RESUMEN
Chronic renal failure (CRF) is an incurable disease with unique challenges. Anemia is a frequent complication affecting dialysis patients. Erythropoietin (EPO) is used to treat anemia, but a poor response may result. We investigated genetic polymorphisms of store-operated calcium channel (SOC) signaling, an important erythropoietin-activated pathway that may induce EPO resistance in patients with renal failure. A total of 108 end stage renal disease (ESRD) patients were selected for this study. Patients were divided into two groups according to their erythropoietin resistance index (ERI): 39 patients with an ERI>10 and 69 patients with an ERI<10. We selected four tagging single nucleotide polymorphisms (tSNPs) in STIM1 and five in ORAI1 in our study. A polymerase chain reaction was performed, and genotyping against EPO resistance was correlated. Patients with the AG genotype of rs1561876 in STIM1, the TC genotype of rs6486795 in ORAI1, and the TG or GG genotypes of rs12320939 in ORAI1 were associated with an increased risk of erythropoietin resistance. Overall, we reported a moderately significant relationship between genetic polymorphisms of STIM1 and EPO resistance. We also reported a highly significant relationship between genetic polymorphisms of ORAI1 and EPO resistance. The (A-A-G) haplotype of STIM1 and the (G-T-G-T-A, G-C-G-C-G, or G-T-T-C-G) haplotypes of ORAI1 were significantly associated with EPO resistance.
Asunto(s)
Eritropoyetina , Fallo Renal Crónico , Proteínas de Neoplasias , Proteína ORAI1 , Polimorfismo de Nucleótido Simple , Molécula de Interacción Estromal 1 , Humanos , Molécula de Interacción Estromal 1/genética , Egipto , Fallo Renal Crónico/genética , Masculino , Eritropoyetina/genética , Femenino , Proteína ORAI1/genética , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Adulto , Resistencia a Medicamentos/genéticaRESUMEN
Erythropoietin (EPO) plays a key role in energy metabolism, with EPO receptor (EpoR) expression in white adipose tissue (WAT) mediating its metabolic activity. Here, we show that male mice lacking EpoR in adipose tissue exhibit increased fat mass and susceptibility to diet-induced obesity. Our findings indicate that EpoR is present in WAT, brown adipose tissue, and skeletal muscle. Elevated EPO in male mice improves glucose tolerance and insulin sensitivity while reducing expression of lipogenic-associated genes in WAT, which is linked to an increase in transcription factor RUNX1 that directly inhibits lipogenic genes expression. EPO treatment in wild-type male mice decreases fat mass and lipogenic gene expression and increase in RUNX1 protein in adipose tissue which is not observed in adipose tissue EpoR ablation mice. EPO treatment decreases WAT ubiquitin ligase FBXW7 expression and increases RUNX1 stability, providing evidence that EPO regulates energy metabolism in male mice through the EPO-EpoR-RUNX1 axis.
Asunto(s)
Tejido Adiposo Blanco , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Metabolismo Energético , Eritropoyetina , Receptores de Eritropoyetina , Animales , Eritropoyetina/metabolismo , Eritropoyetina/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Masculino , Metabolismo Energético/efectos de los fármacos , Ratones , Receptores de Eritropoyetina/metabolismo , Receptores de Eritropoyetina/genética , Tejido Adiposo Blanco/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/genética , Músculo Esquelético/metabolismo , Resistencia a la Insulina , Lipogénesis/genética , Lipogénesis/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Erythropoietin (EPO), expressed in red blood progenitor cells, primarily regulates erythropoiesis by binding to its receptor. Besides anemia, recent studies have identified new therapeutic indications for EPO that are not connected to red blood cell formation. Elevated EPO levels harm bone homeostasis in adult organisms and are associated with increased osteoclast; however, the underlying molecular mechanisms remain unclear. This study demonstrated that EPO enhanced osteoclast differentiation and bone resorption in vitro. We showed that EPO promoted osteoclast formation by up-regulating PPARγ expression through activating the Jak2/ERK signaling pathway. Consistently, PPARγ antagonists rescued the hyperactivation of osteoclasts due to EPO, while PPARγ agonists reversed the EMP9-mediated decrease in osteoclast differentiation. Further, exposing female mice to EPO for two months led to a decrease in bone mass and increased osteoclast numbers. The present results suggested that EPO promotes osteoclastogenesis by regulating the Jak2/ERK/ PPARγ signaling pathway. From a clinical perspective, the risk of compromised bone health should be considered when using EPO to treat anemia in post-operative patients with intertrochanteric fractures of the femur, as it could significantly impact the patient's recovery and quality of life.
