting, their expression was evaluated in three selected groups of cadavers: drug abusers (cocaine), ischemic-stroke-related deaths, and aging damage in elder people who died from other neurological causes. The results demonstrated that the drug abuser group showed a higher expression of miR-132 and miR-34, suggesting a specific pathway in consumption-induced neurodegeneration. Instead, miR-200b and miR-21 dysregulation was linked to age-related cognitive impairment, and finally, stroke events and consequences were associated with an alteration in miR-200b, miR-21, and miR-124; significantly higher levels of this last expression are strongly sensitive for ischemic damage. Moreover, these results suggest that these expression patterns could be studied in other biological samples (plasma, urine) in subjects with brain injury linked to aging, drug abuse, and stroke to identify reliable biomarkers that could be applied in clinical practice. Further studies with larger samples are needed to confirm these interesting findings.

Objective: Low levels of testosterone in men with diabetes are associated with cardiovascular complications. We investigated the effect of testosterone and voluntary exercise on heart angiogenesis in castrated diabetic rats., Methods: Sixty-three diabetic rats were treated with testosterone 2 mg/kg/day or voluntary exercise alone or combination of these two for 6 weeks. At the end of the study, heart tissue samples were collected and used for CD31 detection by immunohistochemical method and determination of miR-132 levels., Results: miR-132 levels and CD31 of heart tissue were higher after testosterone administration and in the voluntary exercise group in diabetic rats after 6 weeks. Combination of testosterone and voluntary exercise had synergistic effect on angiogenesis and miR-132 level. In castrated diabetic rats, there were significantly lower levels of miR-132 and CD31 in heart tissue compared to the diabetic group, whereas testosterone and exercise reversed these effects. In addition, testosterone supplementation plus exercise had an additive effect on miR-132 levels and CD31 in castrated diabetic rats., Conclusions: It was concluded that castration in rats leads to reduced miR-132 levels and subsequently decreased angiogenesis in diabetes. Testosterone plus voluntary exercise improved angiogenesis possibly through enhancement of miR-132 levels in heart of castrated diabetic rats.

Background: Human papillomavirus (HPV) infection and viral proteins expression cause a number of epigenetic alterations leading to cervical carcinogenesis. The recent discovery of a large amount of histone methylation modifiers reveals important roles of these enzymes in regulating tumor progression., Methods: The changes in expression of 48 histone methylation modifiers were assessed following knockdown of HPV16 E7 in CaSki cells. Lysine-specific demethylase 2A (KDM2A)-regulated microRNAs (miRNAs) in cervical cancer pathogenesis were disclosed using quantitative real-time polymerase chain reaction. The function of KDM2A-miRNAs on cervical cancer was investigated in vitro and in vivo., Results: Upregulation of KDM2A induced by HPV16 E7 promotes cervical cancer cell proliferation and invasion and is correlated with poor prognosis in patients with cervical cancer. KDM2A physically interacts with the promoter of miR-132 and suppresses its expression by removing the mono or dimethyl group from H3K36 at the miR-132 locus. Functionally, miR-132 represses cancer cell proliferation and invasion by inhibiting radixin (RDX). Upregulated KDM2A promotes cervical cancer progression by repressing miR-132, which results in a derepression of RDX. Therefore, KDM2A functions as a tumor activator in cervical cancer pathogenesis by binding miR-132 promoter and abrogating its tumor suppressive function., Conclusion: Our results suggest a function for KDM2A in cervical cancer progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of cervical cancer., (© 2018 Wiley Periodicals, Inc.)

MicroRNAs have emerged as essential regulators of beta cell function and beta cell proliferation. One of these microRNAs, miR-132, is highly induced in several obesity models and increased expression of miR-132 in vitro modulates glucose-stimulated insulin secretion. The aim of this study was to investigate the therapeutic benefits of miR-132 overexpression on beta cell function in vivo. To overexpress miR-132 specifically in beta cells, we employed adeno-associated virus (AAV8)-mediated gene transfer using the rat insulin promoter in a double-stranded, self-complementary AAV vector to overexpress miR-132. Treatment of mice with dsAAV8-RIP-mir132 increased miR-132 expression in beta cells without impacting expression of miR-212 or miR-375. Surprisingly, overexpression of miR-132 did not impact glucose homeostasis in chow-fed animals. Overexpression of miR-132 did improve insulin secretion and hence glucose homeostasis in high-fat diet-fed mice. Furthermore, miR-132 overexpression increased beta cell proliferation in mice fed a high-fat diet. In conclusion, our data show that AAV8-mediated gene transfer of miR-132 to beta cells improves beta cell function in mice in response to a high-fat diet. This suggests that increased miR-132 expression is beneficial for beta cell function during hyperglycemia and obesity.

