RESUMEN
Krüppel-like factor 13 (KLF13), a zinc finger transcription factor, is considered as a potential regulator of cardiomyocyte differentiation and proliferation during heart morphogenesis. However, its precise role in the dedifferentiation of vascular smooth muscle cells (VSMCs) during atherosclerosis and neointimal formation after injury remains poorly understood. In this study, we investigated the relationship between KLF13 and SM22α expression in normal and atherosclerotic plaques by bioanalysis, and observed a significant increase in KLF13 levels in the atherosclerotic plaques of both human patients and ApoE-/- mice. Knockdown of KLF13 was found to ameliorate intimal hyperplasia following carotid artery injury. Furthermore, we discovered that KLF13 directly binds to the SM22α promoter, leading to the phenotypic dedifferentiation of VSMCs. Remarkably, we observed a significant inhibition of platelet-derived growth factor BB-induced VSMCs dedifferentiation, proliferation, and migration when knocked down KLF13 in VSMCs. This inhibitory effect of KLF13 knockdown on VCMC function was, at least in part, mediated by the inactivation of p-AKT signaling in VSMCs. Overall, our findings shed light on a potential therapeutic target for treating atherosclerotic lesions and restenosis after vascular injury.
Asunto(s)
Desdiferenciación Celular , Proliferación Celular , Factores de Transcripción de Tipo Kruppel , Proteínas de Microfilamentos , Proteínas Musculares , Músculo Liso Vascular , Miocitos del Músculo Liso , Proteínas Represoras , Animales , Humanos , Masculino , Ratones , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/metabolismo , Traumatismos de las Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/genética , Traumatismos de las Arterias Carótidas/metabolismo , Movimiento Celular/genética , Proliferación Celular/genética , Células Cultivadas , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Ratones Endogámicos C57BL , Proteínas Musculares/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Neointima/metabolismo , Neointima/patología , Neointima/genética , Fenotipo , Placa Aterosclerótica/patología , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/genética , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transducción de Señal , Proteínas de Ciclo Celular , Proteínas de Microfilamentos/genéticaRESUMEN
OBJECTIVE: The present study was performed to localize the articular deposition of monosodium urate (MSU) crystal in joints. We compare the detection efficiencies of dual-energy CT (DECT) and ultrasound scans. METHODS: Analyses by DECT and ultrasound were performed with 184 bilateral joints of the lower limbs of 54 consecutive gout patients. All joints were categorized into (1) knee, (2) ankle, (3) MTP1, and (4) MTP2, and sorted into those with and those without detectable MSU deposition. The comparison of the positive rate between DECT and ultrasound and the agreement was performed using the McNemar test and the Cohen's κ coefficient, respectively. Next, we listed the MSU crystal deposition as assessed by ultrasound between the DECT-positive and -negative joints according to their interior structure. We included tendons, synovia, cartilage, subcutaneous tissue, etc. RESULTS: Among all joints, the percentages with MSU crystal deposition detected by DECT (99/184, 53.8%) and ultrasound (106/184, 57.6%) were comparable (P = 0.530 > 0.05). For MTP1 (21/34, 61.8%; 12/34, 35.3%; P < 0.05) and MTP2-5 (17/34, 50.0%; 10/34, 29.4%, P < 0.05), ultrasound and DECT were more efficient, respectively. The data concordance in 46 of 50 joints (92.00%; κ = 0.769, P < 0.05) for knee; and 27 of 34 joints (79.41%; κ = 0.588, P < 0.05) for MTP2-5 and suggested that tendons were the most frequent anatomical location of MSU crystal deposition. CONCLUSIONS: The tendons are the most frequent anatomical location of MSU crystal depositions. The concordance rate of knee joints and MTP2-5 joints shows good agreement between DECT and ultrasound depending on the location.
Asunto(s)
Articulación del Tobillo/diagnóstico por imagen , Gota/diagnóstico por imagen , Articulación de la Rodilla/diagnóstico por imagen , Tendones/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Ultrasonografía , Ácido Úrico/análisis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Articulación del Tobillo/química , Cristalización , Femenino , Gota/metabolismo , Humanos , Articulación de la Rodilla/química , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Tendones/química , Adulto JovenRESUMEN
Antigen-presenting dendritic cells interpret environmental signals to orchestrate local and systemic immune responses. In this study, the roles of Wnt proteins and their signaling pathway members in the maturation and function of monocyte-derived DCs were investigated. The present study showed higher expression of ß-catenin, as well as pGSK-3ß in DCs than those in monocytes. Wnt3a, Wnt5a and inhibition of GSK-3ß promoted differentiation of DCs, but inhibited maturation of DCs. GSK-3ß induced DCs maturation with unconventional phenotypes. Together with ß-catenin silence, these treatment lead to reduced secretion of cytokines and chemokines except for IL-10 in comparison with LPS treatment, and significantly promoted proliferation of T cells. Wnt3a and inhibition of GSK-3ß increased expression of MAPK signalings (p-ERK, p-p38, p-JNK). However, inhibition of MAPK signalings in turn differently regulated Wnt signaling proteins expression. These data suggest that Wnt pathway regulates DCs differentiation, maturation and function with interaction of MAPK signaling pathways.