Asunto(s)
Diferenciación Celular , Eritropoyetina , Osteoclastos , PPAR gamma , Eritropoyetina/farmacología , Eritropoyetina/metabolismo , Animales , PPAR gamma/metabolismo , Osteoclastos/metabolismo , Osteoclastos/efectos de los fármacos , Ratones , Femenino , Diferenciación Celular/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Janus Quinasa 2/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Humanos , Regulación hacia Arriba/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Resorción Ósea/metabolismo , Ratones Endogámicos C57BLRESUMEN
Experimental autoimmune encephalomyelitis is a demyelinating disease that causes paralysis in laboratory rats. This condition lacks treatment that reverses damage to the myelin sheaths of neuronal cells. Therefore, in this study, treatment with EPO as a neuroprotective effect was established to evaluate the ERK 1/2 signaling pathway and its participation in the EAE model. EPO was administered in 5000 U/Kg Sprague Dawley rats. U0126 was used as an inhibitor of the ERK 1/2 pathway to demonstrate the possible activation of this pathway in the model. Spinal cord and optic nerve tissues were evaluated using staining techniques such as H&E and the Luxol Fast Blue myelin-specific technique, as well as immunohistochemistry of the ERK 1/2 protein. The EPO-treated groups showed a decrease in cellular sampling in the spinal cord tissues but mainly in the optic nerve, as well as an increase in the expression of the ERK 1/2 protein in both tissues. The findings of this study suggest that EPO treatment reduces cellular death in EAE-induced rats by regulating the ERK pathway.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Eritropoyetina , Sistema de Señalización de MAP Quinasas , Fármacos Neuroprotectores , Nervio Óptico , Ratas Sprague-Dawley , Médula Espinal , Animales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Eritropoyetina/farmacología , Nervio Óptico/efectos de los fármacos , Nervio Óptico/patología , Nervio Óptico/metabolismo , Ratas , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Femenino , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismoRESUMEN
Importance: Children born very preterm are at risk for long-term neurodevelopmental sequelae. Prophylactic high-dose recombinant human erythropoietin (rhEpo) shortly after birth has not been shown to improve cognitive, motor, and behavioral development at 2 and 5 years. Objective: To investigate whether early high-dose rhEpo is associated with better executive functions and processing speed-late-maturing cognitive functions-in school-aged children born very preterm. Design, Setting, and Participants: This single-center cohort study was a prospective, observational follow-up study of a multicenter neonatal clinical trial; 365 children born very preterm (mean gestational age, 29.3 weeks [range, 26.0-31.9 weeks]) who had been enrolled in the Swiss EPO Neuroprotection Trial at birth between 2005 and 2012, and who were included in the primary outcome analyses at 2 years, were eligible to be recruited for the EpoKids study between 2017 and 2021 when they were at school age. Term-born children were additionally recruited and included in a control group. Data were analyzed between May and September 2022. Exposure: Administration of rhEpo (3000 IU/kg) or placebo (saline, 0.9%) intravenously 3 times within the first 2 days of life as part of the Swiss EPO Neuroprotection Trial. Main Outcome and Measures: A comprehensive neuropsychological test battery assessed executive functions and processing speed, and parents reported on their child's executive functions in everyday life to test the hypothesis that early high-dose rhEpo administration is associated with better cognitive outcomes at school age. Results: In the EpoKids study, 214 children born very preterm (58.6% of 365 children in eligible cohort) were assessed at a mean age of 10.4 years (range, 6.9-13.4 years); 117 (54.7%) were boys. There was no evidence that the 117 children who had received rhEpo differed from the 97 children who had received placebo in any of the 15 executive function and processing speed tests, nor in parent-rated executive functions (estimates ranged from -0.138 to 0.084, all 95% CIs included 0). Irrespective of rhEpo or placebo allocation, children born very preterm scored lower on 11 of 15 executive function and processing speed tests than term-born peers (estimates ranged from 0.112 to 0.255, 95% CIs did not include 0). Conclusion and Relevance: This study found no evidence for a positive association between prophylactic early high-dose rhEpo administration and long-term neurodevelopmental outcomes after very preterm birth. These results suggest that a comprehensive approach, including pharmacological and nonpharmacological prevention and intervention strategies, is needed to support these children's neurodevelopmental outcome.
