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Background and Purpose Experimental Approach Key Results Conclusion and Implications MicroRNA (miR)‐210 function in endothelial cells and its role in diabetes‐associated endothelial dysfunction are not fully understood. We aimed to characterize the miR‐210 function in endothelial cells and study its therapeutic potential in diabetes.Two different diabetic mouse models (db/db and Western diet‐induced), miR‐210 knockout and transgenic mice, isolated vessels and human endothelial cells were used.miR‐210 levels were lower in aortas isolated from db/db than in control mice. Endothelium‐dependent relaxation (EDR) was impaired in aortas from miR‐210 knockout mice, and this was restored by inhibiting miR‐210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol‐3‐phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR‐210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR‐210. However, plasma miR‐210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR‐210 transgenic mice and pharmacological overexpression using miR‐210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR‐210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR‐210 mimic restored decreased nitric oxide production by high glucose in endothelial cells.This study unravels the mechanisms by which down‐regulated miR‐210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR‐210 serves as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Background: miR-210 is one of the most evolutionarily conserved microRNAs. It is known to be involved in several physiological and pathological processes, including response to hypoxia, angiogenesis, cardiovascular diseases and cancer. Recently, new roles of this microRNA are emerging in the context of eye and visual system homeostasis. Recent studies in Drosophila melanogaster unveiled that the absence of miR-210 leads to a progressive retinal degeneration characterized by the accumulation of lipid droplets and disruptions in lipid metabolism. However, the possible conservation of miR-210 knock-out effect in the mammalian retina has yet to be explored. Results: We further investigated lipid anabolism and catabolism in miR-210 knock-out (KO) flies, uncovering significant alterations in gene expression within these pathways. Additionally, we characterized the retinal morphology of flies overexpressing (OE) miR-210, which was not affected by the increased levels of the microRNA. For the first time, we also characterized the retinal morphology of miR-210 KO and OE mice. Similar to flies, miR-210 OE did not affect retinal homeostasis, whereas miR-210 KO mice exhibited photoreceptor degeneration. To explore other potential parallels between miR-210 KO models in flies and mice, we examined lipid metabolism, circadian behaviour, and retinal transcriptome in mice, but found no similarities. Specifically, RNA-seq confirmed the lack of involvement of lipid metabolism in the mice's pathological phenotype, revealing that the differentially expressed genes were predominantly associated with chloride channel activity and extracellular matrix homeostasis. Simultaneously, transcriptome analysis of miR-210 KO fly brains indicated that the observed alterations extend beyond the eye and may be linked to neuronal deficiencies in signal detection and transduction. Conclusions: We provide the first morphological characterization of the retina of miR-210 KO and OE mice, investigating the role of this microRNA in mammalian retinal physiology and exploring potential parallels with phenotypes observed in fly models. Although the lack of similarities in lipid metabolism, circadian behaviour, and retinal transcriptome in mice suggests divergent mechanisms of retinal degeneration between the two species, transcriptome analysis of miR-210 KO fly brains indicates the potential existence of a shared upstream mechanism contributing to retinal degeneration in both flies and mammals. [ABSTRACT FROM AUTHOR]

Abstract Background miR-210 is one of the most evolutionarily conserved microRNAs. It is known to be involved in several physiological and pathological processes, including response to hypoxia, angiogenesis, cardiovascular diseases and cancer. Recently, new roles of this microRNA are emerging in the context of eye and visual system homeostasis. Recent studies in Drosophila melanogaster unveiled that the absence of miR-210 leads to a progressive retinal degeneration characterized by the accumulation of lipid droplets and disruptions in lipid metabolism. However, the possible conservation of miR-210 knock-out effect in the mammalian retina has yet to be explored. Results We further investigated lipid anabolism and catabolism in miR-210 knock-out (KO) flies, uncovering significant alterations in gene expression within these pathways. Additionally, we characterized the retinal morphology of flies overexpressing (OE) miR-210, which was not affected by the increased levels of the microRNA. For the first time, we also characterized the retinal morphology of miR-210 KO and OE mice. Similar to flies, miR-210 OE did not affect retinal homeostasis, whereas miR-210 KO mice exhibited photoreceptor degeneration. To explore other potential parallels between miR-210 KO models in flies and mice, we examined lipid metabolism, circadian behaviour, and retinal transcriptome in mice, but found no similarities. Specifically, RNA-seq confirmed the lack of involvement of lipid metabolism in the mice’s pathological phenotype, revealing that the differentially expressed genes were predominantly associated with chloride channel activity and extracellular matrix homeostasis. Simultaneously, transcriptome analysis of miR-210 KO fly brains indicated that the observed alterations extend beyond the eye and may be linked to neuronal deficiencies in signal detection and transduction. Conclusions We provide the first morphological characterization of the retina of miR-210 KO and OE mice, investigating the role of this microRNA in mammalian retinal physiology and exploring potential parallels with phenotypes observed in fly models. Although the lack of similarities in lipid metabolism, circadian behaviour, and retinal transcriptome in mice suggests divergent mechanisms of retinal degeneration between the two species, transcriptome analysis of miR-210 KO fly brains indicates the potential existence of a shared upstream mechanism contributing to retinal degeneration in both flies and mammals.

Abstract Ischaemic stroke, a leading cause of global morbidity and mortality, necessitates effective biomarkers for enhanced diagnostic and prognostic stratification. MicroRNAs (miRNAs), particularly miR-210, have emerged as promising candidates due to their intricate regulatory roles in cellular responses to hypoxia and neuroprotective effects. This study explores the potential of miR-210 as a biomarker for ischaemic stroke, considering its expression patterns, regulatory functions and diagnostic/prognostic implications. A literature search was conducted on PubMed, Scopus, Google Scholar and Web of Science to identify studies focusing on miR-210 in ischaemic stroke. Inclusion criteria comprised reports on miR-210 expression in ischaemic stroke patients, excluding non-English studies, reviews, commentaries and conference abstracts lacking primary data. Studies investigating miR-210 levels in ischaemic stroke patients revealed significant alterations in expression patterns compared to healthy controls. Diagnostic potential was explored, indicating miR-210’s sensitivity and specificity in distinguishing ischaemic stroke from other neurological conditions. Prognostic value was evident through associations with infarct size, functional outcomes and long-term survival. Challenges included variability in miR-210 levels, limited diagnostic specificity, absence of standardised assays and concerns regarding cost-effectiveness and accessibility. While miR-210 holds promise as an ischaemic stroke biomarker, challenges must be addressed for its successful integration into clinical practice. Standardised reference ranges, validation studies in diverse populations and collaborative efforts for assay standardisation are crucial. Despite challenges, miR-210’s diagnostic and prognostic potential, particularly in predicting therapeutic responses, suggests a significant role in advancing ischaemic stroke management.

Ischaemic stroke, a leading cause of global morbidity and mortality, necessitates effective biomarkers for enhanced diagnostic and prognostic stratification. MicroRNAs (miRNAs), particularly miR-210, have emerged as promising candidates due to their intricate regulatory roles in cellular responses to hypoxia and neuroprotective effects. This study explores the potential of miR-210 as a biomarker for ischaemic stroke, considering its expression patterns, regulatory functions and diagnostic/prognostic implications. A literature search was conducted on PubMed, Scopus, Google Scholar and Web of Science to identify studies focusing on miR-210 in ischaemic stroke. Inclusion criteria comprised reports on miR-210 expression in ischaemic stroke patients, excluding non-English studies, reviews, commentaries and conference abstracts lacking primary data. Studies investigating miR-210 levels in ischaemic stroke patients revealed significant alterations in expression patterns compared to healthy controls. Diagnostic potential was explored, indicating miR-210's sensitivity and specificity in distinguishing ischaemic stroke from other neurological conditions. Prognostic value was evident through associations with infarct size, functional outcomes and long-term survival. Challenges included variability in miR-210 levels, limited diagnostic specificity, absence of standardised assays and concerns regarding cost-effectiveness and accessibility. While miR-210 holds promise as an ischaemic stroke biomarker, challenges must be addressed for its successful integration into clinical practice. Standardised reference ranges, validation studies in diverse populations and collaborative efforts for assay standardisation are crucial. Despite challenges, miR-210's diagnostic and prognostic potential, particularly in predicting therapeutic responses, suggests a significant role in advancing ischaemic stroke management. [ABSTRACT FROM AUTHOR]

Abstract Background Pulmonary arterial hypertension is most of the time diagnosed late in the course of the disease and necessitates right cardiac catheterization which is an invasive and costly tool. MicroRNAs have a role in the pathogenesis of pulmonary hypertension, systemic sclerosis, and schistosomiasis and their dosages are easy and non-expensive. Therefore, determining their levels in the blood may be helpful in detecting PAH and differentiating its idiopathic form from those caused by systemic sclerosis and schistosomiasis. Purpose of the study To evaluate the role of microRNA (miR) 204 and miR-210 in the diagnosis of PAH and to distinguish between idiopathic PAH (IPAH), systemic sclerosis-associated PAH (SSc-PAH), and schistosomiasis-associated PAH (Sch-PAH) and to identify patients who may benefit from simple non-expensive and non-invasive methods in diagnosis of PAH. Methods Sixty patients with PAH and 30 subjects as control were enrolled in the study. PAH was diagnosed by right heart catheterization, echocardiography, and laboratory tests. Blood samples were taken from all patients for measuring miR-204 and miR-210. Results MiR-204 was downregulated in PAH and there was a highly significant difference between PAH and control (p = 0.003) with cut-off predictive value ≤ 0.15 µM and 70% sensitivity, 85% specificity with AUC (0.749). However, miR-204 failed to distinguish between IPAH, SSc-PAH, and Sch-PAH. MiR-210 was upregulated in PAH with a highly significant difference between PAH and control (p

Introduction The aim of the study is the regulatory effect of MicroRNA-210 (MiR- 210) on cigarette smoke extract (CSE)-induced mouse lung epithelial type II cells (MLE-12) apoptosis and determine whether the MiR-210 is involved in cigarette smoke extract-induced apoptosis of MLE-12 via Shh signaling pathway. Methods Expression of MiR-210 in CSE-induced MLE-12 was assessed by qRTPCR. The emphysema mouse model and MiR-210 knockdown mice were each established by inhaling cigarette smoke or intratracheal lentiviral vector instillation. The Sonic hedgehog (Shh), Ptch1, Gli1, B-cell lymphoma-2 (Bcl-2), and Caspase 3 protein expressions were detected by Western blotting. mRNA expressions of MiR-210, Shh, Ptch1, and Gli1 were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Apoptotic ratios in mice and CSE-induced HPVEC were assessed using TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays and flow cytometry. Results Our results showed that MiR-210 mRNA levels were significantly downregulated in the CSE-induced MLE 12. MLE 12 apoptosis with down-regulated Shh, Ptch1, Gli1, and Bcl-2 expression, increased Caspase 3 expression in the emphysema mouse model and CSE-induced MLE 12. Knockdown MiR-210 can facilitate cell apoptosis and emphysema via the Shh signaling pathway in mice. In vitro , MiR-210 can attenuate the apoptosis of CSE-exposed MLE 12. Moreover, MiR-210 regulated the Shh pathway and promoted its expression. Conclusions MiRNA-210 is involved in cigarette smoke extract-induced apoptosis of MLE-12 via the Shh signaling pathway. The present study reveals that MiRNA-210 may be a key regulator of cellular apoptosis and could be explored as a potential therapeutic target in the future.

