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Background: A significant research gap exists regarding the role of tissue exosomes in intrauterine adhesions (IUAs). This study aims to investigate the involvement of miR-195-5p and its regulatory network in IUAs through the analysis of tissue exosomes., Methods: Exosomes from rat uterine tissue with intrauterine adhesions were analyzed via transcriptomics to identify downstream target genes of miR-195-5p, cross-referencing with the human endometrial transcriptomics database GSE224093. Dual luciferase labeling confirmed miRNA-target gene interactions. The therapeutic efficacy of a miR-195-5p agonist was assessed in vivo through HE staining, Masson staining, and mating tests. The mechanisms underlying extracellular matrix (ECM) deposition and myofibroblast transdifferentiation in endometrial fibrosis were investigated both in vitro and in vivo using RT-PCR, Western Blot, immunofluorescence, and immunohistochemistry. Migration ability of endometrial stromal cells was evaluated using CCK8, scratch tests, and Transwell assays. Finally, the clinical potential of miR-195-5p was compared with autologous adipose-derived mesenchymal stem cells., Results: The expression of miR-195-5p in uterine tissue exosomes from intrauterine adhesions was found to be decreased. Treatment with a miR-195-5p agonist resulted in improved endometrial health, reduced fibrosis, increased glandular density, and enhanced birth rates in rats. Both in vivo and in vitro experiments confirmed that miR-195-5p decreased ECM deposition, reduced myofibroblast transdifferentiation, and inhibited the migration of endometrial stromal cells. This was achieved through the downregulation of YAP expression in the Hippo pathway and the upregulation of Smad7. Notably, the therapeutic efficacy of miR-195-5p agonists was comparable to that of stem cell therapy, offering promising avenues for clinical application., Conclusions: Differential expression of miR-195-5p in tissue exosomes can reduce ECM deposition and myofibroblast transdifferentiation, improving endometrial fibrosis by regulating the YAP-Smad7 pathway in the Hippo signaling cascade., Competing Interests: Declarations. Ethics approval and consent to participate: This study involves the collection of human endometrium and animal as part of the project titled ‘Study on the mechanism of miR-195-5p improving the epithelial-mesenchymal transformation of endometrial adhesion through YAP-SMAD7, which was approved by the Second Affiliated Hospital of Fujian Medical University Animal Care Committee (Approval No. and Date: 2023-179, May 18, 2023). Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

We have previously reported that the expression of miR-34c-5p was up-regulated during acupuncture treatment in the setting of a cerebral ischemia/reperfusion injury (CIRI), indicating that miR-34c-5p plays an important role in healing from a CIRI-induced brain injury. This study sought to evaluate the effects of acupuncture on miR-34c-5p expression and autophagy in the forward and reverse directions using a rat focal cerebral ischemia/reperfusion model. After 120 minutes of middle cerebral artery occlusion and reperfusion, rats were treated with acupuncture at the "Dazhui" (DU20), "Baihui" (DU26) and "Renzhong" (DU14) points. Neurologic function deficit score, cerebral infarct area ratio, neuronal apoptosis and miR-34c-5p expression were evaluated 72 hr after treatment. The autophagy agonist RAPA and the antagonist 3MA were used to evaluate the neuro protective effects of autophagy-mediated acupuncture. We found that acupuncture treatment improved autophagy in the brain tissue of CIRI rats. Acupuncture reversed the negative effects of 3MA on CIRI, and acupuncture combined with RAPA further enhanced autophagy. We also found that acupuncture could increase miR-34c-5p expression in hippocampal neurons after ischemia/reperfusion. Acupuncture and a miR-34c agomir were able to enhance autophagy, improve neurologic deficits, and reduce the cerebral infarct area ratio and apoptosis rate by promoting the expression of miR-34c-5p. Silencing miR-34c resulted in a significantly reduced activating effect of acupuncture on autophagy and increased apoptosis, neurologic deficit symptoms, and cerebral infarct area ratio. This confirms that acupuncture can upregulate miR-34c-5p expression, which is beneficial in the treatment of CIRI., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Grape seed procyanidin extract (GSE), and milk thistle silymarin extract (MTE) contain structurally distinct polyphenols, and each agent has been shown to exert antineoplastic effects against lung cancer. We hypothesize that combinations of GSE and MTE will additively enhance their anticancer effects against lung cancer., Materials and Methods: The anti-proliferative effects of GSE, MTE and combinations were evaluated in lung neoplastic cell lines. A dose range finding (DRF) study to determine safety, bioavailability and bioactivity, followed by human lung cancer xenograft efficacy studies were conducted in female nude mice with once daily gavage of leucoselect phytosome (LP), a standardized GSE, and/or siliphos, a standardized MTE. The roles of tumor suppressors miR-663a and its predicted target FHIT in mediating the additive, anti-proliferative effecs of GSE/MTE were also assessed., Key Findings: GSE with MTE additively inhibited lung preneoplastic and cancer cell proliferations. Mice tolerated all dosing regimens in the DRF study without signs of clinical toxicity nor histologic abnormalities in the lungs, livers and kidneys. Eight weeks of LP and siliphos additively inhibited lung tumor xenograft growth. Plasma GSE/metabolites and MTE/metabolites showed that the combinations did not decrease systemic bioavailabilities of each agent. GSE and MTE additively upregulated miR-663a and FHIT in lung cancer cell lines; transfection of antisense-miR-663a significantly abrogated the anti-proliferative effects of GSE/MTE, upregulation of FHIT mRNA and protein. LP and siliphos also additively increased miR-663a and FHIT protein in lung tumor xenografts., Significance: Our findings support clinical translations of combinations of GSE and MTE against lung cancer., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chondrocyte senescence is a decisive component of age-related osteoarthritis, however, the function of small noncoding RNAs (sncRNAs) in chondrocyte senescence remains underexplored. Human hip joint cartilage chondrocytes were cultivated up to passage 4 to induce senescence. RNA samples were extracted and then analyzed using small RNA sequencing and qPCR. β-galactosidase staining was used to detect the effect of sncRNA on chondrocyte aging. Results of small RNA sequencing showed that 279 miRNAs, 136 snoRNAs, 30 snRNAs, 102 piRNAs, and 5 rasiRNAs were differentially expressed in senescent chondrocytes. The differential expression of 150 sncRNAs was further validated by qPCR. Transfection of sncRNAs and β-galactosidase staining were also performed to further revealed that hsa-miR-135b-5p, SNORA80B-201, and RNU5E-1-201 have the function to restrain chondrocyte senescence, while has-piR-019102 has the function to promote chondrocyte senescence. Our data suggest that sncRNAs have therapeutic potential as novel epigenetic targets in age-related osteoarthritis., Competing Interests: Declaration of Competing Interest The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Polycystic ovary syndrome (PCOS) is a reproductive dysfunction associated with endocrine disorders and is most common in women of reproductive age. Clinical and/or biochemical manifestations include hyperandrogenism, persistent anovulation, polycystic ovary, insulin resistance, and obesity. Presently, the aetiology and pathogenesis of PCOS remain unclear. In recent years, the role of circadian rhythm changes in PCOS has garnered considerable attention. Changes in circadian rhythm can trigger PCOS through mechanisms such as oxidative stress and inflammation; however, the specific mechanisms are unclear. Exosomes are vesicles with sizes ranging from 30-120nm that mediate intercellular communication by transporting microRNAs (miRNAs), proteins, mRNAs, DNA, or lipids to target cells and are widely involved in the regulation of various physiological and pathological processes. Circadian rhythm can alter circulating exosomes, leading to a series of related changes and physiological dysfunctions. Therefore, we speculate that circadian rhythm-induced changes in circulating exosomes may be involved in PCOS pathogenesis. In this review, we summarize the possible roles of exosomes and their derived microRNAs in the occurrence and development of PCOS and discuss their possible mechanisms, providing insights into the potential role of exosomes for PCOS treatment., 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 © 2022 Chen, Huang, Wang, Zhuang, Lin and Shi.)

