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OBJECTIVE: To investigate the expression level and clinical correlation of microRNA-144/451 gene cluster (miR-144/451) in different types of anemia. METHODS: The peripheral blood of patients with aplastic anemia (AA), myelodysplastic syndrome (MDS) and diffuse large B-cell lymphoma (DLBCL) who had been diagnosed with anemia for the first time and after chemotherapy were collected. The expression levels of miR-144 and miR-451 were measured by RT-qPCR, and the correlation between the expression levels of miR-144 and miR-451 and routine laboratory indexes was analyzed by Spearman correlation analysis. RESULTS: The expression levels of miR-144 and miR-451 in the peripheral blood of AA and MDS patients were significantly lower than those in normal controls (all P < 0.01). No statistical differences were observed in the expression level of miR-144 in three subgroups of DLBCL patients (P >0.05), while the expression level of miR-451 in peripheral blood of three subgroups of DLBCL patients were significantly higher than those in normal controls (all P < 0.05). Correlation analysis showed that the expression levels of miR-144 and miR-451 in AA patients were positively correlated with red blood cell distribution width-coefficient of variation (RDW-CV) (r =0.629, 0.574). There were no significant correlations between the expression levels of miR-144 and miR-451 and laboratory parameters in MDS and DLBCL patients. CONCLUSION: Different types of anemia disorders have varying levels of miR-144 and miR-451 expression, which is anticipated to develop into a secondary diagnostic and differential diagnostic indicator for clinical anemia diseases.
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MicroARNs , Síndromes Mielodisplásicos , Humanos , MicroARNs/genética , Síndromes Mielodisplásicos/genética , Linfoma de Células B Grandes Difuso/genética , Anemia Aplásica/genética , Anemia , Familia de MultigenesRESUMEN
The nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor crucial in cellular defense against oxidative and electrophilic stresses. Recent research has highlighted the significance of NRF2 in normal erythropoiesis and anemia. NRF2 regulates genes involved in vital aspects of erythroid development, including hemoglobin catabolism, inflammation, and iron homeostasis in erythrocytes. Disrupted NRF2 activity has been implicated in various pathologies involving abnormal erythropoiesis. In this review, we summarize the progress made in understanding the mechanisms of NRF2 activation in erythropoiesis and explore the roles of NRF2 in various types of anemia. This review also discusses the potential of targeting NRF2 as a new therapeutic approach to treat anemia.
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Anemia , Eritropoyesis , Factor 2 Relacionado con NF-E2 , Humanos , Anemia/tratamiento farmacológico , Anemia/metabolismo , Regulación de la Expresión Génica , Inflamación , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
Myc is a pivotal protooncogenic transcription factor that contributes to the development of almost all Burkitt's lymphomas and about one-third of diffuse large B-cell lymphomas. How B-cells sustain their uncontrolled proliferation due to high Myc is not yet well defined. Here, we found that Myc trans-represses the expression of murine LAPTM5, a gene coding a lysosome-associated protein, by binding to two E-boxes in the LAPTM5 promoter. While the product of intact mRNA (CDS+3'UTR) of LAPTM5 failed to suppress the growth of B-lymphomas, either the protein coded by coding sequence (CDS) itself or the non-coding 3'-untranslated region (3'UTR) mRNA was able to inhibit the growth of B-lymphomas. Moreover, Myc trans-activated miR-17-3p, which promoted tumor growth. Strikingly, LAPTM5 3'UTR contains 11 miR-17-3p-binding sites through which the LAPTM5 protein synthesis was inhibited. The functional interplay between low LAPTM5 mRNA and high miR-17-3p due to high Myc in B-lymphomas leads to further dampening of tumor-suppressive LAPTM5 protein, which promotes tumor progression. Our results indicate that Myc inhibits LAPTM5 expression in B-lymphoma cells by transcriptional and post-transcriptional modifications.