Asunto(s)
Cognición , Eritropoyetina , Recien Nacido Extremadamente Prematuro , Humanos , Eritropoyetina/administración & dosificación , Eritropoyetina/uso terapéutico , Femenino , Masculino , Cognición/efectos de los fármacos , Niño , Estudios Prospectivos , Recién Nacido , Estudios de Seguimiento , Función Ejecutiva/efectos de los fármacos , Preescolar , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéuticoRESUMEN
Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by delayed neurodevelopment, accelerated aging, and increased risk of many co-occurring conditions. Hypoxemia and dysregulated hematopoiesis have been documented in DS, but the underlying mechanisms and clinical consequences remain ill defined. We report an integrative multi-omic analysis of â¼400 research participants showing that people with DS display transcriptomic signatures indicative of elevated heme metabolism and increased hypoxic signaling across the lifespan, along with chronic overproduction of erythropoietin, elevated biomarkers of tissue-specific hypoxia, and hallmarks of stress erythropoiesis. Elevated heme metabolism, transcriptional signatures of hypoxia, and stress erythropoiesis are conserved in a mouse model of DS and associated with overexpression of select triplicated genes. These alterations are independent of the hyperactive interferon signaling characteristic of DS. These results reveal lifelong dysregulation of key oxygen-related processes that could contribute to the developmental and clinical hallmarks of DS.
Asunto(s)
Síndrome de Down , Eritropoyesis , Hemo , Hipoxia , Transducción de Señal , Síndrome de Down/metabolismo , Síndrome de Down/patología , Síndrome de Down/genética , Hemo/metabolismo , Humanos , Animales , Ratones , Hipoxia/metabolismo , Masculino , Femenino , Transcriptoma/genética , Niño , Adulto , Estrés Fisiológico , Eritropoyetina/metabolismo , Adolescente , PreescolarRESUMEN
PURPOSE: This first-in-human trial aimed to investigate the pharmacokinetics and pharmacodynamics characteristics and safety and tolerability of single ascending doses of subcutaneous polyethylene glycol-erythropoietin (PEG-EPO) in healthy subjects. METHODS: In this phase I, randomized, double-blind, placebo-controlled, dose-escalating trial, subjects were sequentially enrolled into 7 cohorts with 12 subjects in each cohort and randomized in a 5:1 ratio to receive a single dose of 0.2, 0.4, 0.8, 1.6, 2.4, 3.6, or 4.8 µg/kg PEG-EPO or matching placebo. Safety and tolerability including dose-limiting toxicities (DLTs) were assessed. Pharmacokinetics parameters, including Cmax, AUC0-inf, Tmax, and t1/2, and pharmacodynamics parameters, including reticulocyte count and hemoglobin content, were evaluated. FINDINGS: Eighty-four subjects (median age 30.4 years and 77.4% male) were enrolled. No subjects developed DLTs. Any grade treatment-related adverse events occurred in 66.7% of the subjects, but most (92.9%) were mild. No serious adverse events and no death occurred. Forty percent of the subjects receiving PEG-EPO had iron decreased, 27.1% reported ferritin decreased, 25.7% showed unsaturated iron binding capacity increased, and 17.1% had neutrophil count decreased. Cmax exhibited a dose-disproportionate rise from a geometric mean of 525 pg/mL with 0.2 µg/kg PEG-EPO to 23196 pg/mL with 4.8 µg/kg PEG-EPO. The mean t1/2 ranged between 82.4 ± 21.3 h with 0.4 µg/kg PEG-EPO and 160.6 ± 65.7 h with 1.6 µg/kg PEG-EPO. AUC0-inf displayed a largely dose-proportional rise from 226264.5 pg*h/mL with 0.2 µg/kg PEG-EPO to 5206434.0 pg*h/mL with 4.8 µg/kg PEG-EPO. The absolute reticulocyte count increased with escalating doses of PEG-EPO, with the mean maximal change from baseline between 3.2 ± 1.5*10^10/L (Q1,Q3 1.8-3.6*10^10/L) with PEG-EPO 0.2 µg/kg and 9.3 ± 4.0*10^10/L (Q1,Q3 6.2-13.5*10^10/L) with 3.6 µg/kg PEG-EPO. The mean maximal change from baseline in the mean hemoglobin content ranged between 5.9 ± 4.4 g/L (Q1,Q3 3.5,7.0) with 0.2 µg/kg PEG-EPO and 15.4 ± 8.7 g/L (Q1,Q3 10.5,20.0) with 2.4 µg/kg PEG-EPO. IMPLICATIONS: This trial demonstrated that PEG-EPO was safe and tolerable in healthy subjects. The subcutaneous route of administration allows outpatient treatment and the pharmacokinetics characteristics of PEG-EPO support less frequent dosing regimens and effective treatment for chronic kidney disease patients with anemia. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03657238.
