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Background: Endoplasmic reticulum (ER) stress and oxidative stress are the major pathologies encountered after intracerebral hemorrhage (ICH). Inositol‐requiring enzyme‐1 alpha (IRE1α) is the most evolutionarily conserved ER stress sensor, which plays a role in monitoring and responding to the accumulation of unfolded/misfolded proteins in the ER lumen. Recent studies have shown that ER stress is profoundly related to oxidative stress in physiological or pathological conditions. The purpose of this study was to investigate the role of IRE1α in oxidative stress and the potential mechanism. Methods: A mouse model of ICH was established by autologous blood injection. The IRE1α phosphokinase inhibitor KIRA6 was administrated intranasally at 1 h after ICH, antagomiR‐25 and agomiR‐25 were injected intraventricularly at 24 h before ICH. Western blot analysis, RT‐qPCR, immunofluorescence staining, hematoma volume, neurobehavioral tests, dihydroethidium (DHE) staining, H2O2 content, brain water content, body weight, Hematoxylin and Eosin (HE) staining, Nissl staining, Morris Water Maze (MWM) and Elevated Plus Maze (EPM) were performed. Results: Endogenous phosphorylated IRE1α (p‐IRE1α), miR‐25‐3p, and Nox4 were increased in the ICH model. Administration of KIRA6 downregulated miR‐25‐3p expression, upregulated Nox4 expression, promoted the level of oxidative stress, increased hematoma volume, exacerbated brain edema and neurological deficits, reduced body weight, aggravated spatial learning and memory deficits, and increased anxiety levels. Then antagomiR‐25 further upregulated the expression of Nox4, promoted the level of oxidative stress, increased hematoma volume, exacerbated brain edema and neurological deficits, whereas agomiR‐25 reversed the effects promoted by KIRA6. Conclusion: The IRE1α phosphokinase activity is involved in the oxidative stress response through miR‐25/Nox4 pathway in the mouse ICH brain. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are key RNA molecules in cancer biology. CircRNA PR/SET domain 5 (circ_PRDM5, hsa_circ_0005654) was downregulated in breast cancer (BC) tissues. This study is designed to investigate the functional mechanism of circ_PRDM5 in BC. Ultrasound examinations were performed to evaluate BC patients and normal individuals. Circ_PRDM5, miR‐25‐3p, and Ankyrin repeat domain 46 (ANKRD46) level detection was carried out by reverse transcription‐quantitative polymerase chain reaction. 3‐(4, 5‐dimethylthiazol‐2‐y1)‐2, 5‐diphenyl tetrazolium bromide (MTT) assay was used for cell viability examination. Cell proliferation was evaluated by ethynyl‐2′‐deoxyuridine assay and colony formation assay. The protein levels were examined using western blot. Cell migration and invasion abilities were assessed via transwell assay. Target interaction was analyzed via dual‐luciferase reporter assay. The role of circ_PRDM5 in vivo was explored via xenograft tumor assay. Circ_PRDM5 expression was downregulated in BC tissues and cells. Overexpression of circ_PRDM5 suppressed proliferation and motility but enhanced apoptosis of BC cells. Circ_PRDM5 served as a sponge of miR‐25‐3p. Circ_PRDM5 impeded BC cell malignant development via sponging miR‐25‐3p. Circ_PRDM5 induced ANKRD46 upregulation by targeting miR‐25‐3p. Inhibition of miR‐25‐3p retarded BC progression by increasing the ANKRD46 level. Circ_PRDM5 repressed BC tumorigenesis in vivo through mediating the miR‐25‐3p/ANKRD46 axis. This study evidenced that circ_PRDM5 inhibited cell progression and tumor growth in BC via interacting with mir‐25‐3p/ANKRD46 network. Highlights: Circ_PRDM5 overexpression suppresses the proliferation, migration, and invasion of BC cells.Circ_PRDM5 acts as a miR‐25‐3p sponge to upregulate ANKRD46 expression.Circ_PRDM5 inhibits tumor growth in vivo via interacting with the miR‐25‐3p/ANKRD46 axis. [ABSTRACT FROM AUTHOR]