Rationale: Obstructive sleep apnea (OSA)-induced endothelial cell (EC) dysfunction contributes to OSA-related cardiovascular sequelae. The mechanistic basis of endothelial impairment by OSA is unclear. Objectives: The goals of this study were to identify the mechanism of OSA-induced EC dysfunction and explore the potential therapies for OSA-accelerated cardiovascular disease. Methods: The experimental methods include data mining, bioinformatics, EC functional analyses, OSA mouse models, and assessment of OSA human subjects. Measurements and Main Results: Using mined microRNA sequencing data, we found that microRNA 210 (miR-210) conferred the greatest induction by intermittent hypoxia in ECs. Consistently, the serum concentration of miR-210 was higher in individuals with OSA from two independent cohorts. Importantly, miR-210 concentration was positively correlated with the apnea-hypopnea index. RNA sequencing data collected from ECs transfected with miR-210 or treated with OSA serum showed a set of genes commonly altered by miR-210 and OSA serum, which are largely involved in mitochondrion-related pathways. ECs transfected with miR-210 or treated with OSA serum showed reduced [Formula: see text]o2 rate, mitochondrial membrane potential, and DNA abundance. Mechanistically, intermittent hypoxia-induced SREBP2 (sterol regulatory element-binding protein 2) bound to the promoter region of miR-210, which in turn inhibited the iron-sulfur cluster assembly enzyme and led to mitochondrial dysfunction. Moreover, the SREBP2 inhibitor betulin alleviated intermittent hypoxia-increased systolic blood pressure in the OSA mouse model. Conclusions: These results identify an axis involving SREBP2, miR-210, and mitochondrial dysfunction, representing a new mechanistic link between OSA and EC dysfunction that may have important implications for treating and preventing OSA-related cardiovascular sequelae.

Background: Pulmonary arterial hypertension is most of the time diagnosed late in the course of the disease and necessitates right cardiac catheterization which is an invasive and costly tool. MicroRNAs have a role in the pathogenesis of pulmonary hypertension, systemic sclerosis, and schistosomiasis and their dosages are easy and non-expensive. Therefore, determining their levels in the blood may be helpful in detecting PAH and differentiating its idiopathic form from those caused by systemic sclerosis and schistosomiasis. Purpose of the study: To evaluate the role of microRNA (miR) 204 and miR-210 in the diagnosis of PAH and to distinguish between idiopathic PAH (IPAH), systemic sclerosis-associated PAH (SSc-PAH), and schistosomiasis-associated PAH (Sch-PAH) and to identify patients who may benefit from simple non-expensive and non-invasive methods in diagnosis of PAH. Methods: Sixty patients with PAH and 30 subjects as control were enrolled in the study. PAH was diagnosed by right heart catheterization, echocardiography, and laboratory tests. Blood samples were taken from all patients for measuring miR-204 and miR-210. Results: MiR-204 was downregulated in PAH and there was a highly significant difference between PAH and control (p = 0.003) with cut-off predictive value ≤ 0.15 µM and 70% sensitivity, 85% specificity with AUC (0.749). However, miR-204 failed to distinguish between IPAH, SSc-PAH, and Sch-PAH. MiR-210 was upregulated in PAH with a highly significant difference between PAH and control (p < 0.001) with cut-off predictive value ≥ 1.16 µM and 93.33% sensitivity, 85% specificity with AUC (0.917). MiiR-210 showed a significant difference between SSc-PAH and idiopathic PAH (P = 0.012) and between SSc-PAH and Sch-PAH (P = 0.035). Conclusions: MiR-204 and miR-210 are useful non-invasive and non-expensive markers for the diagnosis of PAH, miR-210 is an excellent predictor in the diagnosis of PAH and also miR-210 might be used to distinguish SSc-PAH from idiopathic PAH and Sch-PAH. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Late Fetal Growth Restriction (LFGR), a condition associated with perinatal and long-term neurodevelopmental problems, is caused by inadequate placental transfer of oxygen and nutrients to the fetus. This preliminary study evaluates the expression profiles and clinical significance of hypoxia-sensitive microRNA-210 (miR-210) and microRNA-185-5p (miR-185-5p) in placental and maternal circulation. The potential clinical implications of this research could significantly enhance the management of LFGR. STUDY DESIGN: In this prospective cohort study conducted at the Gynecology and Obstetrics Clinic of Trakya University Faculty of Medicine Hospital, miR-210 and miR-185-5p expression was evaluated in the placenta of healthy (n=30) and LFGR (n=30) cases. In healthy (n=15) and LFGR (n=15) cases, miRNA levels in maternal plasma were studied. We determined these two miRNAs using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and statistically analyzed them with clinical data to determine robustness. We provided a comprehensive evaluation. RESULTS: Both the placenta and maternal plasma samples exhibited significant correlations with miR- 210 and miR-185-5p expression (r=0.615; r=0.771, p<0.01). The expression levels in both placenta and plasma were significantly higher in the LFGR group. Placental miR-210 demonstrated an AUC (0.908), sensitivity (93.3%), and specificity (96.7%), while plasma miR-210 showed AUC (0.738), sensitivity (86.7%), and specificity (66.7%). In contrast, placental miRNA 185-5p displayed a diagnostic performance with AUC (0.926), sensitivity (76.1%), and specificity (63.8%); plasma miRNA 185-5p exhibited an AUC (0.778), sensitivity (86.7%), and specificity (86.7%). However, placental miR-210 and miR-185-5p did not fully correlate with birth weight, placental weight, and fetal cerebroplacental Doppler ratio. CONCLUSION: Placental miRNA-210 showed superior diagnostic performance over placental miRNA 185-5p in LFGR pregnancies. However, it is crucial to emphasize that further studies are needed to validate these findings and correlate them with clinical data, underscoring the ongoing importance of research in this field. [ABSTRACT FROM AUTHOR]

The field cancerization theory is an important paradigm in head and neck carcinoma as its oncological repercussions affect treatment outcomes in diverse ways. The aim of this study is to assess the possible interconnection between peritumor mucosa and the process of tumor neoangiogenesis. Sixty patients with advanced laryngeal carcinoma were enrolled in this study. The majority of patients express a canonical HIF-upregulated proangiogenic signature with almost complete predominancy of HIF-1α overexpression and normal expression levels of the HIF-2α isoform. Remarkably, more than 60% of the whole cohort also exhibited an HIF-upregulated proangiogenic signature in the peritumoral benign mucosa. Additionally, the latter subgroup had a distinctly shifted phenotype towards HIF-2α upregulation compared to the one in tumor tissue, i.e., a tendency towards an HIF switch is observed in contrast to the dominated by HIF-1α tumor phenotype. ETS-1 displays stable and identical significant overexpression in both the proangiogenic phenotypes present in tumor and peritumoral mucosa. In the current study, we report for the first time the existence of an abnormal proangiogenic expression profile present in the peritumoral mucosa in advanced laryngeal carcinoma when compared to paired distant laryngeal mucosa. Moreover, we describe a specific phenotype of this proangiogenic signature that is significantly different from the one present in tumor tissue as we delineate both phenotypes, quantitively and qualitatively. This finding is cancer heterogeneity, per se, which extends beyond the "classical" borders of the malignancy, and it is proof of a strong interconnection between field cancerization and one of the classical hallmarks of cancer—the process of tumor neoangiogenesis. [ABSTRACT FROM AUTHOR]

Smoking during lactation harmfully affects the amount and constituents of breast milk. Infants who consume breast milk containing miR-210-5p may have a higher risk of brain-related diseases. We investigated whether smoking during lactation decreases β-casein concentrations in milk and whether miR-210-5p expression is involved in smoking-induced β-casein suppression. During lactation, maternal CD1 mice were exposed to cigarette smoke (1.7 mg of tar and 14 mg of nicotine) in a smoke chamber for 1 h twice/day for five consecutive days. Control mice were placed in an air-filled chamber equivalent in size to the smoke chamber, with maternal separation times identical to those of the smoked mice. Maternal exposure to smoke during lactation significantly decreased β-casein expression in the mammary epithelia of smoked mice compared to that of the control mice. Signal transducer and activator transcription 5 (STAT5) and phosphorylated STAT5 (pSTAT5) are transcription factors involved in β-casein expression. In the mammary epithelia of smoked mice, the pSTAT5 and STAT5 levels were significantly lower, and miR-210-5p expression was significantly higher than that of the control mice. The β-casein, pSTAT5, and STAT5 protein levels of miR-210-5p mimic-transfected human mammary epithelial MCF-12A cells were significantly lower than those of control siRNA-transfected cells. These results indicate that smoke exposure led to an increase in miR-210-5p expression in mammary epithelium and a decrease in pSTAT5 and β-casein protein levels through the inhibition of STAT5 expression. Moreover, nicotine treatment decreased β-casein protein levels and increased miR-210-5p expression in non-malignant human mammary epithelial MCF-12A cells in a concentration-dependent manner, demonstrating that nicotine significantly affects the β-casein and miR-210-5p levels of breast milk. These results highlight the adverse effects of smoking on breast milk, providing essential information for healthcare professionals and general citizens.

