RESUMEN
Sorafenib is currently the first-line treatment for patients with advanced liver cancer, but its therapeutic efficacy declines significantly after a few months of treatment. Therefore, it is of great importance to investigate the regulatory mechanisms of sorafenib sensitivity in liver cancer cells. In this study, we provided initial evidence demonstrating that circPHKB, a novel circRNA markedly overexpressed in sorafenib-treated liver cancer cells, attenuated the sensitivity of liver cancer cells to sorafenib. Mechanically, circPHKB sequestered miR-1234-3p, resulting in the up-regulation of cytochrome P450 family 2 subfamily W member 1 (CYP2W1), thereby reducing the killing effect of sorafenib on liver cancer cells. Moreover, knockdown of circPHKB sensitized liver cancer cells to sorafenib in vivo. The findings reveal a novel circPHKB/miR-1234-3p/CYP2W1 pathway that decreases the sensitivity of liver cancer cells to sorafenib, suggesting that circPHKB and the axis may serve as promising targets to improve the therapeutic efficacy of sorafenib against liver cancer.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Humanos , Sorafenib/farmacología , Sorafenib/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , MicroARNs/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Regulación hacia Arriba , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proliferación Celular , Resistencia a Antineoplásicos , Familia 2 del Citocromo P450/genéticaRESUMEN
Adaptation to reduced energy production during aging is a fundamental issue for maintaining healthspan or prolonging life span. Currently, however, the underlying mechanism in long-lived people remains poorly understood. Here, we analyzed transcriptomes of 185 long-lived individuals (LLIs) and 86 spouses of their children from two independent Chinese longevity cohorts and found that the ribosome pathway was significantly down-regulated in LLIs. We found that the down-regulation is likely controlled by ETS1 (ETS proto-oncogene 1), a transcription factor down-regulated in LLIs and positively coexpressed with most ribosomal protein genes (RPGs). Functional assays showed that ETS1 can bind to RPG promoters, while ETS1 knockdown reduces RPG expression and alleviates cellular senescence in human dermal fibroblast (HDF) and embryonic lung fibroblast (IMR-90) cells. As protein synthesis/turnover in ribosomes is an energy-intensive cellular process, the decline in ribosomal biogenesis governed by ETS1 in certain female LLIs may serve as an alternative mechanism to achieve energy-saving and healthy aging.
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Envejecimiento Saludable , Niño , Femenino , Humanos , Regiones Promotoras Genéticas , Proteína Proto-Oncogénica c-ets-1/genética , Proteína Proto-Oncogénica c-ets-1/metabolismo , Ribosomas/genética , Ribosomas/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Sorafenib is the firstline drug used in the treatment of liver cancer; however, drug resistance seriously limits the clinical response to sorafenib. The present study investigated the molecular mechanisms of sorafenib resistance in liver cancer cells. The data indicated that forkhead box M1 (FoxM1) was significantly overexpressed in sorafenibresistant cells, at the mRNA and protein levels. Knockdown of FoxM1 rendered drugtolerant cells sensitive to sorafenib. Furthermore, FoxM1 was upregulated at the transcriptional level. Overexpression of cjun was associated with the upregulation of FoxM1. The results of a reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that there is an activator protein1 (AP1) binding site in the promoter of FoxM1, located at 608 to 618. Knockdown of cjun significantly decreased the levels of FoxM1, accompanied by enhanced cell sensitivity to sorafenib. Furthermore, the activation of AKT contributed to the upregulation of cjun and FoxM1. Inhibition of AKT using BEZ235 markedly suppressed the upregulation of cjun and FoxM1, and increased the sensitivity of drugresistant cells to sorafenib in vitro and in vivo. The data indicated that the activation of the AKT/AP1/FoxM1 signaling axis is an important determinant of sorafenib tolerance.