Asunto(s)
Relación Dosis-Respuesta a Droga , Eritropoyetina , Voluntarios Sanos , Polietilenglicoles , Humanos , Masculino , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Polietilenglicoles/farmacocinética , Femenino , Adulto , Método Doble Ciego , Eritropoyetina/farmacocinética , Eritropoyetina/administración & dosificación , Eritropoyetina/efectos adversos , Adulto Joven , Hemoglobinas/análisis , Persona de Mediana Edad , Recuento de Reticulocitos , Inyecciones Subcutáneas , Área Bajo la CurvaRESUMEN
OBJECTIVE: Our study aimed to investigate the relationship between vascular endothelial growth factor (VEGF), NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory complex, erythropoietin (EPO) levels, and ocular hemodynamics in patients diagnosed with primary open-angle glaucoma (POAG). METHODS: This is a prospective observational study. Patients diagnosed with POAG at The Sixth Hospital of Wuhan hospital between November 2022 and February 2023were enrolled.The patients were categorized into three groups based on the average visual field defect (mean deviation, MD) value: severe injury group (MD > 12 dB, 93 cases), moderate injury group (7 ≤ MD ≤ 12 dB, 89 cases), and mild injury group (MD < 7 dB, 85 cases). The levels of VEGF, NLRP3 inflammatory complex, EPO, and ocular hemodynamics were compared among the groups. Furthermore, the relationship between VEGF, NLRP3, EPO levels, and ocular hemodynamics in patients with POAG was analyzed using Pearson correlation analysis. After adjusting for confounding factors such as age and gender, multivariate Logistic regression analysis was performed with the ocular hemodynamics indexes being used as dependent variables, and VEGF, NLRP3, ASC, Caspase-1, and EPO being used as independent variables. RESULTS: A total of267 patients with POAG were enrolled. There were no significant differences in sex, age, body mass index, systolic blood pressure, diastolic blood pressure, smoking, alcohol consumption, and blood glucose between the two groups (P > 0.05). The levels of NLRP3, ASC, Caspase-1, and EPO in the severe and moderate injury groups were higher than those in the mild injury group, whereas the VEGF levels were lower in the severe and moderate groups compared to the mild group, showing significant differences (P < 0.05). The severe group exhibited higher levels of NLRP3, ASC, Caspase-1, and EPO than the moderate group, while the VEGF levels were lower in the severe group compared to the moderate group, showing significant differences (P < 0.05). The peak systolic velocity(PSV) and resistance index (RI) were higher in the severe and moderate groups than in the mild group, whereas the EDV was significantly lower in the severe and moderate groups compared to the mild group (P < 0.05). The severe group exhibited higher PSV and RI values compared to the moderate group, while the EDV was lower in the severe group compared to the moderate group, showing significant differences (P < 0.05). Pearson correlation analysis was performed to examine the relationship between VEGF, NLRP3, EPO levels, and ocular hemodynamics in patients with POAG. VEGF, NLRP3, ASC, Caspase-1, and EPO showed positive correlations with PSV and RI, and negative correlations with EDV in patients with POAG. Regression analysis showed that VEGF, NLRP3, ASC, Caspase-1 and EPO were significantly correlated with ocular hemodynamics in POAG (all P < 0.001). CONCLUSION: We demonstrated that the levels of VEGF, NLRP3 inflammatory complex, and EPO were highly associated with ocular hemodynamics in patients diagnosed with POAG.
Asunto(s)
Eritropoyetina , Glaucoma de Ángulo Abierto , Hemodinámica , Presión Intraocular , Proteína con Dominio Pirina 3 de la Familia NLR , Factor A de Crecimiento Endotelial Vascular , Humanos , Masculino , Femenino , Eritropoyetina/sangre , Eritropoyetina/metabolismo , Glaucoma de Ángulo Abierto/fisiopatología , Glaucoma de Ángulo Abierto/sangre , Glaucoma de Ángulo Abierto/metabolismo , Factor A de Crecimiento Endotelial Vascular/sangre , Persona de Mediana Edad , Estudios Prospectivos , Hemodinámica/fisiología , Presión Intraocular/fisiología , Anciano , Campos Visuales/fisiología , Biomarcadores/sangreRESUMEN
We aimed to compare the clinical efficacy and safety of roxadustat with erythropoiesis-stimulating agents, particularly erythropoietin (EPO), in the treatment of maintenance hemodialysis patients with renal anemia. A prospective cohort study was carried out at the Nephrology Department of the Nantong First People's Hospital and Nantong University Affiliated Hospital from December 2020 to December 2021. We compared hemoglobin (Hb) levels, serum ferritin (SF) levels, and adverse cardiovascular events between the roxadustat and EPO groups at 1, 3, and 6 months into the treatment. A total of 209 patients participated in the study, with 112 in the roxadustat group and 97 in the EPO group. At baseline, no statistically significant differences were observed between the 2 groups in terms of age, gender, weight, dialysis modality and duration, previous EPO dosage, Hb levels, SF levels, transferrin saturation, heart function classification, and blood pressure levels (Pâ >â .05). After 1 month, Hb levels in the roxadustat group were significantly higher than those in the EPO group (Pâ <â .05). However, no statistically significant differences were found between the 2 groups at 3 and 6 months (Pâ >â .05). Additionally, there were no significant differences in SF levels and the occurrence of adverse cardiovascular events between the 2 groups after treatment (Pâ >â .05). Roxadustat was superior to EPO in the initial treatment phase, while its cardiovascular safety was comparable to that of EPO.