AbstractObjectiveMethodsResultsConclusionTo analyze the significance of serum miR-145 and miR-210 expression levels in the diagnosis of carotid artery stenosis.During the same period, 55 healthy individuals who received physical examination in the same hospital were recruited as controls and assigned to a non-stenosis group. Among the included patients, there were 45 cases of mild stenosis, 14 cases of moderate stenosis, and 6 cases of severe stenosis after carotid color Doppler ultrasonography. The expression levels of miR-145 and miR-210 in serum were measured using real-time fluorescence quantitative polymerase chain reaction (qPCR) technology.The expression levels of serum miR-145 and miR-210 in carotid artery stenosis group were significantly lower than those in non-stenosis group (p < 0.001). Multivariate Logistic regression analysis showed that smoking history, diabetes, hypertension and total cholesterol were positively correlated with the occurrence of carotid artery stenosis (p < 0.05). The expression levels of miR-145 and miR-210 were significantly negatively correlated with carotid artery stenosis (p < 0.001). In addition, patients with carotid artery stenosis and low expression levels of miR-145 and miR-210 had a greater risk of cerebral ischemia (p < 0.05). Cox regression analysis showed that the low expression of miR-145 and miR-210 were independent predictors of cerebral ischemic events. ROC analysis confirmed that miR-145 and miR-210 had good diagnostic efficacy in cerebral ischemia (p < 0.001).The decreased expression of miR-145 and miR-210 in serum is closely related to the diagnostic significance of carotid artery stenosis, and may be used to predict the occurrence of cerebral ischemic events. [ABSTRACT FROM AUTHOR]

BACKGROUND: With rapid progression, severe illness and high fatality rate, sepsis has become an acute and critical condition that seriously threatens human life and health. OBJECTIVE: To detect miR-210 and miR-494 expression in patients with sepsis and their relationship with severity and prognosis. METHODS: A total of 165 sepsis patients participated, including 105 patients with septic non-shock and 60 patients with septic shock. 53 sepsis patients died in 28 days, and 112 patients survived. The clinical information of all sepsis patients was retrospectively searched and reviewed. Based on the status of 28-day survival, they were categorized into survival group and death group. The expression levels in each group were compared on the first, third and seventh day. The ROC curve was applied to know the expression level of plasma miR-210 and miR-494 to predict the death. RESULTS: The two miRNAs expression of the septic shock group were significantly higher than that in sepsis non-shock group on the first, third and seventh day (all were P < 0.05). The ROC curve found that the AUC combined to predict the death on the third day was the largest, which was 0.925 (95%CI: 0.864–0.983). The sensitivity and specificity were 94.6% and 86.3%, respectively. CONCLUSION: The increased expression levels of plasma miR-210 and miR-494 are closely relevant to the severity and prognosis of sepsis patients. Combining the two items on the third day can predict the death of sepsis patients. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment and portend poor prognosis. However, the molecular mechanisms underlying the tumor promotion of TAMs have not been fully elucidated. Methods: Coculture of gastric cancer cells with U937 cells was performed to investigate the impact of TAMs on cancer cell behavior. MicroRNA (miRNA) microarray and bioinformatics were applied to identify the involved miRNAs and the functional target genes. The regulation of the miRNA on its target gene was studied using anti-miRNA and miRNA mimic. Results: Coculture with CD204+ M2-like TAMs increased proliferation, migration, and epithelial-mesenchymal transition of gastric cancer cells. MiR-210 was the most upregulated miRNA in cancer cells identified by miRNA microarray after coculture. In gastric cancer tissues, miR-210 expression was positively correlated with CD204+ M2-like TAM infiltration. Inactivation of miR-210 by antimir attenuated CD204+ M2-like TAMs-induced cancer cell migration. Using pharmacological inhibitors and neutralizing antibodies, CD204+ M2-like TAMs-secreted TNFα was found to upregulate miR-210 through NF-κB/HIF-1α signaling. Bioinformatics analysis showed netrin-4 (NTN4) as a potential target of miR-210 to suppress gastric cancer cell migration. We also found an inverse expression between miR-210 and NTN4 in cancer cells after coculture or in tumor xenografts. Anti-miR-210 increased NTN4 expression, while miR-210 mimics downregulated NTN4 in cancer cells. Reporter luciferase assays showed that MiR-210 mimics suppressed NTN4 3' untranslated region-driven luciferase activity in cancer cells, but this effect was blocked after mutating miR-210 binding site. Conclusions: CD204+ M2-like TAMs can utilize the TNF-α/NF-κB/HIF-1α/miR-210/NTN4 pathway to facilitate gastric cancer progression. [ABSTRACT FROM AUTHOR]

Abstract Purpose In osteoporosis, the balance between osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) is disrupted. The osteogenic differentiation of bone marrow MSCs (BMSCs) is important for improving osteoporosis. The aim of this study was to explore the role and molecular mechanism of miR-210 in the balance of osteogenic/adipogenic differentiation of BMSCs in postmenopausal osteoporosis. Methods Postmenopausal osteoporosis rat models were constructed by ovariectomy (OVX). BMSCs were isolated from the femur in rats of Sham and OVX groups. MiR-210 was overexpressed and suppressed by miR-210 mimics and inhibitor, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative mRNA expression of miR-210, ephrin type-A receptor 2 (EPHA2), alkaline phosphatase (ALP), osterix (OSX), osteocalcin (Bglap), Runt-related transcription factor 2 (Runx2), peroxisome proliferator activated receptor gamma, and fatty acid binding protein 4 (FABP4) in each group of rat femoral tissues or BMSCs. Western blot was applied to detect the protein expression level of EPHA2 in rat femoral tissues and cells. Alizarin red S staining and oil red O staining were performed to assess the osteogenic and adipogenic differentiation of BMSCs, respectively. In addition, the targeting relationship between miR-210 and EPHA2 was verified by a dual luciferase gene reporter assay. Results The expression of miR-210 was significantly reduced in femoral tissues and BMSCs of OVX rats, and its low expression was associated with reduced bone formation. The osteogenic differentiation was enhanced in OVX rats treated with miR-210 mimic. Overexpression of miR-210 in transfected BMSCs was also found to significantly promote osteogenic differentiation and even inhibit adipogenic differentiation in BMSCs, while knockdown of miR-210 did the opposite. Further mechanistic studies showed that miR-210 could target and inhibit the expression of EPHA2 in BMSCs, thus promoting osteogenic differentiation and inhibiting adipogenic differentiation of BMSCs. Conclusion MiR-210 promotes osteogenic differentiation and inhibits adipogenic differentiation of BMSCs by down-regulating EPHA2 expression. As it plays an important role in the osteogenic/adipogenic differentiation of osteoporosis, miR-210 can serve as a potential miRNA biomarker for osteoporosis.

Angiogenesis is critical for successful bone repair, and interestingly, miR-210 and miR-16 possess counter-active targets involved in both angiogenesis and osteogenesis: miR-210 acts as an activator by silencing EFNA3 & AcvR1b, while miR-16 inhibits both pathways by silencing VEGF & Smad5. It was thus hypothesized that dual delivery of both a miR-210 mimic and a miR-16 inhibitor from a collagen-nanohydroxyapatite scaffold system may hold significant potential for bone repair. Therefore, this systems potential to rapidly accelerate bone repair by directing enhanced angiogenic-osteogenic coupling in host cells in a rat calvarial defect model at a very early 4 week timepoint was assessed. In vitro , the treatment significantly enhanced angiogenic-osteogenic coupling of human mesenchymal stem cells, with enhanced calcium deposition after just 10 days in 2D and 14 days on scaffolds. In vivo , these dual-miRNA loaded scaffolds showed more than double bone volume and vessel recruitment increased 2.3 fold over the miRNA-free scaffolds. Overall, this study demonstrates the successful development of a dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair for the first time, and the possibility of extending this 'off-the-shelf' platform system to applications beyond bone offers immense potential to impact a myriad of other tissue engineering areas. miRNAs have potential as a new class of bone healing therapeutics as they can enhance the regenerative capacity of bone-forming cells. However, angiogenic-osteogenic coupling is critical for successful bone repair. Therefore, this study harnesses the delivery of miR-210, known to be an activator of both angiogenesis and osteogenesis, and miR-16 inhibitor, as miR-16 is known to inhibit both pathways, from a collagen-nanohydroxyapatite scaffold system to rapidly enhance osteogenesis in vitro and bone repair in vivo in a rat calvarial defect model. Overall, it describes the successful development of the first dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair. This 'off-the-shelf' platform system offers immense potential to extend beyond bone applications and impact a myriad of other tissue engineering areas. [Display omitted] [ABSTRACT FROM AUTHOR]

TOPC (2-(2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl) ethyl piperazine-1-carbodithioate) is a coleolic acid-dithiocarbamate derivative synthesized by our team. Notably, this compound exhibits superior inhibitory effects on the proliferation of human non-small-cell lung cancer (NSCLC) cell lines A549 and H1975 compared to coleolic acid. The primary objective of this study was to investigate the potential molecular mechanisms of TOPC against H1975 cells. Cell proliferation was assessed using the MTT assay, while apoptosis induced by TOPC was evaluated using Hoechst 33342 staining and Western blotting analysis. The expressions of autophagy proteins and the associated PI3K/AKT/mTOR signaling pathway were determined through Western blotting analysis. The transfection efficiency of the miR-210 mimic, inhibitor, and inhibitor NC, as well as the expressions of miR-210 and Atg7, were assessed using qRT-PCR. TOPC demonstrated significant inhibition of A549 and H1975 cell proliferation. Hoechst 33342 staining and Western blotting analysis revealed that TOPC induced apoptosis in H1975 cells. Moreover, TOPC induced autophagy in H1975 cells, as evidenced by increased expressions of autophagy-related proteins, such as Beclin-1, Atg5, Atg7, Atg12, and LC3-II. Additionally, qRT-PCR demonstrated that TOPC significantly downregulated the expression of miR-210 in H1975 cells. Further investigation suggested that TOPC-induced autophagy was mediated by inhibiting the PI3K/AKT/mTOR signaling pathway and suppressing the function of miR-210 on Atg7. The findings clearly demonstrated that TOPC substantially suppressed the growth of A549 and H1975 cells, making it a promising therapeutic agent for NSCLC. Its potential merits further development. [ABSTRACT FROM AUTHOR]