Asunto(s)
Células Dendríticas/fisiología , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Linfocitos T/inmunología , Proteína Wnt-5a/metabolismo , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Interleucina-10/metabolismo , Activación de Linfocitos , Monocitos/fisiología , ARN Interferente Pequeño/genética , Transducción de Señal , beta Catenina/genéticaRESUMEN
Acute kidney injury (AKI) is a critical complication known for their extremely high mortality rate and lack of effective clinical therapy. Disorders in mitochondrial dynamics possess a pivotal role in the occurrence and progression of contrast-induced nephropathy (CIN) by activating NLRP3 inflammasome. The activation of dynamin-related protein-1 (Drp1) can trigger mitochondrial dynamic disorders by regulating excessive mitochondrial fission. However, the precise role of Drp1 during CIN has not been clarified. In vivo experiments revealed that inhibiting Drp1 through Mdivi-1 (one selective inhibitor of Drp1) can significantly decrease the expression of p-Drp1 (Ser616), mitochondrial p-Drp1 (Ser616), mitochondrial Bax, mitochondrial reactive oxygen species (mROS), NLRP3, caspase-1, ASC, TNF-α, IL-1ß, interleukin (IL)-18, IL-6, creatinine (Cr), malondialdehyde (MDA), blood urea nitrogen (BUN), and KIM-1. Moreover, Mdivi-1 reduced kidney pathological injury and downregulated the interaction between NLRP3 and thioredoxin-interacting protein (TXNIP), which was accompanied by decreased interactions between TRX and TXNIP. This resulted in increasing superoxide dismutase (SOD) and CAT activity, TRX expression, up-regulating mitochondrial membrane potential, and augmenting ATP contents and p-Drp1 (Ser616) levels in the cytoplasm. However, it did not bring impact on the expression of p-Drp1 (Ser637) and TXNIP. Activating Drp-1though Acetaldehyde abrogated the effects of Mdivi-1. In addition, the results of in vitro studies employing siRNA-Drp1 and plasmid-Drp1 intervention in HK-2 cells treated with iohexol were consistent with the in vivo experiments. Our findings revealed inhibiting Drp1 phosphorylation at Ser616 could ameliorate iohexol -induced acute kidney injury though alleviating the activation of the TXNIP-NLRP3 inflammasome pathway.
Asunto(s)
Lesión Renal Aguda , Proteínas Portadoras , Inflamasomas , Dinámicas Mitocondriales , Proteína con Dominio Pirina 3 de la Familia NLR , Quinazolinonas , Animales , Humanos , Masculino , Ratones , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/tratamiento farmacológico , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Línea Celular , Medios de Contraste/efectos adversos , Dinaminas/metabolismo , Inflamasomas/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Dinámicas Mitocondriales/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Quinazolinonas/farmacología , Quinazolinonas/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Tiorredoxinas/metabolismo , Tiorredoxinas/genéticaRESUMEN
Oxidative stress and apoptosis play vital role in diabetic rats suffering from renal ischemia reperfusion injury (IRI). As a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, Saxagliptin(SAX)has been confirmed in the regulation of inflammation and apoptosis by targeting Nrf-2/HO-1signalling. The study was designed to explore the efficacy and potential mechanisms of SAX on inflammation and apoptosis for treating of IRI in diabetic rats. Through testing the expressions of Nrf-2, HO-1, Cleaved-Caspase9, Cleaved-Caspase3, Bax, BCL-2, Bak, Apaf-1, cytochrome C (Cytc), Cystatin C (CysC), ß2-microglobulin (ß2-MG), creatinine (Cr), urea nitrogen (BUN), TUNEL and pathological morphology, the effects of SAX on IRI diabetic rats have been investigatedg. The results has displayed SAX treatment significantly attenuate the cell apoptosis and pathological damage of kidney as well as lessening the expression of cleaved-caspase-9, cleaved-caspase3, Bax, cytoplasmic-Cytc, MDA, Bak, and Apaf-1 molecules, and the contents of ROS, Cr, CysC, ß2-MG, and BUN. Furthermore, SAX therapy also increased the expression of Nrf-2, BCL-2, HO-1 and mitochondrial cytochrome Cytc, and enhanced the activity of SOD, CAT and GPx. Therefore, our study has indicated that SAX treatment alleviated IRI in diabetic rats by suppressing oxidative stress and mitochondrial apoptotic pathways by activating the Nrf-2/HO-1 signaling.
Asunto(s)
Diabetes Mellitus Experimental , Daño por Reperfusión , Ratas , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Estrés Oxidativo , Riñón/patología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Apoptosis , Inflamación/metabolismoRESUMEN
Backgrounds. Heme oxygenase-1 (HO-1) has been reported to play a regulatory role in osteoclastogenesis. Bone morphogenetic protein (BMP) pathways induce osteoblastic differentiation and bone remodeling. Aims. To identify serum levels of HO-1, BMP-7, and Runt related-transcription factor 2 (Runx2) in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) and to investigate the relationships between HO-1, BMP-7, Runx2, and other common biomarkers for bone metabolism. Results. Serum levels of HO-1 and BMP-7 were revealed to be significantly higher in patients with RA or AS than in healthy controls (p < 0.01). In RA group, HO-1 was positively correlated with BMP-7, Runx2, and tartrate-resistant acid phosphatase-5b (TRAP-5b) (p < 0.05, resp.), BMP-7 was positively correlated with Runx2 and TRAP-5b (p < 0.05, resp.), and Runx2 was negatively correlated with N-terminal midfragment of osteocalcin (NMID) (p < 0.05). In AS group, we observed identical correlation between HO-1 and BMP-7, but opposite correlations between BMP-7 and TRAP-5b and between Runx2 and NMID, when comparing with the RA cohort. Conclusion. Our findings suggest that HO-1 and BMP-7 are potential biomarkers for bone metabolism in patients with RA and AS. The different correlations between the bone markers point to distinct differences in bone remodeling pathways in the two types of arthritis.