Asunto(s)
Anemia , Hemoglobinas , Isoquinolinas , Diálisis Renal , Humanos , Masculino , Femenino , Diálisis Renal/efectos adversos , Anemia/tratamiento farmacológico , Anemia/etiología , Persona de Mediana Edad , Estudios Prospectivos , Isoquinolinas/uso terapéutico , Isoquinolinas/efectos adversos , Isoquinolinas/administración & dosificación , Hemoglobinas/análisis , Hemoglobinas/metabolismo , Anciano , Eritropoyetina/uso terapéutico , Hematínicos/uso terapéutico , Hematínicos/efectos adversos , Hematínicos/administración & dosificación , Glicina/análogos & derivados , Glicina/uso terapéutico , Ferritinas/sangre , Resultado del TratamientoRESUMEN
The objective of this study was to examine the effect of consuming ketone monoester plus a high dose of carbohydrate from glucose (KE + CHO) on the change in erythropoietin (EPO) concentrations during load carriage exercise compared with carbohydrate (CHO) alone. Using a randomized, crossover design, 12 males consumed KE + CHO (573 mg KE/kg body mass, 110 g glucose) or CHO (110 g glucose) 30 min before 4 miles of self-paced treadmill exercise (KE + CHO:51 ± 13%, CHO: 52 ± 12% VÌO2peak) wearing a weighted vest (30% body mass; 25 ± 3 kg). Blood samples for analysis were obtained under resting fasted conditions before (Baseline) consuming the KE + CHO or CHO supplement and immediately after exercise (Post). ßHB increased (p < 0.05) from Baseline to Post in KE + CHO, with no change in CHO. Glucose and glycerol increased (p < 0.05) from Baseline to Post in CHO, with no effect of time in KE + CHO. Insulin and lactate increased (p < 0.05) from Baseline to Post independent of treatment. EPO increased (p < 0.05) from Baseline to Post in KE + CHO and CHO with no difference between treatments. Although KE + CHO altered ßHB, glucose, and glycerol concentrations, results from this study suggest that KE + CHO supplementation before load carriage exercise does not enhance immediate post-exercise increases in EPO compared with CHO alone.
Asunto(s)
Suplementos Dietéticos , Eritropoyetina , Ejercicio Físico , Glucosa , Humanos , Masculino , Eritropoyetina/administración & dosificación , Eritropoyetina/sangre , Ejercicio Físico/fisiología , Adulto , Glucosa/metabolismo , Glucosa/administración & dosificación , Glucemia/metabolismo , Estudios Cruzados , Cetonas/sangre , Cetonas/administración & dosificación , Adulto Joven , Carbohidratos de la Dieta/administración & dosificación , Ácido Láctico/sangre , Insulina/sangreRESUMEN
The clinical treatment of bone defects includes allogeneic bone transplantation and autologous bone transplantation. However, they all have their own limitations, and the scope of application is limited. In recent years, bone tissue engineering scaffolds based on a variety of materials have been well developed and achieved good bone regeneration ability. However, most scaffold materials always face problems such as high biotoxicity, leading to inflammation and poor bioactivity, which limits the bone regeneration effect and prolongs the bone regeneration time. In our work, we prepared hydroxyapatite, erythropoietin (EPO), and osteogenic growth peptide (OGP) codoped type-I collagen (Col I) polypeptide nanofiber membranes (NFMs) by electrostatic spinning. In cell experiments, the composite NFMs had low cytotoxicity and promoted osteogenic differentiation of rat bone marrow mesenchymal stem cells. Quantitative real-time polymerase chain reaction and alkaline phosphatase staining confirmed the high expression of osteogenic genes, and alizarin red S staining directly confirmed the appearance of calcium nodules. In animal experiments, the loaded hydroxyapatite formed multiple independent mineralization centers in the defect center. Under the promotion of Col I, EPO, and OGP, the bone continued to grow along the mineralization centers as well as inward the defect edge, and the bone defect completely regenerated in about two months. The hematological and histological analyses proved the safety of the experiments. This kind of design to promote bone regeneration by simulating bone composition, introducing mineralization center and signal molecules, can shorten repair time, improve repair effect, and has good practical prospects in the future.