Exosomes are nano-scale extracellular vesicles secreted by cells and constitute an important part in the cell-cell communication. The main contents of the exosomes include proteins, microRNAs, and lipids. The mechanism and safety of stem cell-derived exosomes have rendered them a promising therapeutic strategy for regenerative medicine. Nevertheless, limited yield has restrained full explication of their functions and clinical applications To address this, various attempts have been made to explore the up- and down-stream manipulations in a bid to increase the production of exosomes. This review has recapitulated factors which may influence the yield of stem cell-derived exosomes, including selection and culture of stem cells, isolation and preservation of the exosomes, and development of artificial exosomes., (© 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To observe the effect of acupuncture on the expression of miR-34c-5p, autophagy-related proteins and apoptosis rate in hippocampus of rats with cerebral ischemia/reperfusion injury (CI/RI), so as to explore its mechanism in regulating autophagy in hippocampal neurons in CI/RI rats., Methods: SD rats were randomly divided into sham operation, model, medication and acupuncture groups, with 20 rats in each group. The rat model of CI/RI was established by occlusion of the middle cerebral artery. In the acupuncture group, "Dazhui" (GV14), "Baihui" (GV20) and "Shuigou" (GV26) were punctured with filiform needles and stimulated manually once every 15 min, for 30 min. The rats of the medication group were intraperito-neally injected with edaravone (5 mg/kg). The treatment was conducted once every 12 h for a total of 7 times. The neurological de-ficit score of all the rats were evaluated according to Garcia's methods, and TTC staining was employed to assess the cerebral ischemic area (percentage of cerebral infarct area, CIA). Transmission electron microscopy (TEM) was used to observe the ultrastructural changes of hippocampal neurons. The expression of hippocampal miR-34c-5p was measured by real-time PCR, and the protein expressions of hippocampal LC3B, Beclin1 and p62 were measured by Western blot. The apoptosis rate of ischemic brain tissue was observed by TUNEL staining., Results: Compared with the sham operation group, the neurological deficit score, the expressions of miR-34c-5p, Beclin1, p62 and LC3B-Ⅱ/LC3B-Ⅰ were significantly decreased ( P <0.01, P <0.05), and the CIA and the apoptosis rate significantly increased ( P <0.01) in the model group. Compared with the model group, the neurological deficit scores, the expressions of miR-34c-5p, Beclin1, p62 and LC3B-Ⅱ/LC3B-Ⅰ were significantly increased ( P <0.01, P <0.05), and the CIA and the apoptosis rate significantly decreased ( P <0.01) in the medication and acupuncture groups. Compared with the medication group, the expression of miR-34c-5p was significantly increased ( P <0.01). The results of electron microscope showed that the neurons in the acupuncture and medication groups were less damaged than those in the model group, the cells showed mild edema, and the structures were relatively complete. Some normal organelles could be seen, and autophagy bodies, autophagy lysosomes and their encapsulated organelles could still be observed., Conclusion: Acupuncture can improve the neurological deficit and reduce the area of cerebral infarction in CI/RI rats, which is closely with its effect in promoting hippocampal neuronal autophagy and anti-apoptosis via up-regulating the expression of miR-34c-5p.