Asunto(s)
Carcinoma Hepatocelular/patología , Resistencia a Antineoplásicos , Proteína Forkhead Box M1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sorafenib/farmacología , Factor de Transcripción AP-1/metabolismo , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferación Celular , Proteína Forkhead Box M1/genética , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-akt/genética , Factor de Transcripción AP-1/genética , Activación Transcripcional , Células Tumorales CultivadasRESUMEN
BACKGROUND: There has been recent recognition that the GSTM1 gene is associated with successful aging and longevity. It has been hypothesized that individuals with a GSTM1 deletion are at a greater risk for developing a plethora of diseases. This study was carried out to investigate the association between the rs574344 single nucleotide polymorphism, an expression quantitative trait locus of GSTM1, and longevity in the Han Chinese population. MATERIALS AND METHODS: We performed a case-control study that comprised 526 long-lived subjects (>97 years of age) and 783 younger subjects (aged 19-80 years) from the general population who served as controls. Identification of the genotypes of rs574344 was accomplished by combining polymerase chain reaction with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: The long-lived study population, when compared with the controls, showed a significantly higher frequency of the T/T genotype and the T allele of rs574344. We determined that the T/T genotype is associated with a longer lifespan (OR = 5.972, 95% CI 1.798-19.833, p = 0.001, for all genders; p = 0.006 adjusted by gender). We also observed a significant difference (p < 0.05) in the distribution of alleles and genotypes in both the male group (TT vs. TA, OR = 1.043, 95% CI 1.022-1.067, p = 0.043) and the female group (TT vs. TA, OR = 3.592, 95% CI 0.982-13.147, p = 0.039) Conclusion: We found significant associations between both the T allele and the T/T genotype of rs574344 with longevity in the Han Chinese population.
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Glutatión Transferasa/genética , Longevidad/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Etnicidad/genética , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética/métodos , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Centenarians (CENs) are excellent subjects to study the mechanisms of human longevity and healthy aging. Here, we analyzed the transcriptomes of 76 centenarians, 54 centenarian-children, and 41 spouses of centenarian-children by RNA sequencing and found that, among the significantly differentially expressed genes (SDEGs) exhibited by CENs, the autophagy-lysosomal pathway is significantly up-regulated. Overexpression of several genes from this pathway, CTSB, ATP6V0C, ATG4D, and WIPI1, could promote autophagy and delay senescence in cultured IMR-90 cells, while overexpression of the Drosophila homolog of WIPI1, Atg18a, extended the life span in transgenic flies. Interestingly, the enhanced autophagy-lysosomal activity could be partially passed on to their offspring, as manifested by their higher levels of both autophagy-encoding genes and serum beclin 1 (BECN1). In light of the normal age-related decline of autophagy-lysosomal functions, these findings provide a compelling explanation for achieving longevity in, at least, female CENs, given the gender bias in our collected samples, and suggest that the enhanced waste-cleaning activity via autophagy may serve as a conserved mechanism to prolong the life span from Drosophila to humans.
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Autofagia/genética , Longevidad/genética , Transcriptoma , Anciano , Anciano de 80 o más Años , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Beclina-1/genética , Beclina-1/metabolismo , Catepsina B/genética , Catepsina B/metabolismo , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Femenino , Humanos , Lisosomas/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , ATPasas de Translocación de Protón Vacuolares/genética , ATPasas de Translocación de Protón Vacuolares/metabolismoRESUMEN
Recent studies suggested that forkhead box class O3 (FOXO3) functions as a key regulator for the insulin/insulin-like growth factor-1signaling pathway that influence aging and longevity. This study aimed to comprehensively elucidate the association of common genetic variants in FOXO3 with human longevity in a Chinese population. Eighteen single-nucleotide polymorphisms (SNPs) in FOXO3 were successfully genotyped in 616 unrelated long-lived individuals and 846 younger controls. No nominally significant effects were found. However, when stratifying by gender, four SNPs (rs10499051, rs7762395, rs4946933 and rs3800230) previously reported to be associated with longevity and one novel SNP (rs4945815) showed significant association with male longevity (P-values: 0.007-0.032), but all SNPs were not associated with female longevity. Correspondingly, males carrying the G-G-T-G haplotype of rs10499051, rs7762395, rs4945815 and rs3800230 tended to have longer lifespan than those carrying the most common haplotype A-G-C-T (odds ratio = 2.36, 95% confidence interval = 1.20-4.63, P = 0.013). However, none of the associated SNPs and haplotype remained significant after Bonferroni correction. In conclusion, our findings revealed that the FOXO3 variants we tested in our population of Chinese men and women were associated with longevity in men only. None of these associations passed Bonferroni correction. Bonferroni correction is very stringent for association studies. We therefore believe the effects of these nominally significant variants on human longevity will be confirmed by future studies.