Asunto(s)
Regeneración Ósea , Colágeno Tipo I , Durapatita , Células Madre Mesenquimatosas , Nanofibras , Osteogénesis , Nanofibras/química , Animales , Regeneración Ósea/efectos de los fármacos , Colágeno Tipo I/metabolismo , Colágeno Tipo I/química , Colágeno Tipo I/farmacología , Colágeno Tipo I/genética , Osteogénesis/efectos de los fármacos , Durapatita/química , Durapatita/farmacología , Ratas , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Diferenciación Celular/efectos de los fármacos , Andamios del Tejido/química , Ingeniería de Tejidos/métodos , Péptidos/farmacología , Péptidos/química , Eritropoyetina/química , Ratas Sprague-Dawley , Péptidos y Proteínas de Señalización Intercelular/farmacología , Masculino , Membranas Artificiales , HistonasRESUMEN
Enucleated erythrocytes are characteristic of adult mammals. In contrast, fish, amphibians, reptiles, birds, and fetal mammals possess nucleated erythrocytes in their circulation. Erythroid maturation is regulated by erythropoietin (EPO) and its receptor (EPOR), which are conserved among vertebrates. In mammals, EPOR on the erythroid progenitor membrane disappears after terminal differentiation. However, in western clawed frog, Xenopus tropicalis, mature erythrocytes maintain EPOR expression, suggesting that they have non-canonical functions of the EPO-EPOR axis rather than proliferation and differentiation. In this study, we investigated the non-canonical functions of EPOR in Xenopus mature erythrocytes. EPO stimulation of peripheral erythrocytes did not induce proliferation but induced phosphorylation of intracellular proteins, including signal transducer and activator of transcription 5 (STAT5). RNA-Seq analysis of EPO-stimulated peripheral erythrocytes identified 45 differentially expressed genes (DEGs), including cytokine inducible SH2 containing protein gene (cish) and suppressor of cytokine signaling 3 gene (socs3), negative regulators of the EPOR-Janus kinase (JAK)-STAT pathway. These phosphorylation studies and pathway analysis demonstrated the activation of the JAK-STAT pathway through EPO-EPOR signaling in erythrocytes. Through comparison with EPO-responsive genes in mouse erythroid progenitors obtained from a public database, we identified 31 novel EPO-responsive genes indicating non-canonical functions. Among these, we focused on ornithine decarboxylase 1 gene (odc1), which is the rate-limiting enzyme in polyamine synthesis and affects hematopoietic progenitor differentiation and the endothelial cell response to hypoxic stress. An EPO-supplemented culture of erythrocytes showed increased odc1 expression followed by a decrease in polyamine-rich erythrocytes, suggesting EPO-responsive polyamine excretion. These findings will advance our knowledge of the unknown regulatory systems under the EPO-EPOR axis and functional differences between vertebrates' nucleated and enucleated erythrocytes.
Asunto(s)
Eritrocitos , Eritropoyetina , Receptores de Eritropoyetina , Xenopus , Animales , Eritropoyetina/metabolismo , Eritropoyetina/genética , Receptores de Eritropoyetina/metabolismo , Receptores de Eritropoyetina/genética , Eritrocitos/metabolismo , Transducción de Señal , Regulación de la Expresión Génica , Eritroblastos/metabolismoRESUMEN
BACKGROUND: Recent studies have reported that helix B surface polypeptide (HBSP), an erythropoietin derivative, exhibits strong tissue protective effects, independent of erythropoietic effects, in a renal ischemia-reperfusion (IR) injury model. Meanwhile, the transforming growth factor-ß (TGF-ß) superfamily member glial cell line-derived neurotrophic factor (GDNF) demonstrated protective effect on podocytes in vitro. Using a rat puromycin aminonucleoside nephropathy (PAN) model, this study observed the renal protective effect of HBSP and investigated its renal protective effect on podocytes and mechanism related to GDNF. METHODS: Rats nephropathy model was induced by injection of 60 mg/kg of PAN via the tail vein. Rats in the PAN + HBSP group were injected intraperitoneally with HBSP (8 nmol/kg) 4 h before the model was induced, followed by intraperitoneal injections of HBSP once every 24 h for 7 consecutive days. The 24-hour urinary protein level was measured once every other day, and blood and renal tissue samples were collected on the 7th day for the examination of renal function, complete blood count, renal pathological changes and the expression levels of GDNF. RESULTS: Compared with the control group, the PAN nephropathy rat model showed a large amount of urinary protein. The pathological manifestations were mainly extensive fusion and disappearance of foot processes, along with vacuolar degeneration of podocytes and their separation from the glomerular basement membrane. GDNF expression was upregulated. Compared with the PAN + vehicle group, the PAN + HBSP group showed decreased urinary protein (p < 0.05). Pathological examination revealed ameliorated glomerular injury and vacuolar degeneration of podocytes. The expression of GDNF in the PAN nephropathy group was increased, when compared with the control group. The greatest expression of GDNF observed in the PAN + HBSP group (p < 0.05). CONCLUSIONS: The expression of GDNF in the kidney of PAN rat model was increased. HBSP reduced urinary protein, ameliorated pathological changes in renal podocytes, increased the expression of GDNF in the PAN rat model. HBSP is likely to exert its protective effects on podocytes through upregulation of GDNF expression.
