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Acidity is an important property of particulate matter (PM) in the atmosphere, but its association with PM toxicity remains unclear. Here, this study quantitively reports the effect of the acidity level on PM toxicity via pH-control experiments and cellular analysis. Oxidative stress and cytotoxicity potencies of acidified PM samples at pH of 1-2 were up to 2.8-5.2 and 2.1-13.2 times higher than those at pH of 8-11, respectively. The toxic potencies of PM samples from real-world smoke plumes at the pH of 2.3 were 9.1-18.2 times greater than those at the pH of 5.6, demonstrating a trend similar to that of acidified PM samples. Furthermore, the impact of acidity on PM toxicity was manifested by promoting metal dissolution. The dramatic increase by 2-3 orders of magnitude in water-soluble metal content dominated the variation in PM toxicity. The significant correlation between sulfate, the pH value, water-soluble Fe, IC20, and EC1.5 (p < 0.05) suggested that acidic sulfate could enhance toxic potencies by dissolving insoluble metals. The findings uncover the superficial association between sulfate and adverse health outcomes in epidemiological research and highlight the control of wet smoke plume emissions to mitigate the toxicity effects of acidity.
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Poluentes Atmosféricos , Material Particulado , Material Particulado/análise , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Metais/toxicidade , Metais/análise , Fumaça/análise , Sulfatos/análise , Água , Monitoramento AmbientalRESUMO
PURPOSE: Previous reports demonstrated a bleeding avoidance potential of angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) and ß-blocker. It remains unclear whether early guideline-directed medical therapy [GDMT, i.e., the combined use of ß-blocker, angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) and statin] confers protection against bleeding in the setting of high-intensity antithrombotic therapy. METHODS: We assessed associations between the use of early (within the first 24 h) GDMT and in-hospital major bleeds, ischemic events and mortality among ST-elevation myocardial infarction (STEMI) patients treated with percutaneous coronary intervention (PCI) in the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. RESULTS: Among 34,538 STEMI patients without contra-indications to GDMT and eligible for analysis, 35.5% received early GDMT. In a 1-to-2 propensity-score matched cohort, compared with non-early GDMT, early GDMT was associated with a 25% reduction in major bleeds [odds ratio (OR) 0.75, 95% confidence interval (CI) 0.60-0.94], with parallel reductions in ischemic events (OR 0.60, 95%CI 0.45-0.78) and in-hospital mortality (OR 0.43, 95%CI 0.31-0.61). Early GDMT-associated reduction in major bleeds was generally consistently observed across different major bleeding definitions and in sensitivity analyses. Additionally, no significant interaction was observed in subgroup analyses. CONCLUSION: In a large nationwide registry, early initiation of GDMT was associated with reduced risk for in-hospital major bleeds in STEMI patients treated with PCI. To improve the outcome of STEMI, further effort should be made to reinforce the early use of GDMT in this patient population.
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Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina , Antagonistas de Receptores de Angiotensina , Resultado do Tratamento , Antagonistas Adrenérgicos beta , Sistema de RegistrosRESUMO
Construction of a "net-zero-emission" system through CO2 hydrogenation to methanol with solar energy is an eco-friendly way to mitigate the greenhouse effect. Traditional CO2 hydrogenation demands centralized mass production for cost reduction with mass water electrolysis for hydrogen supply. To achieve continuous reaction with intermittent and fluctuating flow of H2 on a small-scale for distributed application scenarios, modulating the catalyst interface environment and chemical adsorption capacity to adapt fluctuating reaction conditions is highly desired. This paper describes a distributed clean CO2 utilization system in which the surface structure of catalysts is carefully regulated. The Ni catalyst with unsaturated electrons loaded on In2 O3 can reduce the dissociation energy of H2 to overcome the slow response of intermittent H2 supply, exhibiting a faster response (12â min) than bare oxide catalysts (42â min). Moreover, the introduction of Ni enhances the sensitivity of the catalyst to hydrogen, yielding a Ni/In2 O3 catalyst with a good performance at lower H2 concentrations with a 15â times adaptability for wider hydrogen fluctuation range than In2 O3 , greatly reducing the negative impact of unstable H2 supplies derived from renewable energies.
