MicroRNA-29b inhibits human vascular smooth muscle cell proliferation via targeting the TGF-ß/Smad3 signaling pathway.

Intracranial aneurysms (IAs) are bulges of blood vessels in the cerebral area. The development and progression of IAs are associated with the proliferation of vascular smooth muscle cells (VSMCs) during phenotypic modulation under environmental cues. MicroRNA-29b (miR-29b) has been studied extensively and demonstrated to reduce cell proliferation in various diseases by binding to the 3'-untranslated region (3'-UTR) of a variety of target messenger RNAs (mRNAs), thereby inhibiting their translation. The present study aimed to investigate the role of miR-29b on the proliferation of VSMCs and human umbilical artery smooth muscle cells. The results indicated that the overexpression of miR-29b reduced cell migration and proliferation. Western blotting results indicated that this effect may be attributed to the attenuation of a signaling pathway involving transforming growth factor ß (TGF-ß) and Smad3 proteins. Luciferase assay confirmed the binding of miR-29b to TGF-ß1 and the knockdown of TGF-ß1 reduced miR-29b inhibitor-induced cell migration. The present study indicates that miR-29b downregulates the expression of TGF-ß1 by targeting the 3'-UTR of its mRNA and modulates cell migration and proliferation via the TGF-ß1/Smad3 signaling pathway.

Nimodipine Improves Cognitive Impairment After Subarachnoid Hemorrhage in Rats Through IncRNA NEAT1/miR-27a/MAPT Axis.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a cerebral hemorrhage disease that severely damages the brain and causes cognitive impairment (CI). Therefore, accurate and appropriate treatment strategies are urgently needed. The application of nimodipine can not only improve blood circulation in patients with SAH but also repair ischemic neuron injury. PURPOSE: To investigate the effects of nimodipine and lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1)/miR-27a/microtubule-associated protein tau (MAPT) axis on CI after SAH. METHODS: One hundred and twenty healthy male rats were selected and equally divided into control group, sham operation group, model group, PBS group, nimodipine group (drug group), NC siRNA group, NC mimics group, NEAT1 siRNA, miR-27a mimics, MAPT siRNA, drug + NEAT1-ad, and drug + NC-ad groups by random number table. Rats in the model group were constructed by double-hemorrhage model, and expression vectors were injected into the tail to regulate the expression of lncRNA NEAT1, miR-27a and MAPT. In addition, Western blot was employed to detect brain tissue protein, flow cytometry was applied to measure brain tissue apoptosis, and MTT was utilized to determine cell activity, so as to evaluate brain damage and cognitive function in each group. RESULTS: Nimodipine, down-regulated lncRNA NEAT1, up-regulated miR-27a and down-regulated MAPT all improved brain damage and CI, inhibited brain tissue cell apoptosis, and enhanced brain cell activity. The common binding sites of lncRNA NEAT1 and MAPT were found on the miR-27a sequence fragment, and miR-27a could be paired with the former two. Nimodipine was found to cause the down-regulation of lncRNA NEAT1 and MAPT, as well as the up-regulation of miR-27a. CONCLUSION: Nimodipine can improve CI after SAH in rats through the lncRNA NEAT1/miR-27a/MAPT axis.

Tumor-associated macrophage interleukin-ß promotes glycerol-3-phosphate dehydrogenase activation, glycolysis and tumorigenesis in glioma cells.