Asunto(s)
Modelos Animales de Enfermedad , Factor Neurotrófico Derivado de la Línea Celular Glial , Enfermedades Renales , Podocitos , Puromicina Aminonucleósido , Ratas Sprague-Dawley , Animales , Ratas , Podocitos/efectos de los fármacos , Podocitos/patología , Podocitos/metabolismo , Masculino , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/patología , Riñón/patología , Riñón/efectos de los fármacos , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Eritropoyetina , Fragmentos de PéptidosRESUMEN
Exercise-induced inflammation can influence iron metabolism. Conversely, the effects of vitamin D3, which possesses anti-inflammatory properties, on ultramarathon-induced heart damage and changes in iron metabolism have not been investigated. Thirty-five healthy long-distance semi-amateur runners were divided into two groups: one group received 150,000 IU of vitamin D3 24 h prior to a race (n = 16), while the other group received a placebo (n = 19). Serum iron, hepcidin (HPC), ferritin (FER), erythroferrone (ERFE), erythropoietin (EPO), neopterin (NPT), and cardiac troponin T (cTnT) levels were assessed. A considerable effect of ultramarathon running on all examined biochemical markers was observed, with a significant rise in serum levels of ERFE, EPO, HPC, NPT, and cTnT detected immediately post-race, irrespective of the group factor. Vitamin D3 supplementation showed a notable interaction with the UM, specifically in EPO and cTnT, with no other additional changes in the other analysed markers. In addition to the correlation between baseline FER and post-run ERFE, HPC was modified by vitamin D. The ultramarathon significantly influenced the EPO/ERFE/HPC axis; however, a single substantial dose of vitamin D3 had an effect only on EPO, which was associated with the lower heart damage marker cTnT after the run.
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Biomarcadores , Colecalciferol , Suplementos Dietéticos , Hierro , Carrera de Maratón , Humanos , Colecalciferol/administración & dosificación , Método Doble Ciego , Masculino , Hierro/sangre , Hierro/administración & dosificación , Adulto , Femenino , Biomarcadores/sangre , Persona de Mediana Edad , Carrera/fisiología , Hepcidinas/sangre , Troponina T/sangre , Cardiopatías/prevención & control , Cardiopatías/etiología , Eritropoyetina/sangre , Eritropoyetina/administración & dosificaciónRESUMEN
INTRODUCTION: In end stage renal disease )ESRD(, reduced EPO production resulted in decreased oxygen diffusion that cause Hypoxia-inducible factors (HIFs) stabilization. The mechanism of beneficial effects of H2S in chronic kidney disease (CKD) is the aim of the present study to examine the effects of the H2S donor sodium hydrosulfide (NaHS) on renal function parameters, oxidative stress indices and expression levels of HIF-2α gene and erythropoietin protein in 5/6 nephrectomy-induced chronic renal failure in rats. METHODS AND MATERIALS: Male rats were assigned into 3 groups (n = 8): Sham, CKD and NaHS groups. In the CKD group, 5/6 nephrectomy was performed. In the sham group, rats were anesthetized but 5/6 nephrectomy was not induced. In the NaHS group, 30 µmol/L of NaHS in drinking water for 8 weeks was adminstrated 4 weeks after 5/6 nephrectomy induction. At the end of the 12 week, blood and renal tissues were taken to evaluate renal function parameters, oxidative stress indices and expression levels of HIF-2α gene and erythropoietin protein. RESULTS: The induction of 5/6 nephrectomy significantly caused renal dysfunction, oxidative stress, increased HIF-2α gene expression and decreased erythropoietin levels in renal tissue samples. NaHS administration resulted in a marked improvement in renal function and oxidative stress indicators, a marked reduction in HIF-2α gene expression as well as an increase in erythropoietin protein levels in comparison with the CKD group. CONCLUSION: In this study, regional hypoxia and oxidative stress in CKD, may cause the stabilization of the HIFs complexes, although erythropoietin synthesis was not increased due to destructive effects of CKD on the kidney tissues. Administration of NaHS caused up-regulating HIF-erythropoietin signaling pathway.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Eritropoyetina , Sulfuro de Hidrógeno , Nefrectomía , Estrés Oxidativo , Insuficiencia Renal Crónica , Animales , Eritropoyetina/genética , Eritropoyetina/metabolismo , Eritropoyetina/farmacología , Masculino , Ratas , Sulfuro de Hidrógeno/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Estrés Oxidativo/efectos de los fármacos , Riñón/metabolismo , Riñón/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Sulfuros/farmacología , Modelos Animales de EnfermedadRESUMEN