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Linfoma de Burkitt , Linfoma de Células B Grandes Difuso , MicroARNs , Humanos , Animales , Ratones , Regiones no Traducidas 3'/genética , Linfoma de Burkitt/metabolismo , Factores de Transcripción/genética , Linfoma de Células B Grandes Difuso/genética , MicroARNs/genética , Proteínas de la Membrana/genéticaRESUMEN
Recent studies have demonstrated that a particular group of nucleated cells that exhibit erythroid markers (TER119 in mice and CD235a in humans) possess the ability to suppress the immune system and promote tumor growth. These cells are known as CD45+ erythroid progenitor cells (EPCs). According to our study, it appears that a subset of these CD45+ EPCs originate from B lymphocytes. Under conditions of hypoxia, mouse B lymphoma cells are capable of converting to erythroblast-like cells, which display phenotypes of CD45+TER119+ cells, including immunosuppressive effects on CD8 T cells. Furthermore, non-neoplastic B cells have similar differentiation abilities and exert the same immunosuppressive effect under anemia or tumor conditions in mice. Similar B cells exist in neonatal mice, which provides an explanation for the potential origin of immunosuppressive erythroid cells in newborns. Additionally, CD19+CD235a+ double-positive cells can be identified in the peripheral blood of patients with chronic lymphocytic leukemia. These findings indicate that some CD45+ EPCs are transdifferentiated from a selective population of CD19+ B lymphocytes in response to environmental stresses, highlighting the plasticity of B lymphocytes. We anticipate a potential therapeutic implication, in that targeting a specific set of B cells instead of erythroid cells should be expected to restore adaptive immunity and delay cancer progression.
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Anemia , Eritroblastos , Humanos , Recién Nacido , Animales , Ratones , Eritroblastos/patología , Células Precursoras Eritroides , Diferenciación Celular , Linfocitos B/patologíaRESUMEN
miR-144/451 and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulate two antioxidative systems that have been identified to maintain redox homeostasis in erythroid cells by removing excess reactive oxygen species (ROS). Whether these two genes coordinate to affect ROS scavenging and the anemic phenotype, or which gene is more important for recovery from acute anemia, has not been explored. To address these questions, we crossed miR-144/451 knockout (KO) and Nrf2 KO mice and examined the phenotype change in the animals as well as the ROS levels in erythroid cells either at baseline or under stress condition. Several discoveries were made in this study. First, Nrf2/miR-144/451 double-KO mice unexpectedly exhibit similar anemic phenotypes as miR-144/451 single-KO mice during stable erythropoiesis, although compound mutations of miR-144/451 and Nrf2 lead to higher ROS levels in erythrocytes than single gene mutations. Second, Nrf2/miR-144/451 double-mutant mice exhibit more dramatic reticulocytosis than miR-144/451 or Nrf2 single-KO mice during days 3 to 7 after inducing acute hemolytic anemia using phenylhydrazine (PHZ), indicating a synergistic effect of miR-144/451 and Nrf2 on PHZ-induced stress erythropoiesis. However, the coordination does not persist during the whole recovery stage of PHZ-induced anemia; instead, Nrf2/miR-144/451 double-KO mice follow a recovery pattern similar to miR-144/451 single-KO mice during the remaining period of erythropoiesis. Third, the complete recovery from PHZ-induced acute anemia in miR-144/451 KO mice takes longer than in Nrf2 KO mice. Our findings demonstrate that complicated crosstalk between miR-144/451 and Nrf2 does exist and the crosstalk of these two antioxidant systems is development-stage-dependent. Our findings also demonstrate that miRNA deficiency could result in a more profound defect of erythropoiesis than dysfunctional transcription factors.
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Anemia Hemolítica , MicroARNs , Factor 2 Relacionado con NF-E2 , Animales , Ratones , Anemia Hemolítica/genética , Anemia Hemolítica/inducido químicamente , Antioxidantes/farmacología , Eritrocitos , Hemólisis , Ratones Noqueados , Factor 2 Relacionado con NF-E2/genética , Especies Reactivas de Oxígeno , MicroARNs/genéticaRESUMEN
Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that, for the Transwell invasion assay experiments with the SKMES1 cell line shown in Fig. 4A on p. 1748, the 'mimic'NC' and 'inhibitorNC' data panels showed overlapping sections, such that these data may have been derived from the same original source even though they were intending to show the results of different experiments. The authors have consulted their original data, and realize that the 'inhibitorNC' data panel was inadvertently selected incorrectly for Fig. 4A. The revised version of Fig. 4, showing the correct data for the 'inhibitorNC' experiment, is shown on the next page. Note that the error made during the assembly of Fig. 4 did not significantly affect either the results or the conclusions reported in this paper, and all the authors agree to this Corrigendum. The authors are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 17421752, 2018; DOI: 10.3892/mmr.2017.8050].
