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Growing evidence suggests that neuroinflammation is a critical driver of the development, worsening, and cell death observed in acute ischemic stroke (AIS). While prior research has demonstrated that tirofiban enhances functional recovery in AIS patients by suppressing platelet aggregation, its impact and underlying mechanisms in AIS-related neuroinflammation remain elusive. The current study established an AIS mouse model employing photochemical techniques and assessed neurological function and brain infarct size using the modified neurological severity scale (mNSS) and 2,3,5-Triphenyltetrazolium chloride (TTC) staining, respectively. Tirofiban significantly reduced the volume of cerebral infarction in AIS mice, accompanied by an enhancement in their neurological functions. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays along with experiments assessing oxidative stress showed that tirofiban mitigated oxidative damage and apoptosis in the ischemic penumbra post-AIS. Additionally, DNA microarray analysis revealed alterations in gene expression patterns in the ischemic penumbra after tirofiban treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that most gene-level downregulated signaling pathways were closely related to the inflammatory response. Moreover, the protein microarray analysis revealed that tirofiban diminished the expression levels of inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha, in the ischemic penumbra. Additionally, immunofluorescence staining showed that tirofiban regulated inflammatory responses by altering the state and phenotype of microglia. In conclusion, this study suggests that tirofiban reduces inflammatory response by regulating microglial state and phenotype and lowering the levels of inflammatory factors, providing neuroprotection in acute ischemic stroke.

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Acute myocardial infarction is one of the leading causes of death worldwide. Although timely reperfusion could attenuate myocardial ischemia injury and reduce mortality, it causes severe secondary injury to the myocardium known as myocardial ischemia/reperfusion injury (MIRI) with unmet clinical needs. Emodin has a protective effect on MIRI in rodents. However, the precise mechanism underlying its pharmacological effect remains poorly understood. Accordingly, the present study used mRNA and microRNA (miRNA) sequencing based on MIRI mouse models to determine the mechanism involved. Emodin was found to prevent MIRI and attenuate the inflammation of myocardium in the MIRI model. In addition, by using an interdisciplinary approach, the present study uncovered that emodin suppressed the runt-related transcription factor 1 (RUNX1), which is a transcription factor of miR-142-3p, in either MIRI or the hypoxia/reoxygenation injury model. Furthermore, miR-142-3p can negatively regulate dopamine receptor D2 (DRD2), which acted as an anti-inflammatory factor to suppress NF-κB-dependent inflammation and prevent MIRI. These results were demonstrated by both cellular hypoxia/reoxygenation and mouse MIRI models. Overall, the present study provided an unrevealed molecular mechanism for emodin function. Emodin could inhibit NF-κB-triggered inflammation in MIRI by regulating the RUNX1/miR-142-3p/DRD2 pathway. Therefore, the RUNX1/miR-142-3p/DRD2 pathway presented a novel target for MIRI treatment, and the application of emodin in clinical practice may improve the treatment of MIRI.

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[This corrects the article DOI: 10.3389/fonc.2020.00184.].

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Gastric cancer (GC) is the TOP3 leading cause of human mortality in malignant tumors. Notwithstanding, the association between GC and circRNAs is not clear. The purpose of this research was to determine the association between GC progression and circRNAs. The data of circRNAs was obtained from the Gene Expression Omnibus (GEO) database to identify gene, which differentially expressed circRNAs in GC tissues and paired normal tissues. The expression of circRNAs in cancer tissues and normal tissues were tested, and the target circRNA was verified before and after surgery in the plasma. A circRNA-micro(mi)RNA-mRNA competing endogenous RNAs (ceRNAs) network was established, and GO and KEGG analysis are performed. Five candidate circRNAs were identified through bioinformatics analysis. Hsa_circ_0021087 and hsa_circ_0005051 were both downregulated in GC tissues, cells and plasma by RTq-PCR. Additionally, there was a significant difference in the expression of plasma hsa_circ_0021087 in patients with GC at the preoperative and postoperative stages (P < 0.001). Hsa_circ_0021087 also promoted the proliferation of GC cells in vitro. Next, the circRNA-miRNA-mRNA network of hsa_circ_0021087 was predicted, which may be associated with the development of GC by bioinformatics analysis. In summary, the aforementioned dual-circular RNAs may have important implications on the potential, novel and non-invasive diagnostic method for patients with GC.