Purpose: In osteoporosis, the balance between osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) is disrupted. The osteogenic differentiation of bone marrow MSCs (BMSCs) is important for improving osteoporosis. The aim of this study was to explore the role and molecular mechanism of miR-210 in the balance of osteogenic/adipogenic differentiation of BMSCs in postmenopausal osteoporosis. Methods: Postmenopausal osteoporosis rat models were constructed by ovariectomy (OVX). BMSCs were isolated from the femur in rats of Sham and OVX groups. MiR-210 was overexpressed and suppressed by miR-210 mimics and inhibitor, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative mRNA expression of miR-210, ephrin type-A receptor 2 (EPHA2), alkaline phosphatase (ALP), osterix (OSX), osteocalcin (Bglap), Runt-related transcription factor 2 (Runx2), peroxisome proliferator activated receptor gamma, and fatty acid binding protein 4 (FABP4) in each group of rat femoral tissues or BMSCs. Western blot was applied to detect the protein expression level of EPHA2 in rat femoral tissues and cells. Alizarin red S staining and oil red O staining were performed to assess the osteogenic and adipogenic differentiation of BMSCs, respectively. In addition, the targeting relationship between miR-210 and EPHA2 was verified by a dual luciferase gene reporter assay. Results: The expression of miR-210 was significantly reduced in femoral tissues and BMSCs of OVX rats, and its low expression was associated with reduced bone formation. The osteogenic differentiation was enhanced in OVX rats treated with miR-210 mimic. Overexpression of miR-210 in transfected BMSCs was also found to significantly promote osteogenic differentiation and even inhibit adipogenic differentiation in BMSCs, while knockdown of miR-210 did the opposite. Further mechanistic studies showed that miR-210 could target and inhibit the expression of EPHA2 in BMSCs, thus promoting osteogenic differentiation and inhibiting adipogenic differentiation of BMSCs. Conclusion: MiR-210 promotes osteogenic differentiation and inhibits adipogenic differentiation of BMSCs by down-regulating EPHA2 expression. As it plays an important role in the osteogenic/adipogenic differentiation of osteoporosis, miR-210 can serve as a potential miRNA biomarker for osteoporosis. [ABSTRACT FROM AUTHOR]

Abstract Background To explore the effect and mechanism of action of miR-210 on postmenopausal osteoporosis (PMPO) in ovariectomized rats in vivo. Methods An ovariectomized (OVX) rat model was established by ovariectomy. Tail vein injection was performed to overexpress and knock down miR-210 in OVX rats, followed by the collection of blood and femoral tissues from each group of rats. And quantitative real-time polymerase chain reaction (qRT-PCR) was applied to assess the expression level of miR-210 in femoral tissues of each group. Micro computed tomography (Micro CT) was adopted to scan the microstructure of the femoral trabecula in each group to obtain relevant data like bone mineral density (BMD), bone mineral content (BMC), trabecular bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone surface-to-volume ratio (BS/BV), and trabecular separation (Tb.Sp). ELISA was used for determining the level of bone alkaline phosphatase (BALP), amino-terminal propeptide of type I procollagen (PINP), osteocalcin (OCN), and C-terminal telopeptide of type I collagen (CTX-1) in serum; and Western blot for the protein level of Runt-related transcription factor 2 (Runx2), osteopontin (OPN), and collagen type I alpha 1 (COL1A1) in femoral tissues. Results MiR-210 expression was significantly decreased in femoral tissues of OVX rats. Overexpression of miR-210 could obviously increase BMD, BMC, BV/TV and Tb.Th, whereas significantly decrease BS/BV and Tb.Sp in femurs of OVX rats. Moreover, miR-210 also downregulated BALP and CTX-1 level, upregulated PINP and OCN level in the serum of OVX rats promoted the expression of osteogenesis-related markers (Runx2, OPN and COL1A1) in the femur of OVX rats. Additionally, further pathway analysis revealed that high expression of miR-210 activated the vascular endothelial growth factor (VEGF)/Notch1 signaling pathway in the femur of OVX rats. Conclusion High expression of miR-210 may improve the micromorphology of bone tissue and modulate bone formation and resorption in OVX rats by activating the VEGF/Notch1 signaling pathway, thereby alleviating osteoporosis. Consequently, miR-210 can serve as a biomarker for the diagnosis and treatment of osteoporosis in postmenopausal rats.

Objective To investigate the effect of miR-210 on hydrogen peroxide (H2O2)-induced adipogenic differentiation of rat bone marrow mesenchymal stem cells (BM-MSCs). Methods The SD rat BM-MSCs were isolated, cultured and identified. BM-MSCs were induced by 200 μmol/L H2O2 for 1 h to construct an adipogenic differentiation model. Adipogenic differentiation models were transfected with miR-210 mimic or inhibitor, respectively. RT-qPCR to detect the expression of miR-210; oil red O staining to detect the fat particles in the cytoplasm of cells; Western blot to detect the expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT enhancer binding protein (C/EBPa) and Wnt/β-catenin pathway related proteins of cells. Results SD rat BM-MSCs were successfully isolated. In adipogenic differentiation model of BM-MSCs, the levels of miR-210, β-catenin, c-Myc, and cyclin D1 protein decreased, while the number of fat granules, PPARγ and C/EBPα protein levels increased; In BM-MSCs transfected with miR-210 mimic, the levels of miR-210, β-catenin, c-Myc, and cyclin D1 protein increased, while the fat granules, PPARγ, and C/EBPα protein level all decreased; The change trend of corresponding indexes in BM-MSCs transfected with miR-210 inhibitor was opposite to that in BM-MSCs transfected with miR-210 mimic. Conclusions Over-expression of miR-210 could inhibit the adipogenic differentiation of BM-MSCs induced by H2O2. This mechanism may be related to the activation of Wnt/β-catenin pathway.

MicroRNAs (miRNAs) are a class of small non-coding, single-stranded RNAs (ribonucleic acids) that play important roles in many vital processes through their impact on gene expression. One such miRNA, miR210, represents a hypoxia-induced cellular miRNA group that hold a variety of functions. This review article highlights the importance of miR-210 in the development of pre-eclampsia.KEY MESSAGEmiR-210 is a promising biomarker for monitoring pregnancy with pre-eclampsia. Overexpression of miR-210 had a negative impact on the process of cell migration and trophoblast invasion.

Tumor-associated macrophages (TAMs) play an important role in tumor development. Increasing research suggests that miR-210 may promote the progression of tumor virulence, but whether its pro-carcinogenic effect in primary hepatocellular carcinoma (HCC) is via an action on M2 macrophages has not been examined. Differentiation of THP-1 monocytes into M2-polarized macrophages was induced with phorbol myristate acetate (PMA) and IL-4, IL-13. M2 macrophages were transfected with miR-210 mimics or miR-210 inhibitors. Flow cytometry was used to identify macrophage-related markers and apoptosis levels. The autophagy level of M2 macrophages, expression of PI3K/AKT/mTOR signaling pathway-related mRNAs and protein were detected by qRT-PCR and Western blot. HepG2 and MHCC-97H HCC cell lines were cultured with M2 macrophages conditioned medium to explore the effects of M2 macrophage-derived miR-210 on the proliferation, migration, invasion and apoptosis of HCC cells. qRT-PCR showed increased expression of miR-210 in M2 macrophages. Autophagy-related gene and protein expression was enhanced in M2 macrophages transfected with miR-210 mimics, while apoptosis-related proteins were decreased. MDC staining and transmission electron microscopy observed the accumulation of MDC-labeled vesicles and autophagosomes in M2 macrophages in the miR-210 mimic group. The expression of PI3K/AKT/mTOR signaling pathway in M2 macrophages was reduced in miR-210 mimic group. HCC cells co-cultured with M2 macrophages transfected with miR-210 mimics exhibited enhanced proliferation and invasive ability as compared to the control group, while apoptosis levels were reduced. Moreover, promoting or inhibiting autophagy could enhance or abolish the above observed biological effects, respectively. miR-210 can promote autophagy of M2 macrophages via PI3K/AKT/mTOR signaling pathway. M2 macrophage-derived miR-210 promotes the malignant progression of HCC via autophagy, suggesting that macrophage autophagy may serve as a new therapeutic target for HCC, and targeting miR-210 may reset the effect of M2 macrophages on HCC. • miR-210 promotes autophagy and inhibits apoptosis in M2 macrophages. • miR-210 targets PI3K/AKT/mTOR signaling pathway and inhibits its expression in M2 macrophages. • miR-210 preconditioned M2 macrophage promotes proliferation, invasion and inhibits apoptosis of HCC cells. • miR-210-mediated autophagy of M2 macrophage contributes to the malignant progression of HCC. [ABSTRACT FROM AUTHOR]