Tumor-immune crosstalk within the tumor microenvironment (TME) occurs at all stages of tumorigenesis. Tumor-associated M2 macrophages play a central role in tumor development, but the molecular underpinnings have not been fully elucidated. We demonstrated that M2 macrophages produce interleukin 1ß (IL-1ß), which activates phosphorylation of the glycolytic enzyme glycerol-3-phosphate dehydrogenase (GPD2) at threonine 10 (GPD2 pT10) through phosphatidylinositol-3-kinase-mediated activation of protein kinase-delta (PKCδ) in glioma cells. GPD2 pT10 enhanced its substrate affinity and increased the catalytic rate of glycolysis in glioma cells. Inhibiting PKCδ or GPD2 pT10 in glioma cells or blocking IL-1ß generated by macrophages attenuated the glycolytic rate and proliferation of glioma cells. Furthermore, human glioblastoma tumor GPD2 pT10 levels were positively correlated with tumor p-PKCδ and IL-1ß levels as well as intratumoral macrophage recruitment, tumor grade and human glioblastoma patient survival. These results reveal a novel tumorigenic role for M2 macrophages in the TME. In addition, these findings suggest possible treatment strategies for glioma patients through blockade of cytokine crosstalk between M2 macrophages and glioma cells.

The lncRNA DAPK-IT1 regulates cholesterol metabolism and inflammatory response in macrophages and promotes atherogenesis.

Atherosclerosis is the leading cause of cardiovascular disease (CVD) and the leading reason behind mortality and morbidity in Western countries. The role of long noncoding RNAs (lncRNAs) in CVD is still unexplored with inadequate research on the involvement of lncRNAs in atherogenesis. We found the lncRNA DAPK1-IT1 and lipoprotein lipase (LPL) to be up-regulated in THP-1 macrophage-derived foam cells. We demonstrated that DAPK1-IT1 mediated its promoting effect on LPL expression via regulating an intermediary miRNA hsa-miR-590-3p. This DAPK1-IT1/hsa-miR-590-3p/LPL axis regulates cholesterol metabolism and the inflammatory response in macrophages in vitro. Overexpressing LPL using lentiviral vectors led to decreased circulation of high-density lipoprotein cholesterol (HDL-C), increased circulation of low-density lipoprotein cholesterol (LDL-C) and very-LDL-C (VLDL-C), increased circulating pro-inflammatory cytokine levels (IL-1ß, IL-6, TNF-α), and enhanced atherogenesis in apolipoprotein E-deficient (apoE-/-) mice. In sum, the DAPK1-IT1/hsa-miR-590-3p/LPL axis regulates cholesterol metabolism and the inflammatory response in macrophages and may contribute to atherogenesis in vivo. These findings suggest this axis may be a promising therapeutic target in ameliorating CVD.

Protective effect of isoliquiritigenin against cerebral injury in septic mice via attenuation of NF-κB.

BACKGROUND: The study was conducted to scrutinize the outcome of isoliquiritigenin (ISL) against cerebral injury in septic mice. METHODS: The sepsis was introduced using cecal ligation and puncture (CLP) method in experimental mice. The effect of ISL was quantified using the content of brain water and blood brain barrier (BBB) permeability. The effect on the levels of myeloperoxidase (MPO), superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) in brain homogenates was also determined. The effect of ISL on the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in serum was also estimated. The levels of various inflammatory biomarkers (COX-2 and PGE2) were also studied. The expression of NF-κB signalling cascade and inducible nitric oxide synthase (iNOS) was estimated by Western blot. RESULTS: Compared with CLP group, the brain water content was found to be reduced significantly together with the enhanced BBB integrity in ISL treated group. The level of MDA was reduced together with enhanced level of SOD and GSH in the ISL treated group. The levels of TNF-α, IL-1ß, and IL-6 were also found to be modulated in ISL group. The level of COX-2 and PGE2 was reduced to near normal after ISL administration together with increase in the IκBα expression and reduction of p65 and p-p65 expression in a concentration-dependent manner. The expression of iNOS was also found to be reduced in ISL group. CONCLUSION: These results demonstrate that ISL causes protection of CLP-induced sepsis in experimental mice via multiple pathways.

Efficacy of Minimally Invasive Intervention in Patients With Acute Cerebral Infarction.