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PURPOSE: Thrombus aspiration in ST-elevation myocardial infarction (STEMI) with high thrombus burden did not improve clinical outcomes. The clinical efficacy of the bailout use of platelet glycoprotein IIb/IIIa inhibitors (GPIs) in this clinical scenario remains unknown. METHODS: We assessed associations between GPI use and in-hospital major bleeds, ischemic events, and mortality among STEMI patients treated with percutaneous coronary intervention (PCI) and thrombus aspiration in a nationwide acute coronary syndrome registry (the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project). RESULTS: A total of 5896 STEMI patients who received thrombus aspiration were identified, among which 56.3% received GPI therapy. In a 1-to-1 propensity-score-matched cohort, compared with STEMI patients not treated with GPI, GPI use was associated with a 69% increase in major in-hospital bleeds, with an odds ratio (OR) of 1.69, a 95% confidence interval (CI) of 1.08 to 2.65, and a nonsignificant reduction in ischemic events (OR: 0.61, 95% CI: 0.36 to 1.06), as well as a neutral effect on mortality (OR: 0.93, 95% CI: 0.55 to 1.58). However, among patients aged < 60 years, GPI use was associated with a reduction in ischemic events (OR: 0.27, 95% CI: 0.08 to 0.98), and no significant increase in major bleeds was observed. CONCLUSION: In a nationwide registry, routine use of GPI following thrombus aspiration was not associated with reduced in-hospital ischemic events and mortality but at the cost of increased major bleeding. However, for patients aged < 60 years, there may be a potential net benefit.
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BACKGROUND: Immune abnormalities and inflammatory responses play critical roles in progression of hypertension. Basic studies have confirmed that Th17 cell and related cytokines are important in promoting hypertension-mediated organ damage, but few clinical evidences have been published. Therefore, our study aimed to investigate the relationship between Th17 cell and its related cytokines and hypertension-mediated organ damage in human. METHODS: This study enrolled 179 patients with hypertension (including 92 with hypertension-mediated organ damage and 87 without hypertension-mediated organ damage) and 63 healthy participants. The proportion of Th17 cells in peripheral blood mononuclear cells was measured by flow cytometry. The concentrations of interleukin-17 and interleukin-23 were detected by enzyme-linked immunosorbent assay. Real time-polymerase chain reaction was used to detect the mRNA expression levels of interleukin-17, retinoic acid-related orphan receptor (ROR) γt and signal transducer and activator of transcription-3 (STAT-3). RESULTS: The proportion of Th17 cells, the concentration of interleukin-17 and interleukin-23 and the mRNA expression levels of interleukin-17, retinoic acid-related orphan receptor γt and signal transducer and activator of transcription-3 were significantly increased in hypertension-mediated organ damage group compared with those in non-hypertension-mediated organ damage group and control group (P < 0.005). CONCLUSION: Th17 cells and their associated cytokines may be involved in hypertension-mediated organ damage formation and may be able to serve as new biomarkers of hypertension-mediated organ damage and potential therapeutic targets.
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Hipertensão , Células Th17 , Estudos de Casos e Controles , Citocinas/metabolismo , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Hipertensão/metabolismo , Interleucina-17/genética , Interleucina-23/genética , Leucócitos Mononucleares/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Tretinoína/metabolismoRESUMO
AIMS: Emerging evidence has linked cholesterol metabolism with platelet responsiveness. We sought to examine the dose-response relationship between low-density lipoprotein cholesterol (LDL-C) and major in-hospital bleeds in acute coronary syndrome (ACS) patients. METHODS AND RESULTS: Among 42 378 ACS patients treated with percutaneous coronary intervention (PCI) enrolled in 240 hospitals in the Improving Care for Cardiovascular Disease in China-ACS project from 2014 to 2019, a total of 615 major bleeds, 218 ischaemic events, and 337 deaths were recorded. After controlling for baseline variables, a non-linear relationship was observed for major bleeds, with the higher risk at lower LDL-C levels. No dose-response relationship was identified for ischaemic events and mortality. A threshold value of LDL-C <70 mg/dL was associated with an increased risk for major bleeds (adjusted odds ratio: 1.49; 95% confidence interval: 1.21-1.84) in multivariable-adjusted logistic regression models and in propensity score-matched cohorts. The results were consistent in multiple sensitivity analyses. Among ticagrelor-treated patients, the LDL-C threshold for increased bleeding risk was observed at <88 mg/dL, whereas for clopidogrel-treated patients, the threshold was <54 mg/dL. Across a full spectrum of LDL-C levels, the treatment effect size associated with ticagrelor vs. clopidogrel on major bleeds favoured clopidogrel at lower LDL-C levels, but no difference at higher LDL-C levels. CONCLUSIONS: In a nationwide ACS registry, a non-linear association was identified between LDL-C levels and major in-hospital bleeds following PCI, with the higher risk at lower levels. As the potential for confounding may exist, further studies are warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02306616.