Background: To explore the effect and mechanism of action of miR-210 on postmenopausal osteoporosis (PMPO) in ovariectomized rats in vivo. Methods: An ovariectomized (OVX) rat model was established by ovariectomy. Tail vein injection was performed to overexpress and knock down miR-210 in OVX rats, followed by the collection of blood and femoral tissues from each group of rats. And quantitative real-time polymerase chain reaction (qRT-PCR) was applied to assess the expression level of miR-210 in femoral tissues of each group. Micro computed tomography (Micro CT) was adopted to scan the microstructure of the femoral trabecula in each group to obtain relevant data like bone mineral density (BMD), bone mineral content (BMC), trabecular bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone surface-to-volume ratio (BS/BV), and trabecular separation (Tb.Sp). ELISA was used for determining the level of bone alkaline phosphatase (BALP), amino-terminal propeptide of type I procollagen (PINP), osteocalcin (OCN), and C-terminal telopeptide of type I collagen (CTX-1) in serum; and Western blot for the protein level of Runt-related transcription factor 2 (Runx2), osteopontin (OPN), and collagen type I alpha 1 (COL1A1) in femoral tissues. Results: MiR-210 expression was significantly decreased in femoral tissues of OVX rats. Overexpression of miR-210 could obviously increase BMD, BMC, BV/TV and Tb.Th, whereas significantly decrease BS/BV and Tb.Sp in femurs of OVX rats. Moreover, miR-210 also downregulated BALP and CTX-1 level, upregulated PINP and OCN level in the serum of OVX rats promoted the expression of osteogenesis-related markers (Runx2, OPN and COL1A1) in the femur of OVX rats. Additionally, further pathway analysis revealed that high expression of miR-210 activated the vascular endothelial growth factor (VEGF)/Notch1 signaling pathway in the femur of OVX rats. Conclusion: High expression of miR-210 may improve the micromorphology of bone tissue and modulate bone formation and resorption in OVX rats by activating the VEGF/Notch1 signaling pathway, thereby alleviating osteoporosis. Consequently, miR-210 can serve as a biomarker for the diagnosis and treatment of osteoporosis in postmenopausal rats. [ABSTRACT FROM AUTHOR]

Autophagy is a cellular response to diverse stresses within tumor microenvironment (TME) such as hypoxia. It enhances cell survival and triggers resistance to therapy. This study investigated the prognostic importance of HIF-1α and miR-210 in triple negative breast cancer (TNBC). Also, we studied the relation between beclin-1 and Bcl-2 and their prognostic relevance in triple negative breast cancer. Furthermore, the involvement of hypoxia-related markers, beclin-1 and Bcl-2 in mediating resistance to neoadjuvant chemotherapy (NACT) in TNBC was evaluated. Immunohistochemistry was performed to evaluate HIF-1α, beclin-1 and Bcl-2 expression whereas, miR-210 mRNA was detected by quantitative reverse transcription PCR (q-PCR) in 60 TNBC patients. High HIF-1α expression was related to larger tumors, grade III cases, positive lymphovascular invasion, advanced stage, high Ki-67 and poor overall survival (OS). High miR-210 and negative Bcl-2 expression were related to nodal metastasis, advanced stage and poor OS. High beclin-1 was associated with grade III, nodal metastasis, advanced stage and poor OS. Also, high beclin-1 and negative Bcl-2 were significantly associated with high HIF-1α and high miR-210. High HIF- 1α, miR-210 and beclin-1 as well as negative Bcl-2 were inversely related to pathologic complete response following NACT. High beclin-1 and lack of Bcl-2 are significantly related to hypoxic TME in TNBC. High HIF-1α, miR-210, and beclin-1 expression together with lack of Bcl-2 are significantly associated with poor prognosis as well as poor response to NACT. HIF-1α and miR-210 could accurately predict response to NACT in TNBC. [ABSTRACT FROM AUTHOR]

Hypoxia during pregnancy impairs uterine vascular adaptation via microRNA‐210 (miR‐210)‐mediated mitochondrial dysfunction and mitochondrial reactive oxygen species (mtROS) generation. TET methylcytosine dioxygenase 2 (TET2) participates in regulating inflammation and oxidative stress and its deficiency contributes to the pathogenesis of multiple cardiovascular diseases. Thus, we hypothesize a role of TET2 in hypoxia/miR‐210‐mediated mtROS suppressing spontaneous transient outward currents (STOCs) in uterine arteries. We found that gestational hypoxia downregulated TET2 in uterine arteries of pregnant sheep and TET2 was a target of miR‐210. Knockdown of TET2 with small interfering RNAs suppressed mitochondrial respiration, increased mtROS, inhibited STOCs and elevated myogenic tone. By contrast, overexpression of TET2 negated hypoxia‐ and miR‐210‐induced mtROS. The effects of TET2 knockdown in uterine arteries on mtROS, STOCs and myogenic contractions were blocked by the mitochondria‐targeted antioxidant MitoQ. In addition, the recovery effects of inhibiting endogenous miR‐210 with miR‐210‐LNA on hypoxia‐induced suppression of STOCs and augmentation of myogenic tone were reversed by TET2 knockdown in uterine arteries. Together, our study reveals a novel mechanistic link between the miR‐210‐TET2‐mtROS pathway and inhibition of STOCs and provides new insights into the understanding of uterine vascular maladaptation in pregnancy complications associated with gestational hypoxia. Key points: Gestational hypoxia downregulates TET methylcytosine dioxygenase 2 (TET2) in uterine arteries of pregnant sheep.TET2 is a downstream target of microRNA‐210 (miR‐210) and miR‐210 mediates hypoxia‐induced TET2 downregulation.Knockdown of TET2 in uterine arteries recapitulates the effect of hypoxia and miR‐210 and impairs mitochondrial bioenergetics and increases mitochondrial reactive oxygen species (mtROS).Overexpression of TET2 negates the effect of hypoxia and miR‐210 on increasing mtROS.TET2 knockdown reiterates the effect of hypoxia and miR‐210 and suppresses spontaneous transient outward currents (STOCs) and elevates myogenic tone, and these effects are blocked by MitoQ.Knockdown of TET2 reverses the miR‐210‐LNA‐induced reversal of the effects of hypoxia on STOCs and myogenic tone in uterine arteries. [ABSTRACT FROM AUTHOR]

Ischemia–reperfusion (I-R) injury is a cardinal pathophysiological hallmark of ischemic heart disease (IHD). Despite significant advances in the understanding of what causes I-R injury and hypoxia–reoxygenation (H-R) stress, viable molecular strategies that could be targeted for the treatment of the deleterious biochemical pathways activated during I-R remain elusive. The master hypoxamiR, microRNA-210 (miR-210), is a major determinant of protective cellular adaptation to hypoxia stress but exacerbates apoptotic cell death during cellular reoxygenation. While the hypoxia-induced transcriptional up-regulation of miR-210 is well delineated, the cellular mechanisms and molecular entities that regulate the transcriptional induction of miR-210 during the cellular reoxygenation phase have not been elucidated yet. Herein, in immortalized AC-16 cardiomyocytes, we delineated the indispensable role of the ubiquitously expressed transcription factor, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in H-R-induced miR-210 expression during cellular reoxygenation. Using dominant negative and dominant active expression vectors encoding kinases to competitively inhibit NF-κB activation, we elucidated NF-κB activation as a significant mediator of H-R-induced miR-210 expression. Ensuing molecular assays revealed a direct NF-κB-mediated transcriptional up-regulation of miR-210 expression in response to the H-R challenge that is characterized by the NF-κB-mediated reorchestration of the entire repertoire of histone modification changes that are a signatory of a permissive actively transcribed miR-210 promoter. Our study confers a novel insight identifying NF-κB as a potential novel molecular target to combat H-R-elicited miR-210 expression that fosters augmented cardiomyocyte cell death. [ABSTRACT FROM AUTHOR]

Background There are rare studies assessing the efficacy of inhaled glucocorticoids (ICS) , the common therapy for chronic obstructive pulmonary disease (COPD) . MicroRNAs (miRNAs) have been confirmed to be involved in the development of COPD, among which miR-210 and miR-181a are closely related to COPD. Moreover, there is lack of clinical research on changes of miR-210 and miR-181a in COPD patients treated with ICS. Objective To examine the changes and response predictive values of serum miR-210 and miR-181a levels in stable COPD patients treated with ICS. Methods Eighty-six COPD outpatients were recruited from 363 Hospital from January 2017 to June 2020. All of them received four-week budesonide and formoterol inhalation. Treatment efficacy was assessed by the results of spirometry test or COPD Assessment Test (CAT) 〔responsive to treatment was defined as the COPD stage was reduced at least one stage or CAT score was reduced at least 2 points after treatment〕. Pre- and post-treatment lung function parameters〔including forced expiratory volume in one second (FEV1) , forced vital capacity (FVC) , and peak expiratory flow (PEF) 〕 and serum miR-210 and miR-181a levels were collected. Pearson correlation analysis was used to assess the associations of serum miR-210 and miR-181a levels with FEV1, FVC, and PEF as well as CAT score before and after the treatment. ROC analysis was used to assess the predictive values of serum miR-210 and miR-181a levels for treatment response in stable COPD. Results Compared with pre-treatment, stable COPD patients demonstrated significantly increased values of FEV1, FVC, and PEF, and significantly decreased CAT score, serum miR-210 and miR-181a levels after treatment (P

Object: This study sought to elucidate the role of microRNA-210 (miR-210) in the occurrence and development of lung adenocarcinoma (LUAD). Methods: The levels of lncRNA miR-210HG and miR-210 in LUAD tissues and corresponding normal tissues were analyzed by real-time quantitative PCR. The expression of the anti-hypoxia factor hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were measured by qRT-PCR and Western blot. The target of miR-210 on HIF-1α was confirmed using TCGA, Western blot and luciferase reporter assay. The regulatory role of miR-210 on HIF-1α and VEGF in LUAD was investigated. The correlation of genes with clinical prognosis was analyzed using bioinformatics methods. The effect of miR-210 on LUAD cells was verified through apoptosis assays. Results: The expression of miR-210 and miR-210HG was significantly higher in LUAD tissues than in normal tissues. The expression of hypoxia-related indicators HIF-1α and VEGF was also significantly higher in LUAD tissues. MiR-210 suppressed HIF-1α expression by targeting site 113 of HIF-1α, thereby affecting VEGF expression. Overexpression of miR-210 inhibited HIF-1 expression by targeting the 113 site of HIF-1, thereby affecting VEGF expression. Conversely, inhibition of miR-210 resulted in a significant increase in HIF-1α and VEGF expression in LUAD cells. In TCGA-LUAD cohorts, the expression of VEGF-c and VEGF-d genes in LUAD tissues was significantly lower than in normal tissues, while overall survival was worse in LUAD patients with high expression of HIF-1α, VEGF-c and VEGF-d. Apoptosis was significantly lower in H1650 cells after miR-210 inhibition. Conclusion: This study reveals that miR-210 exerts an inhibitory effect on VEGF expression by down-regulating HIF-1α expression in LUAD. Conversely, inhibition of miR-210 significantly reduced H1650 apoptosis and led to worse patient survival by upregulating HIF-1α and VEGF. These results suggest that miR-210 could serve as a potential therapeutic target for the treatment of LUAD.