Asunto(s)
Proteína Forkhead Box O3/genética , Longevidad/genética , Estudios de Casos y Controles , China , Femenino , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido SimpleAsunto(s)
Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/genética , Longevidad/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Alelos , Pueblo Asiatico , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Modelos GenéticosRESUMEN
Reduced mitochondrial function is an important cause of aging and age-related diseases. We previously revealed a relatively higher level of mitochondrial DNA (mtDNA) content in centenarians. However, it is still unknown whether such an mtDNA content pattern of centenarians could be passed on to their offspring and how it was regulated. To address these issues, we recruited 60 longevity families consisting of 206 family members (cohort 1) and explored their mtDNA copy number. The results showed that the first generation of the offspring (F1 offspring) had a higher level of mtDNA copy number than their spouses (p < 0.05) independent of a gender effect. In addition, we found a positive association of mtDNA copy number in centenarians with that in F1 offspring (r = 0.54, p = 0.0008) but not with that in F1 spouses. These results were replicated in another independent cohort consisting of 153 subjects (cohort 2). RNA sequencing analysis suggests that the single-stranded DNA-binding protein 4 was significantly associated with mtDNA copy number and was highly expressed in centenarians as well as F1 offspring versus the F1 spouses, thus likely regulates the mtDNA copy number in the long-lived family members. In conclusion, our results suggest that the pattern of high mtDNA copy number is likely inheritable, which may act as a favorable factor to familial longevity through assuring adequate energy supply.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , ADN Mitocondrial/genética , Estudios de Asociación Genética , Longevidad/genética , Anciano de 80 o más Años , Proteínas de Unión al ADN/genética , Metabolismo Energético/genética , Femenino , Humanos , MasculinoRESUMEN
The mitochondrion is a double membrane-bound organelle which plays important functional roles in aging and many other complex phenotypes. Transmission of the mitochondrial genome in the matrilineal line causes the evolutionary selection sieve only in females. Theoretically, beneficial or neutral variations are more likely to accumulate and be retained in the female mitochondrial genome during evolution, which may be an initial trigger of gender dimorphism in aging. The asymmetry of evolutionary processes between gender could lead to males and females aging in different ways. If so, gender specific variation loads could be an evolutionary result of maternal heritage of mitochondrial genomes, especially in centenarians who live to an extreme age and are considered as good models for healthy aging. Here, we tested whether the mitochondrial variation loads were associated with altered aging patterns by investigating the mtDNA haplogroup distribution and genetic diversity between female and male centenarians. We found no evidence of differences in aging patterns between genders in centenarians. Our results indicate that the evolutionary consequence of gender dimorphism in mitochondrial genomes is not a factor in the altered aging patterns in human, and that mitochondrial DNA contributes equally to longevity in males and females.
Asunto(s)
ADN Mitocondrial/genética , Longevidad/genética , Mitocondrias/genética , Factores Sexuales , Adulto , Anciano , Anciano de 80 o más Años , China , Femenino , Variación Genética , Genoma Mitocondrial , Haplotipos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The silent information regulator SIR2/SIRT1gene has been demonstrated as regulating lifespan in many model organisms, including yeast, worms, fruit flies and rodents. SIRT1, the human homolog of SIR2, is considered a candidate gene as a modifier of human life expectancy. METHODS: In the current study we included 616 long-lived individuals and 846 matched younger controls to investigate associations between 8 common single nucleotide polymorphisms (SNPs) (i.e., rs12778366, rs3758391, rs3740051, rs33957861, rs7896005, rs12413112, rs11599176 and rs4746720) in the SIRT1 gene and human longevity. RESULTS: The 8 SNPs had strong linkage disequilibrium (LD) and were in an LD block, which was characterized by 4 common haplotypes that capture 99.3% of the genetic variation present within it. We found no evidence for statistically significant associations between the tested SIRT1 SNPs and longevity at the allele, genotype or haplotype levels. CONCLUSIONS: Current findings show that several common variants in SIRT1 are not associated with human longevity.