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Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/tratamento farmacológico , LDL-Colesterol , Fibrinolíticos/efeitos adversos , Hospitais , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Resultado do TratamentoRESUMO
The rapid bone remodeling after osteotomy has been reported for a long time. However, the underlying mechanism promoting the active bone reconstruction was still to be elucidated. Since not only the bone, blood vessels, and supportive tissues, but also the local microenvironment were destroyed, if the changes on the cell metabolism was contributed to the accelerated bone remodeling came into sight. In present study, we found that the mandibular osteotomy in rabbit activated osteoclasts, as well as the expression of hypoxia-inducible factor 1α (HIF-1α) in alveolar bone. Hypoxia or HIF-1α could enhanced osteoclastogenesis, bone absorption, and lactic acid concentration in receptor activator of nuclear factor κΒ ligand-induced RAW264.7 cells. Coincided with the upregulated HIF-1α expression, HIF-driven glycolytic enzymes, such as lactate dehydrogenase A (LDHA), glucokinase (GCK), pyruvate kinase M2 (PKM2), and phosphofructokinase1 (PFK1), were found massively increased in both hypoxic RAW264.7 cells and the alveolar HIF-1α-positive osteoclasts after mandibular osteotomy. Knockdown of HIF-1α suppressed not only the hypoxia-mediated glycolysis, but also the hypoxia-induced acid secretion and bone resorption in RAW264.7 cells. Application of inhibitor on glycolysis gave rise to the similar results as HIF-1α knockdown. Our findings suggested that hypoxia-driven glycolysis in osteoclasts was an adaptive mechanism to permit alveolar bone remodeling after mandibular osteotomy.
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Ácidos/metabolismo , Glucose/metabolismo , Glicólise , Hipóxia , Osteotomia Mandibular , Animais , Clonagem Molecular , Feminino , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Osteoclastos , Células RAW 264.7 , Coelhos , Distribuição AleatóriaRESUMO
Cobalt oxide (CoO x ) catalysts are widely applied in CO2 hydrogenation but suffer from structural evolution during the reaction. This paper describes the complicated structure-performance relationship under reaction conditions. An iterative approach was employed to simulate the reduction process with the help of neural network potential-accelerated molecular dynamics. Based on the reduced models of catalysts, a combined theoretical and experimental study has discovered that CoO(111) provides active sites to break C-O bonds for CH4 production. The analysis of the reaction mechanism indicated that the C-O bond scission of *CH2O species plays a key role in producing CH4. The nature of dissociating C-O bonds is attributed to the stabilization of *O atoms after C-O bond cleavage and the weakening of C-O bond strength by surface-transferred electrons. This work may offer a paradigm to explore the origin of performance over metal oxides in heterogeneous catalysis.
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Nanocrystalline alumina-zirconia-based eutectic ceramics fabricated with high-energy beams and composed of ultrafine, three-dimensionally entangled, single-crystal domains are a special category of eutectic oxides that exhibit exceptionally high-temperature mechanical properties, such as strength and toughness as well as creep resistance. This paper aims to provide a comprehensive review on the basic principles, advanced solidification processes, microstructure and mechanical properties of alumina-zirconia-based eutectic ceramics, with particular attention to the status of the art on a nanocrystalline scale. Some basic principles of coupled eutectic growth are first introduced based on previously reported models, followed by concise introduction of solidification techniques and the control strategy of solidification behavior from the processing variables. Then, the microstructural formation of nanoeutectic structure is elucidated with regard to different hierarchical scales, and mechanical properties such as hardness, flexural and tensile strength, fracture toughness and wear resistance are discussed in detail for a comparative study. Nanocrystalline alumina-zirconia-based eutectic ceramics with unique microstructural and compositional characteristics have been produced with high-energy beam-based processes, and in many cases, promising improvements in mechanical performance have been reported as contrasting with conventional eutectic ceramics.