Hypoxia, or low oxygen tension, is frequently found in highly proliferative solid tumors such as anaplastic thyroid carcinoma (ATC) and is believed to promote resistance to chemotherapy and radiation. Identifying hypoxic cells for targeted therapy may thus be an effective approach to treating aggressive cancers. Here, we explore the potential of the well-known hypoxia-responsive microRNA (miRNA) miR-210-3p as a cellular and extracellular biological marker of hypoxia. We compare miRNA expression across several ATC and papillary thyroid cancer (PTC) cell lines. In the ATC cell line SW1736, miR-210-3p expression levels indicate hypoxia during exposure to low oxygen conditions (2% O2). Furthermore, when released by SW1736 cells into the extracellular space, miR-210-3p is associated with RNA carriers such as extracellular vesicles (EVs) and Argonaute-2 (AGO2), making it a potential extracellular marker for hypoxia. [ABSTRACT FROM AUTHOR]

Long non-coding RNA Small Nucleolar RNA Host Gene 16 (SNHG16) has been reported to participate in Lipopolysaccharide (LPS)-induced inflammatory pathway, which contributes to pneumonia. This study was therefore conducted to explore the role of SNHG16 in pneumonia. In this study, expression of SNHG16 and microRNA (miR)-210 in pneumonia plasma samples (n = 56) and control samples (n = 60) was detected by RT-qPCR. The potential crosstalk between SNHG16 and miR-210 was analyzed by performing overexpression experiments. MSP was performed to study the role of SNHG16 in methylation of miR-210 gene. Cell apoptosis was analyzed by cell apoptosis assay. Decreased expression levels of SNHG16 and increased expression levels of miR-210 were observed in pneumonia. SNHG16 showed an inverse correlation to miR-210. LPS treatment led to downregulated SNHG16 and upregulated miR-210 in Human Bronchial Epithelial Cells (HBEpCs). In HBEpCs, SNHG16 downregulated miR-210 and increased miR-210 DNA gene methylation. Moreover, SNHG16 suppressed the role of miR-210 in cell apoptosis under LPS treatment. In conclusion, SNHG16 is downregulated in pneumonia, and it downregulates miR-210 possibly through methylation to promote lung cell apoptosis induced by LPS. [ABSTRACT FROM AUTHOR]

Therapy for pancreatic ductal adenocarcinoma remains challenging, and the chances of a complete cure are very limited. As in other types of cancer, the expression and role of miRNAs in controlling the biological properties of this type of tumor have been extensively studied. A better insight into miRNA biology seems critical to refining diagnostics and improving their therapeutic potential. In this study, we focused on the expression of miR-21, -96, -196a, -210, and -217 in normal fibroblasts, cancer-associated fibroblasts prepared from a ductal adenocarcinoma of the pancreas, and pancreatic carcinoma cell lines. We compared these data with miRNAs in homogenates of paraffin-embedded sections from normal pancreatic tissues. In cancer-associated fibroblasts and cancer cell lines, miRNAs differed significantly from the normal tissue. In detail, miR-21 and -210 were significantly upregulated, while miR-217 was downregulated. Similar transcription profiles were earlier reported in cancer-associated fibroblasts exposed to hypoxia. However, the cells in our study were cultured under normoxic conditions. We also noted a relation to IL-6 production. In conclusion, cultured cancer-associated fibroblasts and carcinoma cells reflect miR-21 and -210 expression similarly to the cancer tissue samples harvested from the patients. [ABSTRACT FROM AUTHOR]

Rationale: Obstructive sleep apnea (OSA)–induced endothelial cell (EC) dysfunction contributes to OSA-related cardiovascular sequelae. The mechanistic basis of endothelial impairment by OSA is unclear. Objectives: The goals of this study were to identify the mechanism of OSA-induced EC dysfunction and explore the potential therapies for OSA-accelerated cardiovascular disease. Methods: The experimental methods include data mining, bioinformatics, EC functional analyses, OSA mouse models, and assessment of OSA human subjects. Measurements and Main Results: Using mined microRNA sequencing data, we found that microRNA 210 (miR-210) conferred the greatest induction by intermittent hypoxia in ECs. Consistently, the serum concentration of miR-210 was higher in individuals with OSA from two independent cohorts. Importantly, miR-210 concentration was positively correlated with the apnea–hypopnea index. RNA sequencing data collected from ECs transfected with miR-210 or treated with OSA serum showed a set of genes commonly altered by miR-210 and OSA serum, which are largely involved in mitochondrion-related pathways. ECs transfected with miR-210 or treated with OSA serum showed reduced V_ O2 rate, mitochondrial membrane potential, and DNA abundance. Mechanistically, intermittent hypoxia-induced SREBP2 (sterol regulatory element–binding protein 2) bound to the promoter region of miR-210, which in turn inhibited the iron–sulfur cluster assembly enzyme and led to mitochondrial dysfunction. Moreover, the SREBP2 inhibitor betulin alleviated intermittent hypoxia–increased systolic blood pressure in the OSA mouse model. Conclusions: These results identify an axis involving SREBP2, miR-210, and mitochondrial dysfunction, representing a new mechanistic link between OSA and EC dysfunction that may have important implications for treating and preventing OSA-related cardiovascular sequelae. [ABSTRACT FROM AUTHOR]

Inflammatory responses play a critical role in the progress of neurodegenerative disorders. MSC-Exos is considered to have an anti-inflammatory effect on the treatment strategy for brain injury. However, the therapeutic effect and possible mechanism of Exosomal miR-210 on microglia polarization-induced neuroinflammation and neurite outgrowth have not been reported. MSC-Exos were isolated by ultracentrifugation, identified by Nanosight NS300, transmission electron microscopy, and western bolt. In vitro, to explore the protective mechanism of MSC-Exos against neuroinflammation, the microglial BV2 cell was exposed to lipopolysaccharide to assess inflammatory changes. The intake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil)-MSC-Exos into microglia was observed by fluorescence microscopy. The results showed that Exosomal miR-210 treatment significantly inhibited the production of nitric oxide and pro-inflammatory cytokines. Exosomal miR-210 treatment also increased the number of M2 microglia cells and inhibited M1 microglia polarization. In addition, western blot demonstrated that Exosomal miR-210 reduced neuronal apoptosis. Thus, Exosomal miR-210 attenuated neuronal inflammation and promoted neurite outgrowth. Exosomal miR-210 from MSCs attenuated neuronal inflammation and contributed to neurogenesis possibly by inhibiting microglial M1 polarization. [ABSTRACT FROM AUTHOR]

Abstract The specific mechanism of gingerol in cerebral ischemia remains unknown. A neuroprotective function for miR‐210 in cerebral ischemia has been identified. The brain‐derived neurotrophic factor (BDNF)‐mediated signaling pathway protects against cerebral ischemic injury. This investigation aimed to determine whether gingerol plays a neuroprotective role in cerebral ischemia via the miR‐210/BDNF axis. N2a cells subjected to 10 h of hypoxia and 4 h of reoxygenation were treated with 5, 10, or 20 μmol/L gingerol. The levels of viability, apoptosis, and proteins in N2a cells were determined using MTT assays, flow cytometry, and western blotting, respectively. The binding relationship between BDNF and miR‐210 was studied using a dual luciferase reporter assay. The expression levels of miR‐210 and BDNF were determined using qPCR. Gingerol repressed the increase in apoptosis and decrease in viability observed in response to hypoxia/reoxygenation. Gingerol increased Bcl‐2, BDNF, and TrkB levels and reduced Bax and cleaved caspase 3 levels after hypoxia/reoxygenation. Gingerol evoked decreased expression of miR‐210. Inhibition of miR‐210 resulted in increased viability and reduced apoptosis along with increased levels of Bcl‐2, BDNF, and TrkB and reduced levels of Bax and cleaved caspase 3 after hypoxia/reoxygenation. Additionally, the miR‐210 mimic reversed changes induced by gingerol. The cotransfection of the miR‐210 mimic and wild type BDNF led to decreased luciferase activity. BDNF was negatively regulated by miR‐210. BDNF siRNA reversed these changes evoked by miR‐210 inhibition. Gingerol ameliorated hypoxia/reoxygenation‐stimulated neuronal damage by regulating the miR‐210/BDNF axis, indicating that gingerol is worthy of further application in cerebral ischemia therapy.

The immune regulatory roles of microRNAs (miRNAs) have recently attracted considerable attention. Bioinformatics prediction revealed that both let-7 and miR-210 provide potential binding sites for the Akt (rac-alpha serine/threonine-protein kinase) gene sequence in the sea cucumber Apostichopus japonicus (termed AjAkt). In this study, we first used a dual-luciferase reporter assay and functional validation techniques to verify the interactions between these two miRNAs (let-7 and miR-210) and AjAkt , and then investigated the functions of the validated miRNA/mRNA pair as part of the innate immune response against Vibrio splendidus infection. We found that AjAkt interacts with miR-210 rather than let-7, and miR-210 negatively regulates the expression of AjAkt. From 8 to 48 h after infection with V. splendidus , opposite trends were observed in the expression levels of miR-210 and Aj Akt (mRNA and protein) in coelomocytes, suggesting that the miR-210/ AjAkt pair is involved in immune regulation during this period after infection. Both AjAkt silencing and miR-210 overexpression enhanced the phagocytic capacity and reduced the infectivity of A. japonicus after pathogen infection, suggesting that the miR-210/ AjAkt pair may regulate the innate immune response of A. japonicus by altering phagocytic capacity. The findings of this study enrich our knowledge of the role of miRNA/mRNA pairs in immune regulation in sea cucumbers and provide insights into the molecular mechanisms of the innate immune response in marine echinoderms. • MiR-210, not let-7, interacts with Akt in Apostichopus japonicus. • MiR-210 overexpression or Akt silencing reduced the prevalence of Vibrio splendidus infection in A. japonicus. • The miR-210/ AjAkt pair regulates the innate immune response of A. japonicus by altering phagocytic capacity. [ABSTRACT FROM AUTHOR]

Abstract Background Breast cancer is the most common cancer in women around the world, and the molecular mechanisms of breast cancer progression and metastasis are still unclear. This study aims to clarify the function and N6,2′-O-dimethyladenosine (m6A) regulation of lncRNA MIR210HG in breast cancer. Results High expression of MIR210HG was confirmed in breast cancer. MIR210HG promoted breast cancer progression, which was mediated by its encoded miR-210. MIR210HG was regulated by IGF2BP1 mediated m6A modification. IGF2BP1 was confirmed highly expressed in breast cancer and induced both MIR210HG and miR-210 expression, which contributed to breast cancer progression. In addition, MIR210HG transcript was stabilized by IGF2BP1 and co-factor ELAVL1. IGF2BP1 was a direct target of MYCN via E-box binding motif. MYCN induced IGF2BP1 expression in breast cancer cells. MIR210HG and miR-210 expressions were also increased by MYCN. Conclusions In breast cancer, MIR210HG functions as an oncogenic lncRNA, which is also mediated by its encoded miR-210. In addition, both IGF2BP1 and ELAVL1 enhance the stability of MIR210HG, which contributes to the progression of breast cancer. Interestingly, IGF2BP1 is directly activated by MYCN, which explains the oncogenic role of MYCN. These findings clarify the m6A regulation related molecular mechanism of breast cancer progression. The MYCN/IGF2BP1/MIR210HG axis may serve as an alternative molecular mechanism of breast cancer progression.