In recent years, liver fibrosis has become a hotspot in the field of liver diseases. MicroRNA(miRNA)-mediated Nod-like receptor pyrin domain containing 3(NLRP3) inflammasome activation is pivotal in the pathogenesis of liver fibrosis. The present study mainly discussed the role of miRNA-mediated NLRP3 inflammasome activation in the pathogenesis of liver fibrosis. Different miRNA molecules regulated liver fibrosis by mediating NLRP3 inflammasome activation, including miRNA-350-3 p(miR-350-3 p)/interleukin-6(IL-6)-mediated signal transducer and activator of transcription 3(STAT3)/c-myc signaling pathway, miR-148 a-induced autophagy and apoptosis of hepatic stellate cells via hedgehog signaling pathway, miR-155-mediated NLRP3 inflammasome by the negative feedback of the suppressor of cytokine signaling-1(SOCS-1), miR-181 a-mediated downstream NLRP3 inflammatory pathway activation through mitogen-activated protein kinase kinase(MEK)/extracellular signal-regulated kinase(ERK)/nuclear transcription factor κB(NF-κB) inflammatory pathway, miR-21-promoted expression of NF-κB and NLRP3 of RAW264.7 cells in mice by inhibiting tumor necrosis factor-α inducible protein 3(A20), and miR-20 b-promoted expression of IL-1β and IL-18 by activating NLRP3 signaling pathway. Additionally, the anti-liver fibrosis mechanism of different active components in Chinese medicines(such as Curcumae Rhizoma, Glycyrrhizae Radix et Rhizoma, Aurantii Fructus, Polygoni Cuspidati Rhizoma et Radix, Moutan Cortex, Paeoniae Radix Alba, Epimedii Folium, and Cinnamomi Cortex) was also explored based on the anti-liver fibrosis effect of miRNA-mediated NLRP3 inflammasome activation.

Nickel (Ni) compounds are classified as Group 1 carcinogens by the International Agency for Research on Cancer (IARC) and are known to be carcinogenic to the lungs. In our previous study, special AT‑rich sequence‑binding protein 2 (SATB2) was required for Ni‑induced BEAS‑2B cell transformation. In the present study, a pathway that regulates the expression of SATB2 protein was investigated in Ni‑transformed BEAS‑2B cells using western blotting and RT‑qPCR for expression, and soft agar, migration and invasion assays for cell transformation. Runt‑related transcription factor 2 (RUNX2), a master regulator of osteogenesis and an oncogene, was identified as an upstream regulator for SATB2. Ni induced RUNX2 expression and initiated BEAS‑2B transformation and metastatic potential. Previously, miRNA‑31 was identified as a negative regulator of SATB2 during arsenic‑induced cell transformation, and in the present study it was identified as a downstream target of RUNX2 during carcinogenesis. miR‑31 expression was reduced in Ni‑transformed BEAS‑2B cells, which was required to maintain cancer hallmarks. The expression level of miR‑31 was suppressed by RUNX2 in BEAS‑2B cells, and this increased the expression level of SATB2, initiating cell transformation. Ni caused the repression of miR‑31 by placing repressive marks at its promoter, which in turn increased the expression level of SATB2, leading to cell transformation.

Objective: To investigate the clinical correlation of expression level changes of miR-181b and miR-194 to the pathogenesis of acute graft-versus-host disease (aGVHD), and determine plasma miR-181b and miR-194 as the potential biomarkers for aGVHD., Methods: The plasma samples were collected from 31 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at before HSCT, 15 days after HSCT and onset of aGVHD. The expression levels of miR-181b and miR-194 were detected by quantitative real-time PCR. Receiver-operating characteristic (ROC) curves and the area under the ROC curve (AUC) were used to assess the sensitivity and specificity of miRNA biomarkers for the diagnosis of aGVHD., Results: MiR-181b and miR-194 downregulated after treatment were significantly upregulated in the plasma at onset of aGVHD (P<0.05), and there was no significant difference in comparison with the level of before HSCT (P>0.05). The expressions of plasma miR-181b and miR-194 collected on day 15 after HSCT were significantly upregulated in the patients with aGVHD in comparison with non-GVHD patients (P<0.05). Moreover, these elevated miRNAs were detected before aGVHD. The AUC of miR-181b predicting aGVHD was 0.91±0.05 (specificity was 0.94, sensitivity was 0.69). The AUC of miR-194 predicting aGVHD was 0.91±0.06 (specificity was 0.94, sensitivity was 0.77)., Conclusion: MiR-181b and miR-194 may serve as early biomarkers for the diagnosis and prognosis of aGVHD.