The role of microRNA-132 in human pancreatic ductal adenocarcinomas is still ambiguous. We explored the association between microRNA-132 and pancreatic ductal adenocarcinoma prognosis. The expression of microRNA-132 in 50 pancreatic ductal adenocarcinoma tissue samples and pancreatic ductal adenocarcinoma cell lines was examined, and the association between its expression and pancreatic ductal adenocarcinoma prognosis was assessed. Functional analysis and factors downstream of microRNA-132 were investigated. Kaplan-Meier survival curves showed that high expression of microRNA-132 was a significant prognostic factor for 1-year survival of patients with pancreatic ductal adenocarcinoma ( P = .028). Multivariate analysis for overall survival indicated that high expression of microRNA-132 was an independent prognostic factor for patients with pancreatic ductal adenocarcinoma ( P = .044). Low expression of microRNA-132 was associated with poor prognosis in pancreatic ductal adenocarcinoma. Ectopic expression of microRNA-132 significantly inhibited proliferation and promoted apoptosis of 2 pancreatic ductal adenocarcinoma cell lines. Bioinformatic analysis revealed that microRNA-132 may exert its effects on pancreatic ductal adenocarcinoma through downregulating mitogen-activated protein kinase 3 and nuclear transcription factor Y subunit α. The results of this study further our understanding of the relationship between microRNA-132 and pancreatic ductal adenocarcinoma by showing that microRNA-132 might inhibit the progression of pancreatic ductal adenocarcinoma by regulating mitogen-activated protein kinase and nuclear transcription factor Y subunit alpha.

miR-132 and miR-212 are structurally-related microRNAs that are expressed from the same non-coding transcript. Accumulating evidence has shown that the dysregulation of these microRNAs contributes to aberrant neuronal plasticity and gene expression in the mammalian brain. Consistent with this, altered expression of miR-132 is associated with a number of affect-related psychiatric disorders. Here, we tested the functional contribution of the miR-132/212 locus to the development of stress-related and anxiety-like behaviors. Initially, we tested whether expression from the miR-132/212 locus is altered by stress-inducing paradigms. Using a 5-h acute-stress model, we show that both miR-132 and miR-212 are increased more than two-fold in the WT murine hippocampus and amygdala, whereas after a 15 day chronic-stress paradigm, expression of both miR-132 and miR-212 are upregulated more than two-fold within the amygdala but not in the hippocampus. Next, we used a tetracycline-inducible miR-132 overexpression mouse model and a miR-132/212 conditional knockout (cKO) mouse model to examine whether dysregulation of miR-132/212 expression alters basal anxiety-like behaviors. Interestingly, in both the miR-132 overexpression and cKO lines, significant increases in anxiety-like behaviors were detected. Importantly, suppression of transgenic miR-132 expression (via doxycycline administration) mitigated the anxiety-related behaviors. Further, expression of Sirt1 and Pten-two miR-132 target genes that have been implicated in the regulation of anxiety-were differentially regulated in the hippocampus and amygdala of miR-132/212 conditional knockout and miR-132 transgenic mice. Collectively, these data raise the prospect that miR-132 and miR-212 may play a key role in the modulation of stress responsivity and anxiety., (Copyright © 2018. Published by Elsevier Ltd.)