Background: Differences of sex development (DSD) is a term used for conditions in which the chromosomal, gonadal or phenotypical sex is atypical. 46,XY DSD patients frequently present undervirilized external genitalia. The expression of different miRNAs in many organs of the male genital system has been reported, and these miRNAs have been associated with testicular function and its disorders, but no description has been related to DSD conditions. This study aimed to evaluate the plasma expression of miR‐210 in 46,XY DSD patients who presented atypical genitalia at birth. Methods: Eighteen 46,XY DSD patients who presented atypical genitalia (undescended testis and/or hypospadias, bifid scrotum or micropenis) at birth and 36 male control individuals were selected. Plasma levels of miR‐210 and reference miR‐23a were measured using RT‐qPCR and the data were analysed by the 2−ΔCt method. Results: MiR‐210 plasma levels were significantly higher in 46,XY DSD patients with atypical genitalia than in male control subjects (p = 0.0024). A positive association between miR‐210 levels and the presence of cryptorchidism and hypospadias (p = 0.0146 and p = 0.0223) was found in these patients. Significantly higher levels of miR‐210 were observed in patients with 46,XY DSD and cryptorchidism than in control subjects (p = 0.0118). These results are in agreement with previous literature reports, in which increased levels of miR‐210 expression were observed in human testicular tissue from adult males with undescended testes in comparison with samples of descended testes. Conclusion: Our study showed a positive association between the presence of atypical genitalia and plasma levels of miR‐210 expression in the group of patients with 46,XY DSD of unknown aetiology studied. These findings contribute to reveal a new perspective on the role of miRNAs in the development of male external genitalia and the broad spectrum of phenotypes presented by patients with 46,XY DSD. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a class of small non-coding, single-stranded RNAs (ribonucleic acids) that play important roles in many vital processes through their impact on gene expression. One such miRNA, miR210, represents a hypoxia-induced cellular miRNA group that hold a variety of functions. This review article highlights the importance of miR-210 in the development of pre-eclampsia. miR-210 is a promising biomarker for monitoring pregnancy with pre-eclampsia. Overexpression of miR-210 had a negative impact on the process of cell migration and trophoblast invasion. [ABSTRACT FROM AUTHOR]

Abstract Background Nickel nanoparticles (Nano-Ni) are increasingly used in industry and biomedicine with the development of nanotechnology. However, the genotoxic and carcinogenic effects of Nano-Ni and the underlying mechanisms are still unclear. Methods At first, dose–response (0, 10, 20, and 30 μg/mL) and time-response (0, 3, 6, 12, and 24 h) studies were performed in immortalized normal human bronchial epithelial cells BEAS-2B to observe the effects of Nano-Ni on DNA damage response (DDR)-associated proteins and the HIF-1α/miR-210/Rad52 pathway by real-time PCR or Western blot. Then, a Hsp90 inhibitor (1 µM of 17-AAG, an indirect HIF-1α inhibitor), HIF-1α knock-out (KO) cells, and a miR-210 inhibitor (20 nM) were used to determine whether Nano-Ni-induced Rad52 down-regulation was through HIF-1α nuclear accumulation and miR-210 up-regulation. In the long-term experiments, cells were treated with 0.25 and 0.5 µg/mL of Nano-Ni for 21 cycles (~ 150 days), and the level of anchorage-independent growth was determined by plating the cells in soft agar. Transduction of lentiviral particles containing human Rad52 ORF into BEAS-2B cells was used to observe the role of Rad52 in Nano-Ni-induced cell transformation. Nano-Ni-induced DNA damage and dysregulation of HIF-1α/miR-210/Rad52 pathway were also investigated in vivo by intratracheal instillation of 50 µg per mouse of Nano-Ni. gpt delta transgenic mice were used to analyze mutant frequency and mutation spectrum in mouse lungs after Nano-Ni exposure. Results Nano-Ni exposure caused DNA damage at both in vitro and in vivo settings, which was reflected by increased phosphorylation of DDR-associated proteins such as ATM at Ser1981, p53 at Ser15, and H2AX. Nano-Ni exposure also induced HIF-1α nuclear accumulation, miR-210 up-regulation, and down-regulation of homologous recombination repair (HRR) gene Rad52. Inhibition of or knocking-out HIF-1α or miR-210 ameliorated Nano-Ni-induced Rad52 down-regulation. Long-term low-dose Nano-Ni exposure led to cell malignant transformation, and augmentation of Rad52 expression significantly reduced Nano-Ni-induced cell transformation. In addition, increased immunostaining of cell proliferation markers, Ki-67 and PCNA, was observed in bronchiolar epithelial cells and hyperplastic pneumocytes in mouse lungs at day 7 and day 42 after Nano-Ni exposure. Finally, using gpt delta transgenic mice revealed that Nano-Ni exposure did not cause increased gpt mutant frequency and certain DNA mutations, such as base substitution and small base insertions/deletions, are not the main types of Nano-Ni-induced DNA damage. Conclusions This study unraveled the mechanisms underlying Nano-Ni-induced cell malignant transformation; the combined effects of Nano-Ni-induced DNA damage and DNA repair defects through HIF-1α/miR-210/Rad52 pathway likely contribute to Nano-Ni-induced genomic instability and ultimately cell transformation. Our findings will provide information to further elucidate the molecular mechanisms of Nano-Ni-induced genotoxicity and carcinogenicity. Graphical Abstract

Abstract Background Differences of sex development (DSD) is a term used for conditions in which the chromosomal, gonadal or phenotypical sex is atypical. 46,XY DSD patients frequently present undervirilized external genitalia. The expression of different miRNAs in many organs of the male genital system has been reported, and these miRNAs have been associated with testicular function and its disorders, but no description has been related to DSD conditions. This study aimed to evaluate the plasma expression of miR‐210 in 46,XY DSD patients who presented atypical genitalia at birth. Methods Eighteen 46,XY DSD patients who presented atypical genitalia (undescended testis and/or hypospadias, bifid scrotum or micropenis) at birth and 36 male control individuals were selected. Plasma levels of miR‐210 and reference miR‐23a were measured using RT‐qPCR and the data were analysed by the 2−ΔCt method. Results MiR‐210 plasma levels were significantly higher in 46,XY DSD patients with atypical genitalia than in male control subjects (p = 0.0024). A positive association between miR‐210 levels and the presence of cryptorchidism and hypospadias (p = 0.0146 and p = 0.0223) was found in these patients. Significantly higher levels of miR‐210 were observed in patients with 46,XY DSD and cryptorchidism than in control subjects (p = 0.0118). These results are in agreement with previous literature reports, in which increased levels of miR‐210 expression were observed in human testicular tissue from adult males with undescended testes in comparison with samples of descended testes. Conclusion Our study showed a positive association between the presence of atypical genitalia and plasma levels of miR‐210 expression in the group of patients with 46,XY DSD of unknown aetiology studied. These findings contribute to reveal a new perspective on the role of miRNAs in the development of male external genitalia and the broad spectrum of phenotypes presented by patients with 46,XY DSD.

In this study, luciferase reporter assay was used to establish the relationship between miR-210 and ISCU. This research was performed on both cell lines (A2058, G361, and 293T) and tissue samples. We found that miR-210 was upregulated in hypoxia and was elevated in melanoma in comparison with adjacent normal tissues. Expression of ISCU protein was decreased in melanoma tissues, and ISCU gene is a direct target of miR-210. ISCU knockdown with miR-210 enhanced ROS production. The results of our study showed that miR-210/ISCU/ROS axis can serve as a novel therapeutic target in melanoma. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) has a high mortality rate, and therapeutic approaches to treat these cancers are varied and depend on the metabolic state of the tumour. Profiles of CRC tumours have identified several biomarkers, including microRNAs. microRNA‐210 (miR‐210) levels are directly correlated with CRC survival. miR‐210 expression is higher in metastatic colon cancer cells versus non‐metastatic and normal colon epithelium. Therefore, efficient methods to inhibit miR‐210 expression in CRC may provide new advances in treatments. Methods: Expression of miRs was determined in several metastatic and non‐metastatic cell lines. miR‐210 expression was inhibited using PMIS‐miR‐210 in transduced cells, which were transplanted into xenograft mice. In separate experiments, CRC tumours were allowed to grow in xenograft mice and treated with therapeutic injections of PMIS‐miR‐210. Molecular and biochemical experiments identified several new pathways targeted by miR‐210 inhibition. Results: miR‐210 inhibition can significantly reduce tumour growth of implanted colon cancer cells in xenograft mouse models. The direct administration of PMIS‐miR‐210 to existing tumours can inhibit tumour growth in both NSG and Foxn1nu/j mouse models and is more efficacious than capecitabine treatments. Tumour cells further transfer the PMIS‐miR‐210 inhibitor to neighbouring cells by extracellular vesicles to inhibit miR‐210 throughout the tumour. miR‐210 inhibition activates the cleaved caspase 3 apoptotic pathway to reduce tumour formation. We demonstrate that the long non‐coding transcript XIST is regulated by miR‐210 correlating with decreased XIST expression in CRC tumours. XIST acts as a competing endogenous RNA for miR‐210, which reduces XIST levels and miR‐210 inhibition increases XIST transcripts in the nucleus and cytoplasm. The increased expression of NME1 is associated with H3K4me3 and H3K27ac modifications in the NME1 proximal promoter by XIST. Conclusion: Direct application of the PMIS‐miR‐210 inhibitor to growing tumours may be an effective colorectal cancer therapeutic. [ABSTRACT FROM AUTHOR]