Viral myocarditis (VMC) commonly triggers heart failure, for which no specific treatments are available. This study aims to explore the specific role of long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) in VMC. A VMC mouse model was induced by Coxsackievirus B3 (CVB3). Then, MEG3 and TNF receptor-associated factor 6 (TRAF6) were silenced and microRNA-223 (miR-223) was over-expressed in the VMC mice, followed by determination of ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). Dual-luciferase reporter assay was introduced to test the interaction among MEG3, TRAF6 and miR-223. Macrophages were isolated from cardiac tissues and bone marrow, and polarization of M1 or M2 macrophages was induced. Then, the expressions of components of NLRP3 inflammatory body (NLRP3, ASC, Caspase-1), M1 markers (CD86, iNOS and TNF-α) and M2 markers (CD206, Arginase-1 and Fizz-1) were measured following MEG3 silencing. In the VMC mouse model, MEG3 and TRAF6 levels were obviously increased, while miR-223 expression was significantly reduced. Down-regulation of MEG3 resulted in the inhibition of TRAF6 by promoting miR-223. TRAF6 was negatively correlated with miR-223, but positively correlated with MEG3 expression. Down-regulations of MEG3 or TRAF6 or up-regulation of miR-223 was observed to increase mouse weight, survival rate, LVEF and LVFS, while inhibiting myocarditis and inflammation via the NF-κB pathway inactivation in VMC mice. Down-regulation of MEG3 decreased M1 macrophage polarization and elevated M2 macrophage polarization by up-regulating miR-223. Collectively, down-regulation of MEG3 leads to the inhibition of inflammation and induces M2 macrophage polarization via miR-223/TRAF6/NF-κB axis, thus alleviating VMC., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objectives: This study profiled circulating and hippocampal microRNAs (miRNAs) to identify alterations associated with the risk of epileptogenesis in a mouse temporal lobe epilepsy model., Methods: Next-generation sequencing was performed to examine the changes in miRNA expression 24 h after pilocarpine-induced status epilepticus (SE) in C57BL/6NCrl mice using both blood and hippocampus samples. Differentially expressed miRNAs were identified from SE animals and matched controls that failed to develop SE after receiving equal doses of pilocarpine (NS animals). Blood and brain miRNA profiles were then compared to identify circulating miRNA alterations reflecting the changes in the brain., Results: We identified 3 miRNAs that were significantly up-regulated and 4 miRNAs that were significantly down-regulated in the blood of SE animals compared with NS animals. When hippocampal miRNAs of SE animals and NS animals were compared, 5 miRNAs were up-regulated and 4 were down-regulated. Of these, miR-434-3p and miR-133a-3p were observed to have greatest changes in both blood and brain of SE animals., Significance: This study extends current knowledge of changes in miRNAs associated with epileptogenesis by profiling miRNAs in SE and NS animals in an experimental temporal lobe epilepsy model. The study was designed to allow non-specific changes due to the activation of muscarinic cholinergic receptors in peripheral organs by pilocarpine to be ruled out. Significantly altered circulating miRNAs that reflect changes in the brain during epileptogenesis after SE have the potential to be developed as prognostic biomarkers for epileptogenesis., (Copyright © 2020. Published by Elsevier B.V.)

Ischemia stroke is one of the leading causes of death and disability in the world. Long non-coding RNA ANRIL has been reported to play an important role in ischemic injury. In this study, we aim to explore the mechanism by which ANRIL exhibits protective effect. Middle cerebral artery occlusion mouse models were applied and infarction areas were assessed by TTC assay. The expression of ANRIL and miR-199a-5p were determined by qPCR. Oxygen and glucose deprivation treatment was applied to mimic in vitro ischemia injury in N-2a cells. The levels of BCL-2, BAX, MEK, ERK, CAV-1 were determined by western blot. Cell viability were assessed by MTT assay. The direct interaction among miR-199a-5p and ANRIL, miR-199a-5p and CAV-1 were demonstrated by dual Luciferase report assay. ANRIL and miR-199a-5p expression were changed in both in vivo and in vitro ischemia model. Overexpression of ANRIL or inhibition of miR-199a-5p could protect cells against ischemia induced injury by elevating cell viability through CAV-1 mediated MEK/ERK pathway. miR-199a-5p attenuated CAV-1 expression by direct targeting. ANRIL competitively interacted with miR-199a-5p in N-2a cells, leading to a de-repression of CAV-1. ANRIL protects N-2a cells against ischemia induced injury by elevated CAV-1 by competitively interacting with miR-199a-5p, thus activating MEK/ERK pathway and elevating cell viability.