Evidence exists suggesting the anti‐depressive activities of geniposide (GP), a major compound in Gardenia jasminoides Ellis. Accordingly, the present study attempts to explore the anti‐depressive mechanism of GP in chronic unpredictable mild stress (CUMS)‐induced depression‐like behaviors of mice. CUMS‐induced mice were given GP daily and subjected to behavioral tests to observe the effect of GP on the depression‐like behaviors. It was noted that GP administration reduced depression‐like behaviors in CUMS mice. Transcriptome sequencing was conducted in three control and three CUMS mice. Differentially expressed circRNAs, lncRNAs and mRNAs were then screened by bioinformatics analyses. Intersection analysis of the transcriptome sequencing results with the bioinformatics analysis results was followed to identify the candidate targets. We found that Gata2 alleviated depression‐like behaviors via the metabolism‐ and synapse‐related pathways. Gata2 was a target of miR‐25‐3p, which had binding sites to circ_0008405 and Oip5os1. circ_0008405 and Oip5os1 competitively bound to miR‐25‐3p to release the expression of Gata2. GP administration ameliorated depression‐like behaviors in CUMS mice through regulation of the circ_0008405/miR‐25‐3p/Gata2 and Oip5os1/miR‐25‐3p/Gata2 crosstalk networks. Taken together, GP may exert a potential antidepressant‐like effect on CUMS mice, which is ascribed to regulation of the circ_0008405/miR‐25‐3p/Gata2 and Oip5os1/miR‐25‐3p/Gata2 crosstalk networks. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is the primary reason of chronic kidney disease. The aim of our study is to explore the role and action mechanism of M2 macrophage‐derived exosomes in high glucose (HG)‐induced podocytes injury. Here, 30 mmol/L of HG was used to induce podocytes injury. Annexin V‐FITC/PI double staining was performed to measure podocytes apoptosis, and western blot was carried out to ensure proteins expression. The shape of exosomes was identified using TEM. Besides, the expression of miR‐25‐3p was determined by qRT‐PCR, FAM‐labeled miR‐25‐5p combined with DiI‐labeled exosomes were utilized to explore the uptake of podocytes to exosomes. Relationship between miR‐25‐3p and DUSP family members was ensued by luciferase activity assay. In the beginning, we found that M2 macrophage ameliorated HG‐induced podocytes apoptosis and epithelial‐mesenchymal transition through secreting exosomes. Subsequently, highly expressed miR‐25‐3p was found in M2 macrophage‐derived exosomes that effectively improved HG‐induced podocytes injury. Furthermore, inhibition of miR‐25‐3p in M2 macrophage inefficiently repressed HG‐induced podocytes injury, thus we proposed that M2 macrophage attenuated podocytes injury through secreting exosomal miR‐25‐3p. Then, we used an autophagy inhibitor to stimulate podocytes, and demonstrated that M2 macrophage‐derived exosomal miR‐25‐3p improved HG‐induced podocytes injury through activating autophagy. Finally, DUSP1 was proved to be a downstream target and mediated the inhibition of exosomal miR‐25‐3p to HG‐induced podocytes injury. Our results indicated that M2 macrophage could improve HG‐induced podocytes injury via secreting exosomal miR‐25‐3p to activate autophagy of the cells through suppressing DUSP1 expression. We proved a newly potential therapy strategy for DN treatment. [ABSTRACT FROM AUTHOR]

Objectives: The current study aimed to investigate the mechanism by which exosomes secreted by CHB patients with PNALT and liver inflammation grade (≥A2) affected the development of liver cancer. Materials and methods: Gene expression was assessed by RT‐PCR, Western blotting and immunohistochemistry. CCK‐8, colony formation, transwell, scratch‐wound and flow cytometry assays were used to detect cell viability, proliferation, apoptosis and metastasis. The interaction of TCF21 and HHIP was assessed by co‐immunoprecipitation assay. Luciferase reporter was used to detect the combination of TCF21/HHIP and miR‐25‐3p. Xenograft studies in nude mice manifested tumour growth ability of miR‐25‐3p. Bioinformatics analyses were conducted using TargetScan, EVmiRNA, TCGA, GEO, DAVID, COEXPEDIA, UALCAN, UCSC and the Human Protein Atlas databases. Results: CHB‐PNALT‐Exo (≥A2) promoted the proliferation and metastasis of HepG2.2.15 cells. miR‐25‐3p was upregulated in CHB‐PNALT‐Exo (≥A2). miR‐25‐3p overexpression promoted cell proliferation and metastasis and was related to poor survival in patients with CHB‐PNALT (≥A2). The cell proliferation‐ and metastasis‐promoting functions of CHB‐PNALT‐Exo (≥A2) were abolished by miR‐25‐3p inhibitors. TCF21 directly interacted with HHIP. Inhibition of TCF21 or HHIP promoted cell proliferation and metastasis. Knockdown of TCF21 or HHIP counteracted the effects of CHB‐PNALT‐Exo (≥A2) containing miR‐25‐3p inhibitor on cell proliferation, metastasis and the expression of Ki67, E‐cadherin and caspase‐3/‐9. Conclusions: Transfer of miR‐25‐3p by CHB‐PNALT‐Exo promoted the development of liver cancer by inhibiting the co‐expression of TCF21 and HHIP. [ABSTRACT FROM AUTHOR]

Acquisition of epithelial-mesenchymal transition ( EMT) has recently been proposed as an important contributor of drug resistance in cervical cancer cells. However, the underlying mechanisms are still unclear. Micro RNAs play a crucial role in regulating EMT. The aim of this study was to explore the potential role of miR-25-3p in regulating EMT in cisplatin-resistant ( CR) cervical cancer cells. To this end, we established stable CR cervical cancer cells, HeLa- CR and CaSki- CR, and investigated the function of miR-25-3p in regulating EMT. It is found that CR cervical cancer cells possessed more EMT characteristics and demonstrated higher migratory abilities and invasiveness. miR-25-3p downregulation was also seen in HeLa- CR and CaSki- CR cells. Of note, ectopic expression of miR-25-3p reversed the EMT phenotype and sensitized CR cells to cisplatin via targeting Sema4C. Furthermore, stable overexpression of miR-25-3p in HeLa- CR cells suppressed tumor growth in mice, downregulated Sema4C and Snail, and upregulated E-cadherin compared with the control group. These results suggest that miR-25-3p is an important regulator of cervical cancer EMT and chemoresistance. Thus, upregulation of miR-25-3p could be a novel approach to treat cervical cancers that are resistant to chemotherapy. [ABSTRACT FROM AUTHOR]