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OBJECTIVE: To investigate the changes and roles of reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2) related antioxidases during erythroid development. METHODS: Flow cytometry was used to detect the sensibility of peripheral red blood cells of wild-type mice to a strong oxidant hydrogen peroxide (H2O2). Erythroid cells from different developmental stages in bone marrow (BM) were obtained using fluorescence-activated cell sorter and the ROS levels were detected by flow cytometry. RT-qPCR was used to detect the changes of expression levels of Nrf2 and related antioxidases in erythroid cells from different developmental stages in BM. The ROS levels of the peripheral blood and BM nucleated erythrocytes in Nrf2 knockout mice were further examined. The expression level of Nrf2 in erythroid precursors isolated from 14.5 d embryonic liver of wild-type mice during differentiation and culture in vitro was detected. RESULTS: In the peripheral blood of wild-type mice, the ROS level of reticulocytes and mature erythrocytes treated with H2O2 increased about 4 times and 7 times, respectively (P<0.01). In BM erythrocytes, the ROS level gradually decreased as the cells matured (r=0.85), while the expression level of Nrf2 and its related anti-oxidative genes increased (r=0.99). The ROS levels in peripheral blood erythrocytes and BM nucleated erythrocytes of Nrf2 knockout mice were significantly increased compared with wild-type mice (P<0.01). The expression of Nrf2 increased during the early erythroid development after embryonic liver cell sorting (P<0.01). CONCLUSION: The expression levels of Nrf2 and its related factors vary during erythropoiesis. Nrf2 at physiological level plays an important antioxidant role during the erythroid development.
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Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Animales , Ratones , Peróxido de Hidrógeno , Ratones Noqueados , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVE: To investigate the expression of miR-451 during erythroid differentiation and its correlation with hematological diseases. METHODS: The expression of miR-451 in erythroid differentiation of mouse hematopoietic stem cells (derived from fetal liver) was analyzed by cell culture, flow cytometry, magnetic bead sorting and qRT-PCR. The expression of miR-451 during erythroid differentiation of mouse erythroid leukemia cells (MEL) was analyzed by cell culture and qRT-PCR. The expression of miR-451 in peripheral blood of mice was detected by qRT-PCR, and the expression of miR-451 in fetal liver (14.5 days) was analyzed by microarray. The nucleated erythroid cells from bone marrow of wild type (WT) mice and ß-thalassemia (ß-thal) mice were sorted by flow cytometry, and the levels of miR-451 and erythroid genes were detected by qRT-PCR. The expression of miR-451 in peripheral blood of patients with clinical hematological diseases was detected by qRT-PCR. RESULTS: During the differentiation of mouse hematopoietic stem cells (derived from fetal liver) and MEL cells, the expression levels of miR-451 increased gradually. Compared with WT mice, the expression levels of miR-451 in peripheral blood, 14.5-day fetal liver cells and nucleated erythroid cells (sorted from bone marrow) of ß-thal mice were significantly increased(P<0.05). Many erythroid differentiation genes in nucleated erythroid cells (sorted from bone marrow) of ß-thal mice decreased. Compared with healthy controls, the expression levels of miR-451 was increased in peripheral blood of patients with ß-thalassemia and iron deficiency anemia, while the expression levels of miR-451 was decreased in patients with aplastic anemia and myelodysplastic syndrome. CONCLUSION: During erythroid differentiation, the expression levels of miR-451 increases gradually. In hematological diseases, the expression levels of miR-451 is different from that of normal controls, which is expected to become an auxiliary diagnostic index for clinical hematological diseases.