The role of microRNAs has been recently identified in chronic obstructive pulmonary disease (COPD). This study aimed to examine the role of miR-132 in the pathophysiology of COPD and to explore the underlying molecular mechanisms of miR-132 in COPD. MiR-132 and suppressor of cytokine signaling 5 (SOCS5) mRNA expression were detected by qRT-PCR. The number of CD4 + and CD8 + T cells was analyzed by flow cytometry. SOCS5 and epidermal growth factor receptor (EGFR) protein levels were determined by western blot. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) concentrations were measured by ELISA. MiR-132 expression was up-regulated in the serum from COPD patients and smokers compared with nonsmoker controls. The number of CD8 + T cells was significantly increased in the serum from COPD patients and smokers. MiR-132 expression was negatively correlated with FEV 1 /FVC%, and positively correlated with CD8 + T cells (%). MiR-132 overexpression repressed SOCS5 expression via directly targeting SOCS5 3'UTR in human monocyte-like cells (THP-1), which was confirmed by luciferase reporter assay. MiR-132 overexpression increased EGFR protein levels and the concentrations of inflammatory cytokines (IL-1β and TNF-α) in THP-1 cells, and these effects were attenuated by enforced expression of SOCS5. Further, cigarette smoke extract (CSE) treatment up-regulated miR-132 expression, down-regulated SOCS5 expression, and increased inflammatory cytokines levels, which was attenuated by miR-132 knockdown in THP-1 cells. Consistent findings were also found in the human bronchial epithelial cells (BEAS-2B). Collectively, our data implicated that miR-132 may promote inflammation in THP-1 and BEAS-2B cells at least via targeting SOCS5 in COPD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a kind of neurodegenerative disorder associated with age. Investigations suggest that amyliod-β (Aβ) is implicated in the pathogenesis of AD. The accumulation of Aβ in the brain causes oxidative stress and synaptic toxicity, leads to synaptic dysfunction and neuronal death. Previous investigations suggest that melatonin an endogenous hormone can counteract Aβ-induced neurotoxicity. However, the molecular mechanisms of Aβ-induced toxicity and melatonin treatment remain elusive. Studies indicate that microRNA-132 is crucial for neuronal survival and plays a key role in the pathological process of AD. Moreover, PTEN and FOXO3a two key targets of miR-132 are upregulated in the AD brain. Here, we exposed the primary cultured cortical neurons with Aβ25-35 and treated with melatonin. Our investigations demonstrated that Aβ25-35 exposure significantly decreased the expression of miR-132 and elevated the expression of PTEN and FOXO3a. Whereas, melatonin treatment could rescue the expression of miR-132 and downregulate the level of PTEN and FOXO3a. Moreover, melatonin blocked the nuclear translocation of FOXO3a and thereby suppressed its pro-apoptotic pathways. In addition, our investigations suggested that the over-expression of miR-132 could block Aβ-induced neurotoxicity. We also found that VO-OHpic (PTEN inhibitor) could counteract Aβ-induced neuronal damage, and LY294002 (AKT inhibitor) suppressed the protective effect of melatonin. Together, these results indicate that melatonin exerts its neuroprotective effect in Aβ-induced neurotoxicity via miR-132/PTEN/AKT/FOXO3a pathway. © 2018 BioFactors, 44(6):609-618, 2018., (© 2018 International Union of Biochemistry and Molecular Biology.)

Earlier, we showed that micro RNA-132 (miR-132) regulate the immediate early genes (IEGs) in the olfactory bulb (OB) of fruit bat Cynopterus sphinx during olfactory learning. This study was designed to examine whether the miR-132 regulate other proteins in OB during olfactory learning. To test this, miR-132 anti-sense oligodeoxynucleotide (AS-ODN) was delivered to the OB and then trained to novel odor. The 2-dimensional gel electrophoresis analysis showed that inhibition of miR-132 altered olfactory training induced expression of 321 proteins. Further, liquid chromatography-mass spectrometry (LC-MS/MS) analysis reveals the identity of differently expressed proteins such as phosphoribosyl transferase domain containing protein (PRTFDC 1), Sorting nexin-8 (SNX8), Creatine kinase B-type (CKB) and Annexin A11 (ANX A11). Among them PRTFDC 1 showing 189 matching peptides with highest sequence coverage (67.0%) and protein-protein interaction analysis showed that PRTFDC 1 is a homolog of hypoxanthine phosphoribosyltransferase-1 (HPRT-1). Subsequent immunohistochemical analysis (IHC) showed that inhibition of miR-132 down-regulated HPRT expression in OB of C. sphinx. In addition, western blot analysis depicts that HPRT, serotonin transporter (SERT), N-methyl-d-asparate (NMDA) receptors (2A,B) were down-regulated, but not altered in OB of non-sense oligodeoxynucleotide (NS-ODN) infused groups. These analyses suggest that miR-132 regulates the process of olfactory learning and memory formation through SERT and NMDA receptors signalling, which is possibly associated with the PRTFDC1-HPRT interaction., (Copyright © 2018. Published by Elsevier B.V.)

Background It has been reported that both of the miR-132/212 (micro-RNA) cluster members, miR-132 and miR-212, are downregulated in hepatocellular carcinoma. Nevertheless, the expression pattern and clinical utility of serum miR-132/212 in hepatocellular carcinoma are still unknown. Methods In this study, serum concentrations of miR-132 and miR-212 were measured in 80 hepatocellular carcinoma patients, 51 controls with chronic liver diseases and 42 healthy volunteers by using quantitative real-time polymerase chain reaction. Results In hepatocellular carcinoma patients, serum concentrations of miR-132 and miR-212 were significantly reduced and strongly correlated (r = 0.603, p < 0.001). Receiver operator characteristic analyses showed that serum miR-132 and miR-212 might have a potential role in the diagnosis of hepatocellular carcinoma. Moreover, the combination of serum miR-132, miR-212 and alpha-fetoprotein improved the diagnostic efficiency for hepatocellular carcinoma, especially in sensitivity and negative predictive value. Serum miR-132 was associated with tumour differentiation degree ( p = 0.021) and tumour-node-metastasis stage ( p = 0.002); serum miR-212 correlated with tumour size ( p = 0.023) and tumour-node-metastasis stage ( p = 0.007). Kaplan-Meier analyses indicated poorer overall survival in hepatocellular carcinoma patients with lower serum concentrations of miR-132 ( p < 0.001) and miR-212 ( p = 0.005). Conclusions Our results suggest that both components of the miR-132/212 cluster have potential roles as non-invasive serum biomarkers for diagnosis and prognosis of hepatocellular carcinoma.