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Y2O3 doped ZrO2 (YSZ) ceramic material is used to protect alloy components worked in high-temperature. But its phase transformation between tetragonal phase and monoclinic phase occurred at 1150 °C leads to YSZ invalid. Therefore, enhancing the phase stability of YSZ is necessary for meeting the demands of the development of thermal barrier coatings (TBC). In this study, X-ray diffraction and Raman spectra were used to explore the phase stability and phase transformation of Yb2O3 and Y2O3 co-doped ZrO2 (YbYSZ) ceramics after heat treatment at 1300 °C with different times. The stability of tetragonal phase is improved by tetragonality decreasing with Yb3+ doped. Simultaneously, the incorporation of Yb3+ leads to O-O coupling, which is beneficial for increasing the concentration of oxygen vacancies near the substituted ions, thereby improving the stability of the crystal. The 6.5YbYSZ ceramic has the best stability after heat treatment at 1300 °C for different times.
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AIMS: Information regarding ß-blocker use and bleeding risk in patients on antithrombotic therapy in contemporary practice is limited. We examined the association between early (within the first 24 hours) oral ß-blocker therapy and major in-hospital bleeds among acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). METHODS AND RESULTS: In the Improving Care for Cardiovascular Disease in China-ACS project, among patients without contraindications to ß-blocker, we examined the association between early oral ß-blocker exposure [users/non-users, dosing, and type (metoprolol vs. bisoprolol)] and major in-hospital bleeds. Of the 43,640 eligible patients, 36.0% patients received early oral ß-blocker and 637 major bleeds were recorded. Compared with non-users, early oral ß-blocker was associated reduced risks for major bleeds [odds ratio (OR): 0.48; 95% confidence interval (CI): 0.38-0.61] and in-hospital mortality (OR: 0.47; 95%CI: 0.34-0.64) in multivariable-adjusted logistic regression models. Early oral ß-blocker use associated reduction in major bleeding was evident both in high-dose (defined by metoprolol-equivalent dose ≥50 mg/day) users (OR: 0.47; 95%CI: 0.33-0.68) and in low-dose users (metoprolol-equivalent dose <50 mg/day; OR: 0.61; 95%CI: 0.47-0.79). No significant difference was observed between metoprolol and bisoprolol in terms of reductions in major bleeding and mortality. Analyses based on inverse-probability-of-treatment-weighted regression adjustment and propensity-score matching yielded consistent findings. CONCLUSION: In this retrospective study based on the nationwide ACS registry, among patients treated by PCI, in addition to a reduction in in-hospital mortality, oral ß-blocker therapy initiated within the first 24 hours was associated with a reduced risk for major in-hospital bleeds. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02306616.
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PURPOSE: It is unknown if acute coronary syndrome (ACS) patients presenting with advanced Killip class (III/IV) would benefit from early statin therapy. Therefore, we aimed to explore the relationship between statin therapy within the first 24 h of medical contact and in-hospital outcomes in this patient population in a nationwide registry. METHOD: In the Improving Care for Cardiovascular Disease in China-ACS project, among ACS patients presenting with Killip class III/IV, we performed the following three analyses: (i) the associations between early statin therapy and risks for in-hospital mortality and ischaemic events; (ii) the dose effect of statins on mortality and (iii) the interaction between low-density lipoprotein cholesterol (LDL-C) levels and statins on mortality. RESULT: Among 104,516 ACS patients, 12,149 presented with advanced Killip class and 89.3% received early statins. Multivariable-adjusted logistic regression models revealed a 69% reduction in mortality in the statin group (adjusted odds ratio [OR] 0.31; 95% confidence interval [CI] 0.25-0.39), parallel with a reduction in ischaemic events (adjusted OR 0.50, 95% CI 0.33-0.74), compared with those not receiving early statins, which was consistent in multiple sensitivity analyses. Additionally, the protective association of early statins on in-hospital mortality was observed even among patients that received a low-to-moderate dose. Finally, the short-term survival benefit of early statins was independent of LDL-C. CONCLUSION: In a nationwide ACS registry, statin therapy initiated within the first 24 h of medical contact was associated with a reduced risk of in-hospital mortality in ACS patients presenting with advanced Killip class.