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MicroARNs , Talasemia beta , Ratones , Animales , Talasemia beta/genética , Diferenciación Celular , MicroARNs/genéticaRESUMEN
BACKGROUND: CpG island methylator phenotype (CIMP) was closely related to the degree of pathological differentiation of tumors, and it's an important determinant of glioma pathogenicity. However, the molecular and pathological features of CIMP-positive glioma have not been fully elucidated. In addition, CIMP have been reported to be a useful prognostic marker in several human cancers, yet its prognostic value in gliomas is still controversial. Therefore, we aimed to evaluate gene mutations and pathological features of CIMP-positive glioma and explore the prognostic value of CIMP in gliomas. METHODS: We comprehensively searched PubMed, Embase, and MEDLINE for studies describing gene mutations, pathological features and overall survival of gliomas stratified by CIMP status. Odds ratios (OR), hazard ratios (HR), and their 95% confidence intervals (CI) were used to estimate the correlation between CIMP and the outcome parameters. RESULTS: Twelve studies with 2386 gliomas (1051 CIMP-positive and 1335 CIMP-negative) were included. Our results showed that CIMP was more frequent in isocitrate dehydrogenase 1 (IDH1)-mutated gliomas (OR 229.07; 95% CI 138.72-378.26) and 1p19q loss of heterozygosis (LOH) gliomas (OR 5.65; 95% CI 2.66-12.01). Pathological analysis showed that CIMP was common in low-malignant oligodendroglioma (OR 5.51; 95% CI 3.95-7.70) with molecular features including IDH1 mutations and 1p19q LOH, but rare in glioblastoma (OR 0.14; 95% CI 0.10-0.19). However, CIMP showed no obvious correlation with anaplastic oligoastrocytomas (OR 1.57; 95% CI 1.24-2.00) or oligoastrocytomas (OR 0.79; 95% CI 0.35-1.76). Concerning the prognosis, we found that CIMP-positive gliomas had longer overall survival (HR 0.57; 95% CI 0.97-0.16) than CIMP-negative gliomas. CONCLUSIONS: CIMP could be used as a potential independent prognostic indicator for glioma.
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Neoplasias Encefálicas , Glioma , Oligodendroglioma , Neoplasias Encefálicas/patología , Islas de CpG , Metilación de ADN , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Fenotipo , PronósticoRESUMEN
The microRNAs miR-144/451 are highly conserved miRNA that is strongly induced during erythropoiesis. Despite the biological functions of miR-144/451 have been extensively studied in erythropoiesis and tumorigenesis, few studies have been conducted in immune responses. In this study, we showed that miR-144/451-/- DCs exhibit increased activation. Mechanistically, the miR-144 directly targets the 3`-UTR of IRF5 and represses the expression of IRF5 in DCs. Ectopic expression of miR-144/451 by lentiviruses downregulates the levels of IRF5 and suppresses DCs function. In addition, knockdown of IRF5 by shRNA significantly inhibits activities of the miR-144/451-/- DCs. Expression of miR144/451 was decreased in DCs from both patients with IBD and mice with DSS-colitis compared with controls. Human PBMC derived DCs were downregulated expression of miR144/451 after LPS stimulation. In the DSS-induced colitis mice model, we showed that ablation of the miR-144/451 gene causes severe colitis, and their DCs from both periphery and MLN expressed higher co-stimulatory molecules and pro-inflammatory cytokines than wild-type mice. In addition, DCs isolated from miR-144/451-/- mice transfusion exacerbates mice colitis. In the bone marrow transplanted chimeric mice model, we show that miR-144/451-/- bone marrow transplantation deteriorated DSS-induced colitis. At last, we treat the mice with miR-144/451 delivered by chitosan nanoparticles revealing protective effects in DSS-induced colitis mice. Thus, our results reveal a novel miR144/451-IRF5 pathway in DCs that protects experimental colitis. The manipulation of miR-144/451 expression and DCs activation in IBD patients may be a novel therapeutic approach for the treatment of inflammatory diseases.