Background: Type 2 diabetes mellitus (T2DM) is a major cause of death with an increasing incidence at an epidemic rate. The existing treatments for T2DM lack long-term effective blood glucose control. In this study, the effects of miR-21 antagomir on T2DM and the related mechanism were investigated using streptozotocin (STZ)-induced T2DM rats., Methods: 30 T2DM rats were randomly divided into 3 groups (n=10): T2DM group, T2DM rats with miR-21 antagomir group, T2DM rats with NC antagomir group. The expression of miR-21 in rats was detected by qRT-PCR. blood glucose, triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-Cho), insulin, adiponectin, ITT and GTT were detected. The expression of TIMP3 in si-TIMP3 rats and the expression of TIMP3 in T2DM rats with miR-21 antagomir and si-TIMP3 was detected by Western blotting., Results: We found that miR-21 antagomir reduced blood glucose concentration in T2DM rats. MiR21 antagomir improved lipid metabolic disorder by decreasing the levels of triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-Cho) and increasing the level of high-density lipoprotein cholesterol (HDL-Cho). Also, miR-21 antagomir reduced the value of homeostasis model assessment of insulin resistance (HOMA-IR), hemoglobin A1c (HbAc1), plasma insulin, and up-regulated the plasma adiponectin. These results, combined with insulin tolerance tests (ITT) and glucose tolerance tests (GTT) results, showed that miR-21 improved insulin resistance in STZ-induced T2DM rats. Then the target relationship between miR-21 and tissue inhibitor of metalloproteinases 3 (TIMP3) was proved by luciferase reporter assay. More impressively, miR-21 significantly increased the expression level of TIMP3 in STZ-induced T2DM rats., Conclusions: Our study taken together has shown that miR-21 antagomir improved insulin resistance and lipid metabolism disorder in STZ-induced T2DM rats by up-regulating the expression level of TIMP3. This study suggested that miR-21 antagomir could be used as an effective therapeutic strategy and the underlying mechanism was revealed.

It has demonstrated that miR-22 overexpression can suppress the inflammation process of rheumatoid arthritis (RA) in synoviocytes. But, the underlying mechanism of miR-22 expression in regulating RA is still not well illustrated. In this study, we investigated the functional role and underlying mechanism of miR-22 in regulating RA. Human RA fibroblast-like synoviocyte (FLS) cell line MH7A cells was transfected by miR-22 mimic and its control. CCK8 was utilized to detect cell proliferation. Cell apoptosis was analyzed by flow cytometry. MH7A cells stimulating with interleukin-1β (IL-1β) were transfected with miR-22 mimic. Quantitative real time polymerase chain reaction (qRT-PCR) and western blot assays were utilized to detect mRNA and protein expression. miR-22 targets were predicted and validated by Targetscan and luciferase reporter assay. We revealed that miR-22 showed downregulated expression in MH7A after stimulation with IL-1β. Additionally, miR-22 overexpression suppressed the proliferation and facilitated apoptosis in MH7A cells. IL6R was a target of miR-22. Besides, miR-22 overexpression inhibited the expression of IL6R and also suppressed inflammatory pathway NF-κB. These results indicated that miR-22 overexpression could restrain the activity of inflammation cells in RA by targeting IL6R and might be concerned with the inhibition of NF-κB pathway., (© 2019 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Tongue cancer remains a massive threat to public health due to the high rate of metastasis. Tumor cell epithelial-mesenchymal transition (EMT), which can be induced by transforming growth factor β1 (TGFβ1), has been regarded as a significant contributor to cancer invasion and migration. In our previous study, long noncoding RNA (lncRNA) MALAT1/miR-124/JAG1 axis modulates the growth of tongue cancer. In addition to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), another lncRNA, urothelial cancer associated 1 (UCA1), can promote EMT and cancer metastasis. In the present study, UCA1 was overexpressed in tongue cancer tissues and cell lines. UCA1 overexpression was correlated to the poorer prognosis of patients with tongue cancer. UCA1 knockdown significantly suppressed TGFβ1-induced tongue cancer cell invasion and EMT by decreasing vimentin and increasing E-cadherin. Regarding the molecular mechanism, UCA1 could directly bind to microRNA-124 (miR-124) and negatively regulate each other. UCA1 knockdown ameliorated, whereas miR-124 inhibition exacerbated TGFβ1-induced EMT and invasion in tongue cancer cells through miR-124 downstream jagged 1 (JAG1) and Notch signaling. Moreover, miR-124 inhibition partially impaired the effect of UCA1 knockdown. In tongue cancer tissues, miR-124 expression was remarkably decreased, whereas JAG1 mRNA expression was increased. miR-124 was negatively correlated with UCA1 and JAG1. UCA1 and JAG1 were positively correlated. In summary, we provided a novel mechanism by which the EMT process and cancer cell invasion in tongue cancer could be modulated from the perspective of lncRNA-miRNA-mRNA regulation., (© 2019 Wiley Periodicals, Inc.)