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Síndrome Coronariana Aguda , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , LDL-Colesterol , Prevenção Secundária , HospitaisRESUMO
OBJECTIVES: This study aimed to explore the expression of hypoxia-inducible factor 1α (HIF-1α) in chondrocytes with the healing process after unilateral mandibular condylar neck osteotomy and to verify its effect on bone repair. METHODS: Models of mandibular condylar neck osteotomy were established in mice. Transgenic mice with heterozygous deficiency in HIF-1α gene in chondrocytes were used. Radiographic evaluation, quantitative reverse transcription polymerase chain reaction and histomorphometric analyses were used to compare the difference in capacities of chondrogenesis, vasifaction, osteogenesis, and bone resorption. RESULTS: HIF-1α was expressed in the chondrocytes of calluses. Decreased expression of HIF-1α in chondrocytes promoted the proliferation of chondrocytes and upregulated the expression of apoptosis markers. However, the density and thickness of newly formed trabecula in transgenic mice were reduced on post-osteotomy day 28, and some expression of angiogenic, osteogenic, and osteoclastogenic markers was impaired. CONCLUSIONS: These results demonstrated the importance of HIF-1α to chondrocytes and bone repair during the healing process after osteotomy of the mandibular condylar neck. Decreased HIF-1α promoted the chondrocyte proliferation, and effected endochondral ossification.
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Condrócitos/citologia , Condrogênese , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Côndilo Mandibular/metabolismo , Osteogênese , Animais , Proliferação de Células , Camundongos , Camundongos TransgênicosRESUMO
The development of cathode materials with high catalytic activity and low cost is a challenge for CO2 electrolysis based on solid oxide electrolysis cells. Herein, we report a low-cost and highly active metallic Fe nanoparticle-decorated Ruddlesden-Popper (La, Sr)FeO4+δ cathode catalyst (Fe-RPLSF), which shows a high oxygen vacancy concentration and robust CO2 reduction rate. At 850 °C, the current density of the electrolysis cell with the Fe-RPLSF cathode reaches -1920 mA cm-2 at a voltage of 1.5 V, and the Faraday efficiency is as high as 100%. The polarization resistance at low frequency (0.1-10 Hz), which is the rate-limit step for CO2 electrolysis, significantly decreases with the exsolved Fe nanoparticles because of improved CO2 dissociative adsorption. Moreover, our electrolysis cell demonstrates acceptable short-term stability for direct CO2 electrolysis.
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AIMS: Previous observations revealed a negative association between low-density lipoprotein cholesterol (LDL-C) and clinical outcomes following myocardial infarction, i.e., the lower level the higher mortality, which was referred to as lipid paradox. We sought to re-evaluate this association in ST-elevation myocardial infarction (STEMI) in contemporary practice. METHODS AND RESULTS: We examined the association between admission LDL-C and in-hospital mortality among 44 563 STEMI patients enrolled from 2014 to 2019 in a nationwide registry in China. A total of 43 covariates, which were temporally classified into the following three domains were used for adjustment: (i) pre-admission characteristics; (ii) percutaneous coronary intervention (PCI)-related variables; and (iii) other in-hospital medications. In-hospital mortality was 2.01% (897/44 563). When no covariate adjustment was performed, an inversely 'J-shaped' curve was observed between admission LDL-C levels and in-hospital mortality by restricted cubic spline in logistic regression, with a threshold value of <75 mg/dL that associated with increased risk for in-hospital mortality. However, a gradual attenuation for this association was noted when step-wise adjustments were performed, with the threshold values for LDL-C decreasing from 75 mg/dL to 70 mg/dL after accounting for pre-admission characteristics, further to 65 mg/dL after accounting for PCI-related variables, and finally to no statistical association after further adjustment for other in-hospital medications. CONCLUSIONS: In a nationwide registry in China, our findings do not support the lipid paradox in terms of in-hospital mortality in STEMI patients in contemporary practice. Previous findings in this scenario are possibly due to inadequate control for confounders.