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BACKGROUND: Ischemic cardiomyopathy (ICM) leads to heart failure by causing apoptosis of cardiac myocytes. It is generally believed that a therapy targeting apoptosis of cardiac myocytes would improve the prognosis of patients with ischemic heart disease. AIMS: We aimed to investigate the role of Rho GTPase­activating protein 1 (ARHGAP1) in ICM. METHODS: The cellular model of myocardial ischemia (H9c2 cell model) and a rat model of ICM were established to explore the expression of ARHGAP1. The overexpression of ARHGAP1 was induced in H9c2 myocardial cells to assess protein function. RESULTS: The expression of ARHGAP1 as a result of hypoxic conditions in the cellular and rat models was observed. Its overexpression induced apoptosis of cultured H9c2 cells under normal atmospheric conditions. ARHGAP1 was also shown to initiate the apoptosis pathway by regulating the cell death modulators B­cell lymphoma 2 (Bcl­2) and Bcl­2­associated X protein. CONCLUSIONS: Our results show that the ARHGAP1 expression is closely associated with apoptosis of myocardial cells, which in turn leads to ICM. Thus, ARHGAP1 may become a novel molecular marker of the hypoxia­induced apoptosis pathway and serve as a potential therapeutic target in patients with ICM.

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BACKGROUND Oxidative stress in myocardial ischemia results in cardiomyocyte apoptosis. The expression of microRNA-141-3p (miR-141-3p) and the 105 kD toll-like receptor protein (TLR), RP105, have been identified in cardiomyocytes in vitro. This study aimed to investigate the effects of hypoxia in H9c2 rat cardiomyoblasts with and without the inhibition of miR-141-3p and to investigate the expression of RP105 and the PI3K/AKT signaling pathway. MATERIAL AND METHODS H9c2 rat cardiomyoblasts were cultured in conditions of hypoxia and treated with a specific miR-141-3p-inhibitor. RP105 short-interfering RNA (siRNA) was constructed, and LY294002 was used to inhibit the PI3KA/AKT pathway. The fluorescent probe, dihydroethidium (DHE), was used to detect reactive oxygen species (ROS). Flow cytometry evaluated ROS and apoptosis. Quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot studied the expression of the PI3K/AKT pathway genes and proteins. Bioinformatics and dual-luciferase reporter assays were used to identify the targets for miR-141-3p. RESULTS A predictive TargetScan algorithm showed that the RP105 gene was a potential target of miR-141-3p. Expression of miR-141-3p was significantly increased in hypoxic H9c2 cells, and inhibition of miR-141-3p increased cell viability and reduced apoptosis. Also, miR-141-3p was shown to target 3'-UTR of RP105. Down-regulation of RP105 associated with hypoxia and its downstream PI3K/AKT pathway were significantly increased following miR-141-3p inhibition. The protective effect of miR-141-3p inhibition in hypoxic H9c2 cells was abolished by the absence of RP105 and inhibition of PI3K/AKT. CONCLUSIONS Inhibition of miR-141-3p reduced hypoxia-induced apoptosis in H9c2 cardiomyocytes in vitro by activating the RP105-dependent PI3K/AKT signaling pathway.

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Background and purpose: Ginsenoside Rg1 (GS Rg1), as an important active substance of Panax ginseng, has been proven to have elaborate cardioprotective effects. The purpose of this study was to detect that GS Rg1 attenuates cardiac oxidative stress and inflammation in streptozotocin (STZ)-induced diabetic rats (DM). Methods: Cardiac function was assessed by heart rate and blood pressure. Markers relevant to myocardial oxidative stress and antioxidant capacity, and inflammatory reaction factors were detected. The mRNA and protein expression were detected by RT-qPCR and Western blot, respectively. Results: GS Rg1 treatment significantly reduced the symptoms of cardiac hypertrophy and hypertension, and also decreased oxidative stress, inflammation response, NF-κB expression and NLRP3 inflammasome expression. GS Rg1 enhanced mitochondrial biogenesis by increasing PGC-1α, complex III and complex Ⅳ expression. GS Rg1 treatment significantly increased the expression of AMPK, Nrf2 and HO-1 in cardiac tissues. Conclusion: GS Rg1 exhibited protective effect against STZ-induced cardiac dysfunction, which is potentially associated with AMPK/Nrf2/HO-1 signal pathway.