Asunto(s)
Pueblo Asiatico/genética , Longevidad/genética , Polimorfismo de Nucleótido Simple , Sirtuina 1/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , China , Femenino , Técnicas de Genotipaje , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana EdadRESUMEN
Favism is a life-threatening hemolytic anemia resulting from the intake of fava beans by susceptible individuals with low erythrocytic glucose 6-phosphate dehydrogenase (G6PD) activity. However, little is known about the metabolomic changes in plasma and liver after the intake of fava beans in G6PD normal and deficient states. In this study, gas chromatography/mass spectrometry was used to analyze the plasma and liver metabolic alterations underlying the effects of fava beans in C3H- and G6PD-deficient (G6PDx) mice, and to find potential biomarkers and metabolic changes associated with favism. Our results showed that fava beans induced oxidative stress in both C3H and G6PDx mice. Significantly, metabolomic differences were observed in plasma and liver between the control and fava bean treated groups of both C3H and G6PDx mice. The levels of 7 and 21 metabolites in plasma showed significant differences between C3H-control (C3H-C)- and C3H fava beans-treated (C3H-FB) mice, and G6PDx-control (G6PDx-C)- and G6PDx fava beans-treated (G6PDx-FB) mice, respectively. Similarly, the levels of 7 and 25 metabolites in the liver showed significant differences between C3H and C3H-FB, and G6PDx and G6PDx-FB, respectively. The levels of oleic acid, linoleic acid, and creatinine were significantly increased in the plasma of both C3H-FB and G6PDx-FB mice. In the liver, more metabolic alterations were observed in G6PDx-FB mice than in C3H-FB mice, and were involved in a sugar, fatty acids, amino acids, cholesterol biosynthesis, the urea cycle, and the nucleotide metabolic pathway. These findings suggest that oleic acid, linoleic acid, and creatinine may be potential biomarkers of the response to fava beans in C3H and G6PDx mice and therefore that oleic acid and linoleic acid may be involved in oxidative stress induced by fava beans. This study demonstrates that G6PD activity in mice can affect their metabolic pathways in response to fava beans.
Asunto(s)
Sangre , Hígado/metabolismo , Metabolómica , Vicia faba , Animales , Cromatografía en Capa Delgada , Cromatografía de Gases y Espectrometría de Masas , Ratones , Ratones Endogámicos C3H , Estrés OxidativoRESUMEN
Centenarians are a good healthy aging model. Interestingly, centenarians' offspring are prone to achieve longevity. Here we recruited 60 longevity families and investigated the blood biochemical indexes of family members to seek candidate factors associated with familial longevity. First, associations of blood indexes with age were tested. Second, associations of blood parameters in centenarians (CEN) with their first generation of offspring (F1) and F1 spouses (F1SP) were analyzed. Third, genes involved in regulating target factors were investigated. We found that total cholesterol (TC) and triglyceride (TG) increased with age (20-80 years), but decreased in CEN. Similarly, blood urea nitrogen (BUN) and blood creatinine (BCr) increased with age (20-80 years), but were maintained on a plateau in CEN. Importantly, we first revealed dual changes in blood pressure, i.e., decreased diastolic blood pressure but increased systolic blood pressure in CEN, which associated with altered CST3 expression. Genetic analysis revealed a significant association of blood uric acid (BUA) and BCr in CEN with F1 but not with F1SP, suggesting they may be heritable traits. Taken together, our results suggest serum lipids, kidney function and especially diastolic pressure rather than systolic pressure were improved in CEN or their offspring, suggesting these factors may play an important role in familial longevity.