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Colitis , Células Dendríticas , Enfermedades Inflamatorias del Intestino , Factores Reguladores del Interferón , MicroARNs , Animales , Colitis/inducido químicamente , Colitis/genética , Colitis/inmunología , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Factor V , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/inmunología , Interferones/inmunología , Leucocitos Mononucleares/inmunología , Ratones , MicroARNs/genética , MicroARNs/inmunologíaRESUMEN
Background: Sepsis is associated with a high mortality rate. A major cause of death in sepsis patients is respiratory failure, which is characterized by oxidative injury, epithelial apoptosis, and increased lung permeability. MicroRNAs (miRs) are important regulators of sepsis progression. Methods: This study aimed to explore the role of miR-144/451 in sepsis in mice. Experimental sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Results: CLP significantly induced systemic inflammation, lung permeability, and lung epithelial apoptosis with downregulated messenger RNA (mRNA) levels of antioxidant enzymes. The miR-144/451 knockout mice had a lower 48-hour survival rate, higher plasma tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) levels, and greater pulmonary permeability compared with wild-type mice after CLP. CLP also markedly increased interstitial hemorrhage, collapsed more alveolar sacs, and increased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive and Bcl-2-associated X (Bax)-positive cells in miR-144/451 knockout lung tissues, with elevated mRNA levels of Bax and reduced activities of catalase (Cat), glutathione peroxidase 1(Gpx1). MiR-451 negatively regulated 14-3-3ζ expression evidenced in miR-144/451 knockout lungs and the A549 cell line. In lipopolysaccharide (LPS)-induced A549 cells, miR-451 overexpression remarkably suppressed the production of reactive oxygen species, inhibited cell apoptosis, and enhanced levels of FoxO3 protein and related enzymes. Conclusions: Deletion of the miR-144/451 cluster aggravated sepsis-induced oxidative injury of lung epithelial cells.
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BACKGROUND: Gastric cancer (GC) has been identified as one of the most common malignancies. It was found that microRNAs can be used as potential biomarkers for GC diagnosis. The aim of this study was to estimate the diagnostic value of 4 potential microRNAs in GC. METHODS: PubMed, Embase, Cochrane Library, and Web of Science were used to search published studies. The quality of the studies was scored with the Quality Assessment of Diagnostic Accuracy Studies. The pooled sensitivity and specificity, diagnostic odds ratio (DOR) and area under the curve (AUC) were calculated. The heterogeneity was evaluated using Cochrane Q statistics and the inconsistency index. RESULTS: A total of 22 studies reporting the diagnostic value of miR-21 (nâ=â9), miR-106 (nâ=â10), miR-421 (nâ=â5) and miR-223 (nâ=â3) were included. Quality Assessment of Diagnostic Accuracy Studies scores showed the high quality of the selected 22 articles. The random effects model was adopted by evaluating the heterogeneity between articles. The DOR, AUC, and Q value of miRNA-21 were 12.37 (95% confidence interval [CI]: 5.36-28.54), 0.86 and 0.79, respectively. The DOR, AUC and Q value of miRNA-106 were 12.98 [95% CI: 7.14-23.61], 0.85 and 0.78, respectively. The DOR, AUC and Q value of miRNA-421 were 27.86 [95% CI: 6.04-128.48], 0.92 and 0.86, respectively. The DOR, AUC and Q value of miRNA-223 were 18.50 [95% CI: 7.80-43.86], 0.87 and 0.80, respectively. These results indicate that miRNA-421 has the highest diagnostic accuracy, followed by miR-223, miRNA-21, and miRNA-106 among the 4 microRNAs in GC. CONCLUSIONS: miR-21, miR-106, miR-421, and miR-223 have good diagnostic efficacy, especially miR-421, could be used as auxiliary diagnostic indicator for GC.
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MicroARNs , Neoplasias Gástricas , Área Bajo la Curva , Biomarcadores , Biomarcadores de Tumor/genética , Humanos , Sensibilidad y Especificidad , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genéticaRESUMEN
α-synuclein (α-syn) is a highly conserved and thermostable protein that is widely distributed in human brain. An intracellular aggregation of α-syn in dopaminergic neurons is the hallmark of a group of neurodegenerative diseases including Parkinson's disease. Interestingly, α-syn is also highly expressed in red blood cells and is considered as one of the most abundant proteins in red blood cells. Moreover, α-syn is thought to play a regulatory role during normal erythropoiesis. However, whether α-syn participates in the pathogenesis of erythroid diseases has not been reported. In this review, we discuss the protein structure of α-syn and the importance of α-syn in erythropoiesis.