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Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Lipídeos , Sistema de Registros , Fatores de Risco , Resultado do TratamentoRESUMO
Apoptotic osteocytes were found in the hypoxic bone microenvironment in osteoporosis, osteotomy, orthodontic tooth movement and periodontitis, and played a key role in bone remolding and the differentiation of osteoclasts. Hypoxia inducible factor-1α(HIF-1α), as a transcription factor under hypoxic conditions, has been confirmed to participate in cell apoptosis. However, the effect of HIF-1α on osteocytes apoptosis and the osteocyte-mediated osteoclast formation remains elusive. Here, we hypothesized that HIF-1α was involved in osteocytes apoptosis. Our results showed that CoCl2 increased the MLO-Y4 cells apoptosis by upregulating the proapoptotic gene expression of caspase-3. Moreover, siRNA-mediated knockdown of HIF-1α decreased the phosphorylation by JNK and the activation of caspase-3 to inhibit the cell apoptosis in MLO-Y4. Furthermore, SP600125, an inhibitor of JNK, reversed CoCl2-induced the increased apoptosis of MLO-Y4 cells in term of reducing the expression of caspase-3. These findings revealed that HIF-1α served as a pro-apoptotic factor in the apoptosis of MLO-Y4 cells cultured with CoCl2, by activating the JNK/caspase-3 signaling pathway. Besides, the osteocyte-mediated osteoclastogenesis was reduced with the decline of the expression of HIF-1α and caspase-3 in MLO-Y4 cells. Our study provided an idea for a more comprehensive understanding of HIF-1α and the process of bone remodeling.
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Apoptose , Caspase 3/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Sistema de Sinalização das MAP Quinases , Osteócitos/metabolismo , Osteogênese , Animais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Linhagem Celular , Cobalto/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Osteócitos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Pseudogenes, which are long noncoding RNAs that originate from protein-coding genes, have been suggested to play important roles in disease. Although studies have revealed high expression of legumain (LGMN) in many types of tumors, the regulation of LGMN remains largely unknown. Here, we found that a novel LGMN pseudogene (LGMNP1) was upregulated in glioblastoma (GBM) tissues and high LGMNP1 expression in GBM cells enhanced proliferation and invasion. Biochemical analysis showed that cytoplasmic LGMNP1 functionally targeted miR-495-3p in a manner involving an RNA-induced silencing complex. Dual-luciferase reporter assays demonstrated that LGMN was a target of miR-495-3p, and LGMN was upregulated and positively correlated with LGMNP1 in GBM. Moreover, miR-495-3p was downregulated and negatively correlated with LGMNP1 in GBM tissues. Notably, the tumor-promoting effects of LGMNP1 upregulation could be alleviated by miR-495-3p mimics. Furthermore, GBM cells overexpressing LGMNP1 exhibited more aggressive tumor progression and elevated LGMN expression in vivo. Thus, our data illustrate that LGMNP1 exerts its oncogenic activity, at least in part, as a competitive endogenous RNA (ceRNA) that elevates LGMN expression by sponging miR-495-3p. CeRNA-mediated miRNA sequestration might be a novel therapeutic strategy in GBM.
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Neoplasias Encefálicas/patologia , Cisteína Endopeptidases/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/patologia , MicroRNAs/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Cisteína Endopeptidases/metabolismo , Progressão da Doença , Glioblastoma/genética , Glioblastoma/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Pseudogenes/genética , RNA Longo não Codificante/genéticaRESUMO
The Ser/Thr protein kinase, RSK, is associated with oncogenesis, and therefore, there are ongoing efforts to develop RSK inhibitors that are suitable for use in vivo. SL0101 is a natural product that demonstrates selectivity for RSK inhibition. However, SL0101 has a short biological half-life in vivo. To address this issue we designed a set of eight cyclitol analogues, which should be resistant to acid catalyzed anomeric bond hydrolysis. The analogues were synthesized and evaluated for their ability to selectively inhibit RSK in vitro and in cell-based assays. All the analogues were prepared using a stereodivergent palladium-catalyzed glycosylation/cyclitolization for installing the aglycon. The l-cyclitol analogues were found to inhibit RSK2 in in vitro kinase activity with a similar efficacy to that of SL0101, however, the analogues were not specific for RSK in cell-based assays. In contrast, the d-isomers showed no RSK inhibitory activity in in vitro kinase assay.