Asunto(s)
Presión Sanguínea/fisiología , Riñón/metabolismo , Lípidos/sangre , Longevidad , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento , Pueblo Asiatico , Nitrógeno de la Urea Sanguínea , China , Colesterol/sangre , Creatinina/sangre , Cistatina C/metabolismo , Humanos , Pruebas de Función Renal , Metabolismo de los Lípidos/genética , Masculino , Persona de Mediana Edad , Transcriptoma , Triglicéridos/sangre , Ácido Úrico/sangreRESUMEN
Sirtuin 6 (SIRT6) has recently been demonstrated to play an important role in the regulation of longevity in mammals. We therefore aimed to determine whether common variations in the SIRT6 gene are associated with human longevity. Five tag single nucleotide polymorphisms (SNPs) across the SIRT6 gene and its 5 kb up-/downstream region, including rs350852, rs350844, rs352493, rs4807546 and rs3760905, have been successfully determined in 616 unrelated Chinese long-lived individuals (LLIs) (mean age: 102.4 ± 2.3 years) and 846 younger controls (mean age: 48.9 ± 10.6 years) from Hainan Island, China. The allele and genotype frequencies of the five SNPs showed no statistically significant difference between the LLIs and controls (all P > 0.05). The five SNPs were in strong linkage disequilibrium and defined seven common haplotypes. Likewise, no association between these haplotypes and longevity was observed (all P > 0.05). The present study reveals that common genetic variations in the SIRT6 gene are not associated with human longevity.
Asunto(s)
Pueblo Asiatico/genética , Longevidad , Polimorfismo de Nucleótido Simple , Sirtuinas/genética , Adulto , Anciano de 80 o más Años , China , Femenino , Estudios de Asociación Genética , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana EdadRESUMEN
Apolipoprotein E (APOE), translocase of outer mitochondrial membrane 40 homolog (TOMM40) and apolipoprotein C-I (APOC1) may extend lifespan by marked delay or escape from age-related diseases. This study aimed to elucidate the association of human longevity with genetic variations in TOMM40/APOE/APOC1 region in a Chinese population. Ten tag single-nucleotide polymorphisms (SNPs) in the TOMM40/APOE/APOC1 region were successfully genotyped in 616 unrelated long-lived individuals and 846 younger controls. Of the 10 SNPs, rs7254892 in 5' upstream of TOMM40 showed significant association with human longevity (G/A-A/A vs G/G: odds ratio (OR)=1.59, 95% confidence interval (CI)=1.20-2.09, P=0.0011, Bonferroni corrected P (Pc)=0.033). The haplotype analysis suggested that individuals carrying the haplotype A-A-A-A-T-A-T-G-C-A (rs7254892-rs157580-rs2075649-rs2075650-rs157582-rs8106922-rs1160985-rs405697-rs439401-rs445925) tended to have longer lifespan than those carrying the most common haplotype G-G-A-A-C-A-C-A-T-G (OR=1.59, 95% CI=1.19-2.12, P=0.0018, Pc=0.0216). These findings indicated that variants in TOMM40/APOE/APOC1 region might be associated with human longevity. Further studies are needed to identify the causal genetic variants influencing human longevity.
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Apolipoproteína C-I/genética , Apolipoproteínas E/genética , Longevidad/genética , Proteínas de Transporte de Membrana/genética , Adulto , Enfermedad de Alzheimer/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Polimorfismo de Nucleótido SimpleRESUMEN
Replenishment of insulin-producing pancreatic ß-cells would be beneficial in diabetes. The number of ß-cells is maintained primarily by self-neogenesis to compensate for ß-cell failure, loss or dedifferentiation. We present here a polypeptide vglycin, which was isolated and purified from germinating pea seeds. Vglycin exhibited positive effects in our diabetic models by promoting the proliferation and suppressing the apoptosis and dedifferentiation of ß-cells. Vglycin promoted the restoration of ß-cells in both young streptozotocin (STZ)-induced type 1 diabetic SD rats and in aged high-fat diet with (or without) STZ-induced type 2 diabetic C57BL/6 mice. We demonstrated that vglycin triggers this positive signaling by activating the insulin receptor and corresponding transcription factors. Impaired insulin sensitivity and glucose tolerance in aged T2DM mice were dramatically improved after long-term vglycin treatment, consistent with the altered level of inflammatory factor IL-1ß/6. In addition, energy expenditure and body weights were significantly decreased in the mouse models after vglycin therapy. These results provide insight into the protective effects of vglycin on ameliorating ß-cell function in standing glucolipotoxicity. Thus, vglycin may represent a new therapeutic agent for preventing and treating diabetes by replenishing endogenous insulin-positive cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Células Secretoras de Insulina/metabolismo , Proteínas de Soja/farmacología , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Células Secretoras de Insulina/patología , Masculino , Ratones , Ratas , Ratas Sprague-DawleyRESUMEN