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Long noncoding RNAs (lncRNAs) play important roles in endothelium development. A lncRNA, LEF1-AS1, is recently emerging as a potent mediator of the proliferation and migration of a number of cells, including smooth muscle cells. However, the effects of LEF1-AS1 in atherosclerosis remains largely unknown. Specimens from patients with coronary artery atherosclerosis were collected. The quantitative real-time polymerase chain reaction was used to analyze levels of LEF1-AS1 and microRNA-544a (miR-544a). Western blot analysis was used to assess PTEN, P-Akt, and T-Akt protein expression. Proliferation, migration, and invasion of cells were analyzed by cell counting kit-8 assay, scratch wound assay, and transwell assay, respectively. The interaction between LEF1-AS1, miR-544a, and PTEN was probed using bioinformatical analysis and dual-luciferase assay. In plasma and tissue of patients with coronary artery atherosclerosis, LEF1-AS1 was upregulated and miR-544a was downregulated. A negative correlation was found between LEF1-AS1 and miR-544a. miR-544a overexpression reversed the inhibition of LEF1-AS1 in smooth muscle cell proliferation and invasion, which were mediated through the PTEN pathway. LEF1-AS1 regulates smooth muscle cell proliferation and migration through the miR-544a/PTEN axis, indicating that LEF1-AS1 may be a potential therapeutic target in atherosclerosis.

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Myocardial infarction (MI) is a common presentation for ischemic heart disease, which is a leading cause of death. Emodin is a Chinese herbal anthraquinone used in several diseases. However, the effect of emodin in hypoxia-induced injury in cardiomyocytes has not been clearly elucidated. Our study aimed to clarify the functions of emodin in hypoxia-induced injury in rat cardiomyocytes H9c2 and explore the underlying mechanism. The effects of emodin on cell viability and apoptosis were analyzed by the Cell counting kit-8 assay and flow cytometry assay, respectively. The cell proliferation- and cell apoptosis-related proteins were detected by western blot. qRT-PCR was used to determine the relative expression of miR-138. Cell transfection was performed to alter miR-138 and MLK3 expression. miR-138 target was performed by dual luciferase activity assay. Sirt1/AKT and Wnt/ß-catenin pathways-related factors phosphorylation were analyzed by western blot. Emodin inhibited hypoxia-induced injury in H9c2 cells by promoting cell viability and reducing cell apoptosis. miR-138 was down-regulated by hypoxia treatment but up-regulated by emodin. Up-regulation of miR-138 alleviated hypoxia-induced cell injury. Down-regulation of miR-138 attenuated the growth-promoting effect of emodin on hypoxia-induced injury, whereas up-regulation of miR-138 enhanced the growth-promoting effects of emodin. The underlying mechanism might be by inactivating Sirt1/AKT and Wnt/ß-catenin pathways. MLK3 was negatively regulated by miR-138 expression and inactivated Sirt1/AKT and Wnt/ß-catenin pathways. Emodin alleviated hypoxia-induced injury in H9c2 cells via up-regulation of miR-138 modulated by MLK3, as well as by activating Sirt1/AKT and Wnt/ß-catenin pathways.

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Rhynchophylline (RP), the primary active ingredient of Uncaria rhynchophylla, has an anti­hypertensive effect and protects against ischemia­induced neuronal damage. The present study aimed to examine the roles and mechanisms of RP in myocardial ischemia­reperfusion (MI/R) injury of rat cardiomyocytes. Cell viability, reactive oxygen species, mitochondrial membrane potential (MMP) and cell apoptosis were examined by a Cell Counting Kit­8 assay and flow cytometry, respectively. An ELISA was performed to assess the expression of oxidative stress markers. Spectrophotometry was used to detect the degree of mitochondrial permeability transition pore (mPTP) openness. Western blotting and reverse transcription­ quantitative polymerase chain reaction assays were used to evaluate the associated protein and mRNA expression, respectively. The present results demonstrated that RP increased the cell viability of MI/R­induced cardiomyocytes, and suppressed the MI/R­induced apoptosis of cardiomyocytes. Additionally, RP modulated the Ca2+ and MMP levels in MI/R­induced cardiomyocytes. Furthermore, RP decreased the oxidative stress and mPTP level of MI/R­induced cardiomyocytes. It was additionally observed that RP affected the apoptosis­associated protein expression and regulated the mitochondrial­associated gene expression in MI/R­induced cardiomyocytes. In conclusion, RP ameliorated MI/R injury through the modulation of mitochondrial mechanisms. The potential effects of RP on the protection of MI/R­induced apoptosis of cardiomyocytes suggest that RP may be an effective target for MI/R therapy.