Our aim was to explore the efficacy of minimally invasive intervention in patients with acute cerebral infarction (ACI). Seventy patients with ACI were randomized into either an experimental group or a control group. In addition to the regular treatment, patients in the control group also received intravenous thrombolysis with urokinase, while patients in the other group underwent percutaneous transluminal cerebral angioplasty and stenting. Metrics included recanalization rate, serum cytokines, fibrinolytic markers, and 36-Item Short Form Health Survey score and were compared between the 2 groups. After treatment, patients in the experimental group had better recanalization rate, higher SF-36 score and greater levels of vascular endothelial growth factors, neurotrophic factors, and nerve growth factors than those in the control group. Moreover, the values of fibrinolytic markers changed significantly in both groups after treatment. Compared with the control group, the experimental group had lower levels of tissue polypeptide antigen and plasminogen activator inhibitor-1 and a higher level of von Willebrand factor after treatment. In sum, the application of minimally invasive intervention can increase both the recanalization rate and concentrations of serum cytokines, can improve the quality of life in patients with ACI, and has small impacts on the fibrinolytic system in patients.

Linarin suppresses glioma through inhibition of NF-κB/p65 and up-regulating p53 expression in vitro and in vivo.

Glioma is the most common form of malignant brain cancer with high mortality rate in human. Therefore, finding effective therapeutic strategy and revealing the underlying molecular mechanism is necessary. Plant-extracted flavonoid glycosides have been suggested to be bioactive compounds with pleiotropic functions, such as anti-cancer, anti-inflammatory, antioxidant and effects. Our study was attempted to explore the anti-cancer role of linarin (acacetin-7-O-ß-d-rutinoside) in glioma in vitro and in vivo. Nuclear factor kappa-B (NF-κB) activity is a common phenomenon in various cancers, resulting in abnormal cell proliferation, malignant transformation, or resistance to cell death. P53, an essential tumor suppressor, plays an important role in preventing tumor progression. Our data indicated that linarin suppressed glioma cell proliferation and migration by inducing apoptosis, which was through reducing cell cycle-related signals, including Survivin, p-Rb, and Cyclin D1, while promoting p21, Bax, Caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Also, we found that linarin-reduced cellular proliferation of glioma was dependent on p53 up-regulation and Nuclear factor kappa-B (NF-κB)/p65-down-regulation, thereby inhibiting glioma cell growth. We further conformed the inhibitory effect of linarin in vivo using xenograft tumor model. Linarin significantly triggered apoptosis as well as the tumor growth in animals, accompanied with p53 increase and p65 decrease. Our data illustrated that linarin could be used as a promising candidate against glioma progression.

Hyperhomocysteinemia as a Risk Factor for Saccular Intracranial Aneurysm: A Cohort Study in a Chinese Han Population.

BACKGROUND: We evaluated the possible relationships between serum total homocysteine and folate and Vitamin B12 in patients with intracranial aneurysm. METHODS: We enrolled consecutive patients with intracranial aneurysm from the Han population who were admitted to the hospital, as well as control subjects who received medical examination on an outpatient basis. The serum total homocysteine, folate, and Vitamin B12 levels were measured in patients with intracranial aneurysm and the control group, and the associations between those factors were analyzed using multivariate logistic analysis. RESULTS: A total of 140 patients with intracranial aneurysm and 140 control subjects were enrolled from July 2014 to December 2015. The mean serum total homocysteine level in the patient group (19.98 ± 10.84 µmol/L) was significantly higher than that in the control group (15.13 ± 5.55 µmol/L, P < .001). The serum total homocysteine level was negatively correlated with folate and Vitamin B12 levels (r = -.349, P < .001; r = -.531, P < .001, respectively) in the patient group. Homocysteine had an adjusted odds ratio of 2.196 (95% confidence interval: 1.188-4.057, P = .012) for the development of intracranial aneurysm. CONCLUSIONS: The present study provides evidence regarding the association between serum total homocysteine and folate and Vitamin B12 in patients with intracranial aneurysm. Hyperhomocysteinemia is an independent risk factor for intracranial aneurysm, and folate and Vitamin B12 are protective against intracranial aneurysm due to their roles in regulating the metabolism of homocysteine.