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Eritropoyesis , alfa-Sinucleína , Encéfalo/patología , Eritropoyesis/fisiología , Humanos , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , alfa-Sinucleína/química , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND AND AIMS: Oxidative stress and abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) influence atherosclerosis formation and development. Oxidative stress significantly influences the abnormal proliferation and migration of VSMCs, and nuclear factor erythroid 2-related factor 2 (Nrf2) is a major antioxidant factor. However, the precise function of Nrf2 in the regulation of abnormal proliferation and migration of VSMCs and atherosclerosis is unclear. METHODS: We investigated the proliferation and migration of VSMCs in atherosclerosis in male Apoe-/- and Apoe-/-Nrf2-/- mice fed a high-fat diet for 12 weeks. In cultured mouse VSMCs, we studied the effect of Nrf2 on ox-LDL-stimulated proliferation and migration by using siRNA treatment to silence Nrf2. We then performed dual luciferase reporter and immunoprecipitation assays to study the interaction between Nrf2 and the promoter sequence of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). RESULTS: Our results demonstrate that Nrf2 expression levels were increased in the aorta and VSMCs of mice in the atherosclerosis model group compared with the control group. We also provide evidence that Nrf2 deficiency attenuated atherosclerotic plaque burden, diminished proliferation, and migration of VSMCs but enhanced VSMC-specific marker gene expression in vitro and in vivo. This is related to Nrf2 binding to the promoter sequence of LOX-1. Furthermore, Nrf2 downregulation contributes to restrain both transcriptional and translational activities of LOX-1. CONCLUSIONS: Together, our data indicate that Nrf2 insufficiency is linked to attenuation of atherosclerosis, and could diminish the pathological process by blunting LOX-1-mediated proliferation and migration of VSMCs.
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Aterosclerosis , Músculo Liso Vascular , Factor 2 Relacionado con NF-E2 , Receptores Depuradores de Clase E , Animales , Apolipoproteínas E/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Movimiento Celular , Proliferación Celular , Células Cultivadas , Lipoproteínas LDL/metabolismo , Masculino , Ratones , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Factor 2 Relacionado con NF-E2/deficiencia , Factor 2 Relacionado con NF-E2/metabolismo , Receptores Depuradores de Clase E/genética , Receptores Depuradores de Clase E/metabolismo , Transducción de SeñalRESUMEN
It is well known that aging induces a progressive decline in the proliferation and neural differentiation of radial glial cells (RGCs) in the hippocampal dentate gyrus (DG). The function of miR-144/451 is to activate stress-regulated molecular gene expression switches for cell proliferation and differentiation. We found that the miR-144/451 expression in the hippocampus was significantly reduced in aged mice compared to adult mice. Furthermore, the proliferation and neural differentiation of RGCs in the mouse hippocampal DG was decreased by miR-144/451 knockout (miR-144/451-/-). Antioxidant agents, superoxide dismutases (SODs) and catalase, and the expression of melatonin's receptor in the hippocampus were decreased in the miR-144/451-/- mice. In addition, the (protein kinase B) AKT/(glycogen synthase kinase 3ß) GSK3ß/(catenin beta-1) ß-catenin signaling pathway was weakly activated in the hippocampus of miR-144/451-/- mice, which was related to brain neurogenesis. Melatonin treatment improved the expression of miR-144/451 and antioxidant enzymes and activated the AKT/GSK3ß/ß-catenin pathway in the hippocampus of miR-144/451-/- mice. When the AKT pathway was inhibited by LY294002, the neurogenerative and antioxidant effects of melatonin were significantly limited in the hippocampus of miR-144/451-/- mice. In brief, our results indicated that miR-144/451 plays crucial roles in the proliferation and neural differentiation of RGCs via the regulation of the antioxidant and AKT/GSK3ß/ß-catenin pathways.