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Myocardial infarction (MI) is a common presentation for ischemic heart disease, which is a leading cause of death. Emodin is a Chinese herbal anthraquinone used in several diseases. However, the effect of emodin in hypoxia-induced injury in cardiomyocytes has not been clearly elucidated. Our study aimed to clarify the functions of emodin in hypoxia-induced injury in rat cardiomyocytes H9c2 and explore the underlying mechanism. The effects of emodin on cell viability and apoptosis were analyzed by the Cell counting kit-8 assay and flow cytometry assay, respectively. The cell proliferation- and cell apoptosis-related proteins were detected by western blot. qRT-PCR was used to determine the relative expression of miR-138. Cell transfection was performed to alter miR-138 and MLK3 expression. miR-138 target was performed by dual luciferase activity assay. Sirt1/AKT and Wnt/β-catenin pathways-related factors phosphorylation were analyzed by western blot. Emodin inhibited hypoxia-induced injury in H9c2 cells by promoting cell viability and reducing cell apoptosis. miR-138 was down-regulated by hypoxia treatment but up-regulated by emodin. Up-regulation of miR-138 alleviated hypoxia-induced cell injury. Down-regulation of miR-138 attenuated the growth-promoting effect of emodin on hypoxia-induced injury, whereas up-regulation of miR-138 enhanced the growth-promoting effects of emodin. The underlying mechanism might be by inactivating Sirt1/AKT and Wnt/β-catenin pathways. MLK3 was negatively regulated by miR-138 expression and inactivated Sirt1/AKT and Wnt/β-catenin pathways. Emodin alleviated hypoxia-induced injury in H9c2 cells via up-regulation of miR-138 modulated by MLK3, as well as by activating Sirt1/AKT and Wnt/β-catenin pathways.

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BACKGROUND Persistent atrial fibrillation has been indicated to be related with microRNA-28b. However, the exact role of microRNA-28b in persistent atrial fibrillation needs to be further elucidated. Therefore, this study aimed to establish a rat model of persistent atrial fibrillation to investigate the level of microRNA-28b in atrial myocytes and to explore the molecular mechanism involved. MATERIAL AND METHODS A persistent atrial fibrillation model was established in rats by using chronic rapid atrial pacing induction. The size of the heart was measured by ultrasonic method. The expression of microRNA-28b in left atrial myocytes was quantified by RT-PCR. Cardiomyocytes were isolated and cultured to detect cell proliferation and apoptosis by MTT and flow cytometry, respectively. The specific inhibitor of ERK signaling pathway, PD98059, was used to further illustrate the role of ERK signaling pathway in the modulation of cardiomyocytes in persistent atrial fibrillation. RESULTS MicroRNA-28b was up-regulated in the experimental rat model with persistent atrial fibrillation. The proliferation of cardiomyocytes was significantly inhibited with potentiated apoptosis. Blockage of the ERK pathway suppressed the microRNA-28b expression and inhibited cell apoptosis. CONCLUSIONS microRNA-28b-induced growth inhibition and cell apoptosis of atrial myocytes was observed in the rat model with persistent atrial fibrillation, via activation of the ERK signaling pathway.

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OBJECTIVES: Epidemiological studies evaluating the association of nut consumption with coronary heart disease (CHD) risk have produced inconsistent results. The current study aimed to assess the CHD risk for the highest versus the lowest categories of nut consumption, the dose-response association of CHD for every 1 serving/week increment in nut consumption, and the heterogeneity among studies and publication bias. METHODS: Pertinent studies were identified by a search in PubMed and Web of Knowledge up to January 2014. A random-effect model was used to combine the results. The dose-response relationship was assessed by restricted cubic spline and variance-weighted least squares regression analysis. Publication bias was estimated using Egger's regression asymmetry test. RESULTS: Ten articles with 14 studies including 6302 CHD cases were included in this meta-analysis. Pooled results suggested that highest nut consumption amount versus lowest amount was associated significantly with a reduced risk of CHD [summary relative risk (RR)=0.681, 95% confidence interval (CI)=0.592-0.783, I(2)=62.7%], especially among USA (summary RR=0.671, 95% CI=0.591-0.761) and prospective studies (summary RR=0.660, 95% CI=0.581-0.748). A linear dose-response relationship was found, and the risk of CHD decreased by 10% for every 1 serving/week increase intake of nut (summary RR=0.90, 95% CI=0.87-0.94) No publication bias was found. CONCLUSION: Our analysis suggested that higher nut consumption might have a protective effect on CHD risk, especially in the USA, which needs to be confirmed.

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