Allograft Inflammatory Factor-1 (AIF-1) is a 17kDa cytoplasmic, calcium-binding, inflammation-responsive scaffold protein that is mainly expressed in immunocytes. AIF-1 influences the immune system at several key points and thus modulates inflammatory diseases. AIF-1 boosts the expression of inflammatory mediators such as cytokines, chemokines, inducible nitric oxide synthase (iNOS) and promotes inflammatory cell proliferation and migration. Here we provide an overview of the different pathological processes regulated by AIF-1 mainly including allograft rejection, autoimmune diseases, central nervous system (CNS) injury, vasculopathy and cancer et al.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Proteínas de Unión al ADN/inmunología , Rechazo de Injerto/inmunología , Inflamación/inmunología , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes/genética , Secuencia de Bases , Proteínas de Unión al Calcio , Proteínas de Unión al ADN/genética , Rechazo de Injerto/genética , Humanos , Inflamación/genética , Proteínas de Microfilamentos , Datos de Secuencia Molecular , Alineación de SecuenciaRESUMEN
BACKGROUND: Daintain/AIF-1 is an inflammatory polypeptide factor/allograft inflammatory factor 1 derived from macrophages. It is characterized in APOE(-/-) mice as a novel inflammatory factor associated with atherosclerosis. The purpose of this study was to characterize its function in human atherosclerosis. METHODS: Immunohistochemistry was used to identify the expression of daintain/AIF-1 in vessel segments within and far from atherosclerotic plaques; High-performance liquid chromatography (HPLC) was used to display the effects of daintain/AIF-1 on C-reactive protein (CRP), oxidative capacity and superoxide dismutase (SOD) in vivo; Oil Red O Staining was used to show the effects of daintain/AIF-1 on uptake of oxidized low density lipoprotein (ox-LDL) into U937 cells, a macrophage line; Western Blot was used to test scavenger receptor A (SRA) expression. RESULTS: A high density of daintain/AIF-1 was observed in the tunica intima and media of coronary artery with atherosclerotic plaque, and fewer daintain/AIF-1 in the vessels without atherosclerotic plaque; Daintain/AIF-1 injected intravenously into BALB/c mice boosted oxidative capacity, significantly impaired SOD activities and augmented the CRP level in blood. According to the oil red O test, daintain/AIF-1 profoundly facilitated the uptake of ox-LDL in U937 macrophages and formation of foam cells in the endothelium. We also found that the molecular mechanisms are effective by promoting overexpression of SRA on macrophages. CONCLUSION: These findings implicate that the inflammatory factor daintain/AIF-1 is closely associated with atherogenesis, and could be further characterized as a novel risk factor for atherosclerosis.
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Proteínas de Unión al ADN/metabolismo , Células Espumosas/citología , Macrófagos/metabolismo , Animales , Proteína C-Reactiva , Proteínas de Unión al Calcio , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , Humanos , Lipoproteínas LDL/metabolismo , Ratones , Ratones Endogámicos BALB C , Proteínas de Microfilamentos , Receptores Depuradores de Clase A/metabolismo , Superóxido Dismutasa/antagonistas & inhibidores , Superóxido Dismutasa/metabolismo , Células U937RESUMEN
Free heme is potentially cytotoxic, particularly in the presence of oxidants or activated phagocytes. Daintain/AIF-1 (allograft inflammatory factor-1) is a macrophage factor that has been implicated in the regulation of inflammation. In the present study, daintain/AIF-1 was found to induce cytolysis of erythrocytes, resulting in heme release in vitro. Furthermore, the interacting protein of daintain/AIF-1 was purified by daintain/AIF-1-6 histidine antigen fusion protein nickel affinity chromatography. MALDI-TOF-MS analysis identified hemoglobin subunit beta-1 as an interacting protein of daintain/AIF-1.These data suggest that daintain/AIF-1 may be involved in heme-associated diseases.