Breast cancer is a serious health problem worldwide. Acquisition of multi-drug resistance (MDR) during the treatment of breast cancer is still considered a major clinical obstacle. Despite the biological functions of miRNAs becoming increasingly apparent, the function of miRNAs in regulating drug resistance of breast cancer remains under investigation. Quantitative real-time PCR (qRT-PCR) was used to quantify the expression of miR-132/-212 (miR-132 and miR-212) in doxorubicin (DOX)-resistant and -sensitive breast cancer tumors and cells. The function of miR-132/-212 in drug resistance was investigated in vitro (MTT assay, TUNEL assay, fluorescence, immunohistochemistry, luciferase reporter assay, Western blotting). We found that miR-132/-212 were commonly overexpressed in DOX-resistant breast cancer tumors and cells. Silenced miR-132/-212 expression induced DOX accumulation in MCF-7/ADR cells, while overexpression of miR-132/-212 led to breast cancer resistance protein (BCRP)-based DOX efflux in MCF-7 cells. Further study showed that up-regulation of miR-132/-212 in MCF-7/ADR cells suppressed the expression of PTEN, a target gene of miR-132/-212, which activated AKT phosphorylation and the NF-κB pathway and led to increased BCRP expression. Down-regulation of miR-132/-212 sensitized MCF-7/ADR cells to DOX. Mechanistic investigations suggested that miR-132/-212 enhancement was a result of NF-κB-mediated transactivation of the pri-miR-132/-212 gene. Taken together, our findings are among the first to demonstrate a novel aspect of the miR-132/-212-PTEN-AKT/NF-κB-BCRP pathway in the generation of breast cancer resistance and provides a potential method to reverse drug resistance., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The senescence-accelerated SAMP8 mouse is characterized by progressive cognitive decline and is considered to be a specific model of Alzheimer's disease (AD). A growing body of evidence indicates that physical exercise suppresses age-related cognitive decline. In the current study, we investigated the influence of voluntary wheel running on cognitive function in SAMP8 mice. We found that voluntary physical exercise ameliorated cognition decline and suppressed hippocampal neurodegeneration in SAMP8 mice. MicroRNA-132 (miR-132) is a short non-coding RNA which is enriched in the brain and is implicated in the regulation of neuronal activity and cognitive function. Here we show that miR-132 expression was significantly increased in the hippocampus of SAMP8 mice. Voluntary physical exercise, however, suppressed the increase of miR-132 expression in SAMP8 mice. Furthermore, upregulation of hippocampal miR-132 expression exacerbates cognition decline, while downregulation of hippocampal miR-132 ameliorates cognition deficit in the SAMP8 mice. Taking together, our results suggest that miR-132 is associated with the cognition improvement following voluntary exercise in SAMP8 mice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

To investigate the effects of perinatal fluoride exposure on learning and memory ability of mouse offspring, ICR female mice were received different doses of sodium fluoride (0, 25, 50, 100 mg/L NaF) from pregnant day 7 to lactational day 21. Pups were exposed to fluoride through the cord blood and breast milk. Open field test showed that compared to the control group, perinatal fluoride exposure significantly decreased the number of entries into the center zone in 100 mg/L NaF group. In the eight-arm maze test, the number of working memory errors, reference memory errors, and the total arm entries were significantly increased in fluoride treatment groups, compared to the control group. Additionally, 100 mg/L NaF significantly elevated the expression levels of miR-124, miR-132, and DiGeorge syndrome chromosomal region 8 (DGCR8) in hippocampus of mouse pups at postnatal day (PND) 21. Contrarily, methyl CpG binding protein 2 (MeCP2) were dramatically reduced in 50 and 100 mg/L NaF groups, while cAMP-response element binding protein (CREB) mRNA level was significantly decreased in all fluoride groups. These findings suggested that the impairment of learning and memory in mouse offspring induced by perinatal fluoride exposure may partly result from the enhanced miR-124 and miR-132 and the alterations of their target genes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)