Objective: Atopic dermatitis (AD) is a chronic inflammatory skin disease with unexplained points in its pathogenesis. Altered expressions of microRNAs (miRNA, miR) in plasma can serve as markers that distinguish diseased individuals from healthy controls AD. In the present study, plasma expression levels of miR-1910-3p, miR-4649-3p, miR-4296 and miR-210 were investigated in AD. Material and Method: Forty patients with AD and forty healthy control subjects were included in the present study. Quantitative realtime PCR was used to measure miRNAs. Results: The mean plasma miR-4296 level was higher in the patient group (p < 0.001). There was a significant negative correlation between SCORAD scores and miR-210 levels (r:-0.340, p=0.032). miR-210 levels decreased with increasing disease severity. In logistic regression analyses, an increase in plasma miR-4296 levels was found to be statistically significant (OR =5.464, p<0.001). Moreover, although not significant in other analyzes, a decrease in the miR-1910-3p was shown statistically significant. Conclusion: MiRNAs are crucial in the pathogenesis of AD. Increased miR-4296 seems to be significantly better at discriminating AD patients from healthy individuals. [ABSTRACT FROM AUTHOR]

Apoptotic cell death is a deleterious consequence of hypoxia-induced cellular stress. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxia stress. We have recently demonstrated that miR-210 attenuates hypoxia-induced apoptotic cell death. In this paper, we unveil that the miR-210-induced inhibition of the serine/threonine kinase Glycogen Synthase Kinase 3 beta (GSK3β) in AC-16 cardiomyocytes subjected to hypoxia stress underlies the salutary protective response of miR-210 in mitigating the hypoxia-induced apoptotic cell death. Using transient overexpression vectors to augment miR-210 expression concomitant with the ectopic expression of the constitutive active GSK3β S9A mutant (ca-GSK3β S9A), we exhaustively performed biochemical and molecular assays to determine the status of the hypoxia-induced intrinsic apoptosis cascade. Caspase-3 activity analysis coupled with DNA fragmentation assays cogently demonstrate that the inhibition of GSK3β kinase activity underlies the miR-210-induced attenuation in the hypoxia-driven apoptotic cell death. Further elucidation and delineation of the upstream cellular events unveiled an indispensable role of the inhibition of GSK3β kinase activity in mediating the miR-210-induced mitigation of the hypoxia-driven BAX and BAK insertion into the outer mitochondria membrane (OMM) and the ensuing Cytochrome C release into the cytosol. Our study is the first to unveil that the inhibition of GSK3β kinase activity is indispensable in mediating the miR-210-orchestrated protective cellular response to hypoxia-induced apoptotic cell death. [ABSTRACT FROM AUTHOR]

Angiogenesis is a critical process during human skin wound healing. However, hypoxia might lead to the dysfunction of the cellular interplay of endothelial cells and subcutaneous fibroblasts, resulting in the deregulation of angiogenesis. HIF1A is a key regulatory of the recovery of intracellular homeostasis under hypoxia. In the present study, the detailed role and mechanism of HIF1A in the angiogenesis under hypoxia were investigated. Via bioinformatic analyses on microarray profiles (GSE1041 and GSE17944), solube fms-related tyrosine kinase 1 (sFLT1, also known as sVEGFR1) and miR-210/miR-424 might be involved in HIF1A function on the angiogenesis under hypoxia in human umbilical vascular endothelium cells (HUVECs) and human dermal microvascular endothelial cells (HDMECs). In the present study, we identified sFLT1 as a downregulated gene in response to hypoxia and HIF1A overexpression in HUVECs and HDMECs. sFLT1 overexpression inhibited the capacity of migration and angiogenesis and significantly reversed the inducible effects of HIF1A on the migration and angiogenesis in both cell lines. miR-210 and miR-424 were upregulated by hypoxia and targeted sFLT1 3′-UTR to negatively modulate its expression. HIF1A modulated sFLT1 expression, VEGF signaling, and the migration and angiogenesis in HUVECs and HDMECs via miR-210/miR-424. Regarding the molecular mechanism, HIF1A bound the promoter region of miR-210 and miR-424 to activate their transcription, while miR-210/miR-424 bound sFLT1 3′-UTR to suppress its expression. In summary, HIF1A/miR-210/miR-424/sFLT1 axis modulates the angiogenesis in HUVECs and HDMECs upon hypoxic condition via VEGF signaling. [ABSTRACT FROM AUTHOR]

Background: Circular RNA plays a critical role in cell proliferation, differentiation, and autophagy. However, the role and mechanism of circRNA in preeclampsia is yet to be clarified. The present study investigated the function and mechanism of circ‐0002814 in preeclampsia. Methods: The expression level of circ‐0002814, microRNA 210 (miR210), Notch receptor 1 (Notch1), or cytoplasmic polyadenylation element‐binding protein 2 (CPEB2) was investigated by Reverse transcription Real‐time Quantitative PCR (RT‐qPCR). The level of Notch1, CPEB2, and FUS (FUS RNA‐binding protein) proteins was detected by western blot. The localization of circ‐0002814 and miR‐210 was determined by FISH assay. Cell proliferation and invasion were detected by EdU and transwell assays, respectively. The interaction between circ‐0002814 and FUS protein was detected by RNA pulldown assay, while that between circ‐0002814 and miR‐210 was detected by dual‐luciferase reporter assay. Results: The expression of circ‐0002814 was decreased in the placenta and plasma of patients with preeclampsia. The ectopic expression of circ‐0002814 promoted the invasion and proliferation of HTR8 cells compared to the control group (p < 0.05). Silencing circ‐0002814 suppressed the invasion and proliferation of JEG3 cells compared to the control group (p < 0.05). circ_0002814‐regulated Notch1 and CPEB2 by interaction with miR‐210 and also regulated FUS/VEGF axis in HTR8 and JEG3 cells. Conclusion: A low expression of circ‐0002814 was detected in the plasma and placental tissue in preeclampsia patients. circ‐0002814 participated in the proliferation and invasion of HTR8 and JEG3 cells. Thus, circ‐0002814 may be considered as a potential diagnostic marker and therapeutic target for preeclampsia. [ABSTRACT FROM AUTHOR]

We aim to establish a prediction model for pregnancy outcomes through a combinatorial analysis of circulating biomarkers and maternal characteristics to effectively identify pregnant women with higher risks of preeclampsia in the first and third trimesters within the Asian population. A total of two hundred and twelve pregnant women were screened for preeclampsia through a multicenter study conducted in four recruiting centers in Taiwan from 2017 to 2020. In addition, serum levels of sFlt-1/PlGF ratio, miR-181a, miR-210 and miR-223 were measured and transformed into multiples of the median. We thus further developed statistically validated algorithmic models by designing combinations of different maternal characteristics and biomarker levels. Through the performance of the training cohort (0.848 AUC, 0.73–0.96 95% CI, 80% sensitivity, 85% specificity, p < 0.001) and the validation cohort (0.852 AUC, 0.74–0.98 95% CI, 75% sensitivity, 87% specificity, p < 0.001) from one hundred and fifty-two women with a combination of miR-210, miR-181a and BMI, we established a preeclampsia prediction model for the first trimester. We successfully identified pregnant women with higher risks of preeclampsia in the first and third trimesters in the Asian population using the established prediction models that utilized combinatorial analysis of circulating biomarkers and maternal characteristics. [ABSTRACT FROM AUTHOR]

Background Colorectal cancer (CRC) has a high mortality rate, and therapeutic approaches to treat these cancers are varied and depend on the metabolic state of the tumour. Profiles of CRC tumours have identified several biomarkers, including microRNAs. microRNA‐210 (miR‐210) levels are directly correlated with CRC survival. miR‐210 expression is higher in metastatic colon cancer cells versus non‐metastatic and normal colon epithelium. Therefore, efficient methods to inhibit miR‐210 expression in CRC may provide new advances in treatments. Methods Expression of miRs was determined in several metastatic and non‐metastatic cell lines. miR‐210 expression was inhibited using PMIS‐miR‐210 in transduced cells, which were transplanted into xenograft mice. In separate experiments, CRC tumours were allowed to grow in xenograft mice and treated with therapeutic injections of PMIS‐miR‐210. Molecular and biochemical experiments identified several new pathways targeted by miR‐210 inhibition. Results miR‐210 inhibition can significantly reduce tumour growth of implanted colon cancer cells in xenograft mouse models. The direct administration of PMIS‐miR‐210 to existing tumours can inhibit tumour growth in both NSG and Foxn1nu/j mouse models and is more efficacious than capecitabine treatments. Tumour cells further transfer the PMIS‐miR‐210 inhibitor to neighbouring cells by extracellular vesicles to inhibit miR‐210 throughout the tumour. miR‐210 inhibition activates the cleaved caspase 3 apoptotic pathway to reduce tumour formation. We demonstrate that the long non‐coding transcript XIST is regulated by miR‐210 correlating with decreased XIST expression in CRC tumours. XIST acts as a competing endogenous RNA for miR‐210, which reduces XIST levels and miR‐210 inhibition increases XIST transcripts in the nucleus and cytoplasm. The increased expression of NME1 is associated with H3K4me3 and H3K27ac modifications in the NME1 proximal promoter by XIST. Conclusion Direct application of the PMIS‐miR‐210 inhibitor to growing tumours may be an effective colorectal cancer therapeutic.