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MicroARNs , Proteínas Proto-Oncogénicas c-akt , Animales , Proliferación Celular , Giro Dentado , Células Ependimogliales , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipocampo/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , beta Catenina/metabolismoRESUMEN
The solute carrier (SLC) superfamily genes encode more than 300 members that are responsible for the transmembrane transportation of many essential endogenous and exogenous compounds ranging from nutrients to drugs. SLCs are highly expressed in metabolic organs such as the liver, regulating the homeostasis of metabolites and the disposition of drugs. In contrast to their well-studied roles in physiological and pharmacological processes, little is known about the relationship between SLCs and cancer progression. Here, we aimed to explore the potential role of SLCs in progression and prognosis of hepatocellular carcinoma (HCC), one of the most commonly diagnosed cancers and leading causes of death worldwide. By performing bioinformatics analyses of HCC dataset from The Cancer Genome Atlas database, we identified three novel signature SLCs (SLC51B, SLC22A15, and SLC2A1) that are indicative of poor prognosis. Further functional analyses suggested the potential regulation of the three prognostic SLCs on cell proliferation and metastasis. Subsequent knockdown experiments performed in HCC cell lines showed that all three prognostic SLCs positively regulated the proliferation of HCC cells, among which SLC22A15 and SLC2A1 were required for migration and invasion of the cells, demonstrating remarkable consistency with the roles identified by bioinformatics methods in HCC. Therefore, our study provides a novel prognostic biomarker for HCC and reveals the significant roles of SLCs in HCC progression, which might have been undervalued in the past.
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Movimiento Celular , Proliferación Celular , Neoplasias Hepáticas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Familia de Multigenes , Proteínas de Neoplasias/metabolismo , Carcinoma Hepatocelular , Línea Celular Tumoral , Bases de Datos de Ácidos Nucleicos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Proteínas de Transporte de Membrana/genética , Invasividad Neoplásica , Proteínas de Neoplasias/genética , PronósticoRESUMEN
Tectochrysin, a flavonoid compound, can be isolated from propolis, Alpinia oxyphylla Miq, and Lychnophora markgravii. This study evaluated the efficacy of tectochrysin in the treatment of shrimp tropomyosin (ST)-induced mouse asthma. Mice were sensitized with intraperitoneal (i.p.) injection of ST together with aluminum hydroxide as an adjuvant to establish a mouse model of asthma. Mice were i.p.-treated daily with tectochrysin. IgE levels in plasma, Th2 cytokines from both bronchoalveolar lavage (BAL) fluid and splenocytes, and CD200R on basophils in peripheral blood were measured. Histological analyses of lung tissues and accumulation of leukocytes in BAL fluid were performed. Lung eosinophil peroxidase, catalase and glutathione peroxidase activities were examined. ST was found to markedly increase eosinophilic inflammation and Th2 response in mice. Tectochrysin treatment reduced the level of IgE in plasma, the percentage of eosinophils in total white blood cells in peripheral blood, the total number of cells in BAL fluid, and eosinophil peroxidase activity in lung tissues. Tectochrysin attenuated ST-induced infiltration of eosinophils and epithelial mucus secretion in lung tissues and suppressed the overproduction of Th2 cytokines (IL-4 and IL-5) in BAL fluid. Tectochrysin also attenuated Th2 cytokine (IL-4 and IL-5) production from antigen-stimulated murine splenocytes in vitro, decreased the expression of CD200R on basophils in peripheral blood of asthmatic mice and inhibited IL-4 secretion from IgE-sensitized RBL-2H3 cells. In addition, tectochrysin enhanced catalase and glutathione peroxidase activities in lung tissues. Our findings demonstrate that TEC ameliorates allergic airway inflammation by suppressing Th2 response and oxidative stress.