The special AT-rich DNA binding protein (SATB2) is a nuclear matrix-associated protein and an important transcription factor for biological development, gene regulation and chromatin remodeling. Aberrant regulation of SATB2 has been found to highly correlate with various types of cancers including lung, colon, prostate, breast, gastric and liver. Recent studies have revealed that a subset of small non-coding RNAs, termed microRNAs (miRNAs), are important regulators of SATB2 function. As post-transcriptional regulators, miRNAs have been found to have fundament importance maintaining normal cellular development. Evidence suggests that multiple miRNAs, including miR-31, miR-34, miR-182, miR-211, miR-599, are capable of regulating SATB2 in cancers of the lung, liver, colon and breast. This review examines the molecular functions of SATB2 and miRNAs in the text of cancer development and potential strategies for cancer therapy with a focus on systemic miRNA delivery., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Arsenic is a naturally occurring and highly potent metalloid known to elicit serious public health concerns. Today, approximately 200 million people around the globe are exposed to arsenic-contaminated drinking water at levels greater than the World Health Organization's recommended limit of 10 parts per billion. As a class I human carcinogen, arsenic exposure is known to elicit various cancers, including lung, skin, liver, and kidney. Current evidence suggests that arsenic is capable of inducing both genotoxic and cytotoxic injury, as well as activating epigenetic pathways to induce carcinogenesis. Our study identifies a novel pathway that is implicated in arsenic-induced carcinogenesis. Arsenic down-regulated miRNA-31 and the release of this inhibition caused overexpression of special AT-rich sequence-binding protein 2 (SATB2). Arsenic is known to disrupt miRNA expression, and here we report for the first time that arsenic is capable of inhibiting miR-31 expression. As a direct downstream target of miR-31, SATB2 is a prominent transcription factor, and nuclear matrix binding protein implicated in many types of human diseases including lung cancer. Results from this study show that arsenic induces the overexpressing SATB2 by inhibiting miR-31 expression, which blocks the translation of SATB2 mRNA, since levels of SATB2 mRNA remain the same but protein levels decrease. Overexpression of SATB2 induces malignant transformation of human bronchial epithelial (BEAS-2B) cells indicating the importance of the expression of miR-31 in preventing carcinogenesis by suppressing SATB2 protein levels., (© 2018 Wiley Periodicals, Inc.)

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA (lncRNA), was the earliest discovered to be correlated with cancer and contributes to the initiation and development of several types of tumors. Dysregulation of MALAT1 expression is frequently observed in many types of cancer such as gastric cancer, esophageal squamous cell carcinoma and glioma. To date, the role of MALAT1 and the underlying mechanisms in tongue cancer development remain unclear. In the present study, we studied the influence of MALAT1 on tongue cancer cell lines and clinical tongue cancer samples so as to detect its function and the underlying mechanism. In the present study, lncRNA-MALAT1 was specifically upregulated in tongue cancer cell lines and overexpression promoted tongue cancer cell growth by targeting miR-124. Knockdown of MALAT1 suppressed the growth and invasion of human tongue cancer cells and inhibited metastasis in vitro and in vivo. In addition, miR-124-dependent jagged1 (JAG1) regulation was required for MALAT1-induced tongue cancer cell growth. Our data revealed that MALAT1 inhibited tongue cancer cell growth and metastasis through miR-124-dependent JAG1 regulation. In conclusion, we revealed that MALAT1 may play an oncogenic role by increasing proliferation and metastasis of tongue cancer and is a potential therapeutic target in human tongue cancer.

The acute myeloid leukemia is a very common malignant tumor of hematopoietic system, which is seriously harmful to human health. The long-term survival rate of routine chemotherapy is not satisfactory, especially in the high risk patients. Resistance to chemotherapy drugs is one of the major reasons, which causes the refractorines and relapse of the acute myeloid leukemia. The microRNA found in eukaryote is an endogenous non-coding micromolecular signle-stranded RNA of 19 to 25 nt. The miRNA can degrade the specific RNA or inhibit its translation through combining to 3' untranslated regions of the specific RNA, which contributes to regulate the expression of the target gene. There are already some evidences showing that the disorder of miRNA plays an important role in the genesis and progress of the tumors. Recently, more and more researches suggest that the miRNA is also important in the genesis of drug resistance to tumors. This review summarizes the research progress and the major mechanism of drug-resistance mediated by the miRNA in AML, including multiple drug resistance, cell cycle and the tolerance to apoptosis, all of which are associated with ABC transport protein.

Oncomirs are microRNAs (miRNA) associated with carcinogenesis and malignant transformation. They have emerged as potential molecular targets for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects through modulations of oncomirs and their downstream targets. We found that GSE significantly down-regulated oncomirs miR-19a and -19b in a variety of lung neoplastic cells. GSE also increased mRNA and protein levels of insulin-like growth factor II receptor (IGF-2R) and phosphatase and tensin homolog (PTEN), both predicted targets of miR-19a and -19b. Furthermore, GSE significantly increased PTEN activity and decreased AKT phosphorylation in A549 cells. Transfection of miR-19a and -19b mimics reversed the up-regulations of IGF2R and PTEN gene expression and abrogated the GSE induced anti-proliferative response. Additionally, oral administration of leucoselect phytosome, comprised of standardized grape seed oligomeric procyanidins complexed with soy phospholipids, to athymic nude mice via gavage, significantly down-regulated miR-19a, -19b and the miR-17-92 cluster host gene (MIR17HG) expressions, increased IGF-2R, PTEN, decreased phosphorylated-AKT in A549 xenograft tumors, and markedly inhibited tumor growth. To confirm the absorption of orally administered GSE, plasma procyanidin B1 levels, between 60 and 90 min after gavage of leucoselect phytosome (400 mg/kg), were measured by LC/MS at week 2 and 8 of treatment; the estimated concentration that was associated with 50% growth inhibition (IC50) (1.3 μg/mL) in vitro was much higher than the IC50 (0.032-0.13 μg/ml) observed in vivo. Our findings reveal novel antineoplastic mechanisms by GSE and support the clinical translation of leucoselect phytosome as an anti-neoplastic and chemopreventive agent for lung cancer., (Published by Elsevier Inc.)

MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs, which play a critical role in regulating varieties of the biological and pathologic processes. MiR-196a has been reported to take part in tumorigenic progression of osteosarcoma (OS). However, the effects of miR-196a on OS are still unclear. The objective of this study is to investigate the molecular mechanism of miR-196a in osteosarcoma cells. In the present study, the expression of miR-196a in OS cell lines was detected by real-time PCR. We found that the expression level of miR-196a was markedly up-regulated in osteosarcoma cell lines compared with normal osteoblastic cells. Then, the miR-196a mimic was transiently transfected into MG63 and U2OS cells using Lipofectamine™ 2000 reagent. Subsequently, the MTT and Brdu-ELISA results showed that up-regulation of miR-196a promoted the cell viability and proliferation. Our results also showed that miR-196a mimic accelerated cell cycle progression of MG63 and U2OS cells by down regulation of p21 and p27, and upregulation of cyclin D1. In addition, overexpression of miR-196a suppressed apoptosis of MG63 and U2OS cells due to increasing BCL2L2 and MCL-1 expressions, and then inactivating caspase-3. Eventually, the effect of miR-196a mimic on the PTEN/phosphoinositide 3-kinase (PI3K)/Akt signaling pathway was explored by Western blot. From our results, transfection of miR-196a decreased the expression of PTEN and increased the phosphorylation of PI3K and Akt. Taken together, miR-196a should be an oncogene in osteosarcoma. The possible mechanism was that overexpression of miR-196a promoted proliferation of MG63 and U2OS cells by modulating the PTEN/PI3K/Akt signaling pathway.

CUEDC2, a CUE-domain-containing protein, modulates inflammation, but its involvement in tumorigenesis is still poorly understood. Here, we report that CUEDC2 is a key regulator of macrophage function and critical for protection against colitis-associated tumorigenesis. CUEDC2 expression is dramatically upregulated during macrophage differentiation, and CUEDC2 deficiency results in excessive production of proinflammatory cytokines. The level of CUEDC2 in macrophages is modulated by miR- 324-5p. We find that Cuedc2 KO mice are more susceptible to dextran-sodium-sulfate-induced colitis, and macrophage transplantation results suggest that the increased susceptibility results from the dysfunction of macrophages lacking CUEDC2. Furthermore, we find that Cuedc2 KO mice are more prone to colitis-associated cancer. Importantly, CUEDC2 expression is almost undetectable in macrophages in human colon cancer, and this decreased CUEDC2 expression is associated with high levels of interleukin-4 and miR-324-5p. Thus, CUEDC2 plays a crucial role in modulating macrophage function and is associated with both colitis and colon tumorigenesis., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fulminant hepatitis is a severe liver disease characterized by massive hepatocyte necrosis and clinical signs of liver failure. This study explores the expression profile of microRNAs, which are regulators of a number of pathophysiological processes, during the early stage of concanavalin A (Con A)-induced hepatitis., Methods: Balb/c mice were given ConA injections to induce fulminant hepatitis. miRNA expression profiling in liver tissues was carried out by microarray analysis. The differentially expressed miRNAs were subjected to time sequence profile analysis, gene-miRNA regulatory network analysis, and gene ontology-miRNA regulatory network analysis., Results: Eleven miRNAs among multiClass were found to be significantly differentially expressed between liver tissue in early stage fulminant hepatitis and normal control liver tissue. Mmu-miR-133a was the most differentially expressed with the strongest regulatory ability, regulating 47 mRNAs. Mmu-miR-10a was the most highly expressed in the microRNA-GO-Network and also exerted a strong regulatory ability. The expression profiles of miR-133a and miR-10a were verified by RT-PCR., Conclusions: These results show that, in the early stage, ConA-induced fulminant hepatitis induces a distinct miRNA expression profile. This differential miRNA expression profile may provide pathogenic clues and potential diagnostic and prognostic markers in acute and severe liver disease., (© 2014 S. Karger AG, Basel.)

Background: MicroRNAs (miRNAs), a class of highly conserved small non-coding RNA molecules, are known to play essential roles in central nervous system (CNS) by causing post-transcriptional gene silencing. There is much evidence that miRNAs have specific temporal and spatial expression patterns in the mammal brain, but little is known about the role of the region specificity for the gene regulatory networks of the brain. This study represents the first attempt to perform a profiling analysis of the differential expression of miRNAs between hippocampus and the Marginal division (MrD) of the neostriatum in the rat brain., Results: Microarray was used to detect the expression of 357 miRNAs in hippocampus and the MrD from three rats. A short-list of the most dysregulated 30 miRNAs per rat was generated for data analysis, and the miRNAs that were represented in two or three short-lists were then further analyzed. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was employed to validate the aberrantly expressed miRNAs obtained from the miRNA microarray analysis. A family of 11 miRNAs demonstrated differential expression between the MrD and hippocampus in more than one rat. Amongst these, miR-383 was differentially expressed in all three rats and up-regulated to the largest degree in rat one, and the ten other miRNAs, let-7d*, miR-181b, miR-187, miR-195, miR-214, miR-382, miR-411, miR-466b, miR-592 and miR-1224 were differentially expressed in at least two rats. Of these ten, besides miR-382 and miR-411 which were up-regulated in one rat and down-regulated in another, the other eight miRNAs retained a uniform direction of regulation (up-regulation or down-regulation) between different specimens. When further examined by RT-PCR, the aberrantly expressed miRNAs, except miR-383 and let-7d*, demonstrated differential expression that significantly correlated with the microarray findings., Conclusion: This study reported that the miRNA expression patterns in MrD was distinct from that of Hip, suggesting the role of miRNAs in the learning and memory function of the MrD probably different from hippocampus.