Asunto(s)
Antiasmáticos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Asma/tratamiento farmacológico , Flavonoides/farmacología , Hipersensibilidad/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Células Th2/inmunología , Alérgenos/inmunología , Animales , Antiasmáticos/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Asma/inducido químicamente , Asma/inmunología , Asma/patología , Basófilos/metabolismo , Catalasa/metabolismo , Modelos Animales de Enfermedad , Eosinófilos/metabolismo , Femenino , Flavonoides/administración & dosificación , Glutatión Peroxidasa/metabolismo , Hipersensibilidad/inmunología , Inmunoglobulina E/sangre , Inyecciones Intraperitoneales , Ratones Endogámicos C57BL , Moco/efectos de los fármacos , Hipersensibilidad a los Mariscos/tratamiento farmacológico , Hipersensibilidad a los Mariscos/inmunología , Tropomiosina/inmunologíaRESUMEN
ß-thalassemia is a lethal inherited disease resulting from ß-globin gene mutations. Severe ß-thalassemia requires regular blood transfusions. Other active interventions, including iron chelating, stem cell transplantation and gene therapy, have remarkably improved the quality of life and prolonged the survival of patients with transfusion-dependent ß-thalassemia, but all with significant limitations and complications. MicroRNAs (miRNAs), encoded by a class of endogenous genes, are found to play important roles in regulating globin expression. Among the miRNAs of particular interest related to ß-thalassemia, miR-15a/16-1, miR-486-3p, miR-26b, miR-199b-5p, miR-210, miR-34a, miR-138, miR-326, let-7, and miR-17/92 cluster elevate γ-globin expression, while miR-96, miR-146a, miR-223-3p, and miR-144 inhibit γ-globin expression. A couple of miRNAs, miR-144 and miR-150, repress α-globin expression, whereas miR-451 induces α-, ß- and γ-globin expression. Single nucleotide polymorphism in miRNA genes or their targeted genes might also contribute to the abnormal expression of hemoglobin. Moreover, changes in the expression of miR-125b, miR-210, miR-451, and miR-609 reflect the severity of anemia and hemolysis in ß-thalassemia patients. These results suggest that miRNAs are potential biomarkers for the diagnosis and prognosis of ß-thalassemia, and miRNA-based therapeutic strategy might be used as a coordinated approach for effectively treating ß-thalassemia.
Asunto(s)
MicroARNs/genética , Talasemia beta/diagnóstico , Talasemia beta/genética , Animales , Humanos , MicroARNs/biosíntesis , Polimorfismo de Nucleótido Simple/genética , Globinas alfa/biosíntesis , Globinas alfa/genética , Talasemia beta/metabolismo , gamma-Globinas/biosíntesis , gamma-Globinas/genéticaRESUMEN
Allergic asthma remains an important worldwide health issue. Animal models are valuable for understanding the pathophysiological mechanisms of asthma and the development of effective therapeutics. This study aims to develop an alternative murine model induced by shrimp tropomyosin (ST) instead of ovalbumin (OVA). To investigate responses to short-term exposure to antigens, mice were sensitized with intraperitoneal injections of ST or ST plus aluminum adjuvant on days 0, 7, 14 followed by an intranasal challenge with ST for seven consecutive days. We reveal that sensitization with ST alone or ST plus aluminum induces significant levels of serum total IgE and ST-specific IgE in mice. Challenge results show that ST causes severe eosinophilic airway inflammation. Histology analysis of the lung tissues demonstrates airway inflammation and mucus hypersecretion within the bronchi in mice exposed to ST. Analysis of the cell composition in bronchoalveolar lavage fluid (BALF) shows a significant increase in eosinophil count in ST alone and ST plus aluminum groups. We also detect increased CD4+ T lymphocytes in lung tissues and production of helper T cell type 2-associated cytokines (IL-4 and IL-5) in BALF. In addition, airway hyperresponsiveness to methacholine in ST alone and ST plus aluminum groups is much higher than that in control groups. For the chronic model, mice were sensitized by ST or ST plus aluminum adjuvant for 3weeks and challenged with ST for 6weeks. We find severe structural changes in animals upon prolonged exposure to ST, including goblet cell hyperplasia, collagen deposition, and smooth muscle thickening. In conclusion, ST-induced asthma is a simple murine model for studying pathogenesis of asthma and evaluating new therapeutic drugs.