Background: miR-18a is one of the most up-regulated miRNAs in colorectal cancers (CRC) based on miRNA profiling. In this study, we examined the functional significance of miR-18a in CRC., Methods: Expression of miR-18a was investigated in 45 CRC patients. Potential target genes of miR-18a were predicted by in silico search and confirmed by luciferase activity assay and Western blot. DNA damage was measured by comet assay. Gene function was measured by cell viability, colony formation and apoptosis assays., Results: The up-regulation of miR-18a was validated and confirmed in 45 primary CRC tumors compared with adjacent normal tissues (p<0.0001). Through in silico search, the 3'UTR of Ataxia telangiectasia mutated (ATM) contains a conserved miR-18a binding site. Expression of ATM was down-regulated in CRC tumors (p<0.0001) and inversely correlated with miR-18a expression (r = -0.4562, p<0.01). Over-expression of miR-18a in colon cancer cells significantly reduced the luciferase activity of the construct with wild-type ATM 3'UTR but not that with mutant ATM 3'UTR, inferring a direct interaction of miR-18a with ATM 3'UTR. This was further confirmed by the down-regulation of ATM protein by miR-18a. As ATM is a key enzyme in DNA damage repair, we evaluated the effect of miR-18a on DNA double-strand breaks. Ectopic expression of miR-18a significantly inhibited the repair of DNA damage induced by etoposide (p<0.001), leading to accumulation of DNA damage, increase in cell apoptosis and poor clonogenic survival., Conclusion: miR-18a attenuates cellular repair of DNA double-strand breaks by directly suppressing ATM, a key enzyme in DNA damage repair.

Objective: To analyze the interaction between the microRNA-338 and its targeting proteins during the cerebral ischemia and reperfusion injury., Methods: TargetScan was used to predict the targets of microRNA-338. The potential targeting proteins were then selected according to their secondary structures using RNA structure 4.6 software and their involvement in cerebral ischemia and reperfusion injury was studied. Dual-luciferase reporter assay was used to testify whether microRNA-338 can recognize the 3'UTR of target protein. Western blot was applied to analyze the expression of eiF4E3 in both experimental group and control group., Result: EiF4E3 was the most likely potential targeting protein of microRNA-338. The secondary structure of local region of eiF4E3 recognizing microRNA-338 was conservative. The ratio of firefly to renilla luciferase activity in the experimental group was much higher than that of control group. However, there was no significant difference in the expression of eiF4E3 between these two groups., Conclusion: MicroRNA-338 can recognize the 3'UTR of eiF4E3 while it has no significant effect on the expression of eiF4E3. The post-target-recognizing regulation for miRNA do exist and this mechanism is possibly related to the tertiary structure of target mRNA.

Background: Recent literature has revealed that genetic exchange of microRNA between cells can be essential for cell-cell communication, tissue-specificity and developmental processes. In stem cells, as in other cells, this can be accomplished through microvesicles or exosome mediated transfer. However, molecular profiles and functions of microRNAs within the cells and in their exosomes are poorly studied. Next generation sequencing technologies could provide a broad-spectrum of microRNAs and their expression and identify possible microRNA targets. In this work, we performed deep sequencing of microRNAs to understand the profile and expression of the microRNAs in microvesicles and intracellular environment of human embryonic stem cells derived mesenchymal stem cells (hES-MSC). We outline a workflow pertaining to visualizing, statistical analysis and interpreting deep sequencing data of known intracellular and extracellular microRNAs from hES-MSC). We utilized these results of which directed our attention towards establishing hepatic nuclear factor 4 alpha (HNF4A) as a downstream target of let-7 family of microRNAs., Results: In our study, significant differences in expression profile of microRNAs were found in the intracellular and extracellular environment of hES-MSC. However, a high level of let-7 family of microRNAs is predominant in both intra- and extra- cellular samples of hES-MSC. Further results derived from visualization of our alignment data and network analysis showed that let-7 family microRNAs could affect the downstream target HNF4A, which is a known endodermal differentiation marker. The elevated presence of let-7 microRNA in both intracellular and extra cellular environment further suggests a possible intercellular signalling mechanism through microvesicles transfer. We suggest that let-7 family microRNAs might play a signalling role via such a mechanism amongst populations of stem cells in maintaining self renewal property by suppressing HNF4A expression. This is in line with recent paradigm where microRNAs regulate self-renewal and differentiation pathways of embryonic stem cells by forming an integral biological network with transcription factors., Conclusion: In summary, our study using a combination of alignment, statistical and network analysis tools to examine deep sequencing data of microRNAs in hES-MSC has led to a result that (i) identifies intracellular and exosome microRNA expression profiles of hES-MSC with a possible mechanism of miRNA mediated intercellular regulation by these cells and (ii) placed HNF4A within the cross roads of regulation by the let-7 family of microRNAs.