The most popular treatment for end-stage renal illness is hemodialysis (HD). The study aimed to assess serum ferritin levels and their connection to Epoetin alfa resistance, along with exploring the link between hepatitis C virus, iron overload, and the prevalence of hepatitis C and B infections in chronic HD patients. This was a descriptive-analytical study conducted on 50 Patients with chronic kidney disease (CKD) who were on regular HD in the dialysis unit of Ibin Sina Teaching Hospital in Mosul City, Iraq. Out of 50 patients, 26 (52%) tested positive for Hepatitis C Virus (HCV) Antibody, 10 (20%) for Hepatitis B surface Antigen (HBsAg), and 14 (28%) tested negative for both. Higher serum iron and ferritin levels were found in HCV antibody-positive patients (p < 0.05). Despite Epoetin alfa treatment, patients with elevated ferritin levels exhibited lower Hemoglobin (HB) and Packed Cell Volume (p < 0.05). Non-diabetics exhibited significantly higher serum ferritin, Hemoglobin, Blood urea, and serum creatinine than diabetics (p < 0.05). A noteworthy association was seen between the quantity of blood transfusions and elevated levels of serum ferritin and total serum iron (p < 0.05). Most HD patients were anemic, with Hepatitis B and C prevalent. The main CKD causes were diabetes and hypertension. HCV-positive patients often showed mild to moderate iron overload, and high serum ferritin was linked to poor Epoetin alfa response. Dialysis can elevate blood urea, ferritin, and creatinine, worsening anemia. High ferritin levels may hinder response to Epoetin alfa and iron replacement. Excessive blood transfusions can lead to iron overload and inhibit erythropoiesis. Maintaining HB at 110-120 g/l improves quality of life and reduces anemia-related risks.
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Ferritinas , Hepatitis B , Hepatitis C , Diálisis Renal , Humanos , Diálisis Renal/efectos adversos , Ferritinas/sangre , Masculino , Femenino , Persona de Mediana Edad , Hepatitis C/sangre , Hepatitis C/complicaciones , Hepatitis B/sangre , Hepatitis B/complicaciones , Hepatitis B/epidemiología , Adulto , Hierro/sangre , Hemoglobinas/metabolismo , Hemoglobinas/análisis , Epoetina alfa/uso terapéutico , Hepacivirus , Anciano , Antígenos de Superficie de la Hepatitis B/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/complicaciones , Eritropoyetina/sangre , Eritropoyetina/uso terapéuticoRESUMEN
Historically, neonatal neuroscience boasted a robust and successful preclinical pipeline for therapeutic interventions, in particular for the treatment of hypoxic-ischemic encephalopathy (HIE). However, since the successful translation of therapeutic hypothermia (TH), several high-profile failures of promising adjunctive therapies, in addition to the lack of benefit of TH in lower resource settings, have brought to light critical issues in that same pipeline. Using recent data from clinical trials of erythropoietin as an example, the authors highlight several key challenges facing preclinical neonatal neuroscience for HIE therapeutic development and propose key areas where model development and collaboration across the field in general can ensure ongoing success in treatment development for HIE worldwide.
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Eritropoyetina , Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Humanos , Hipoxia-Isquemia Encefálica/terapia , Recién Nacido , Eritropoyetina/uso terapéutico , Hipotermia Inducida/métodos , Animales , Modelos Animales de EnfermedadRESUMEN
With significant advancements in understanding gene functions and therapy, the potential misuse of gene technologies, particularly in the context of sports through gene doping (GD), has come to the forefront. This raises concerns regarding the need for point-of-care testing of various GD candidates to counter illicit practices in sports. However, current GD detection techniques, such as PCR, lack the portability required for on-site multiplexed detection. In this study, we introduce an integrated microfluidics-based chip for multiplexed gene doping detection, termed MGD-Chip. Through the strategic design of hydrophilic and hydrophobic channels, MGD-Chip enables the RPA and CRISPR-Cas12a assays to be sequentially performed on the device, ensuring minimal interference and cross-contamination. Six potential GD candidates were selected and successfully tested simultaneously on the platform within 1 h. Demonstrating exceptional specificity, the platform achieved a detection sensitivity of 0.1 nM for unamplified target plasmids and 1 aM for amplified ones. Validation using mouse models established by injecting IGFI and EPO transgenes confirmed the platform's efficacy in detecting gene doping in real samples. This technology, capable of detecting multiple targets using portable elements, holds promise for real-time GD detection at sports events, offering a rapid, highly sensitive, and user-friendly solution to uphold the integrity of sports competitions.
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Técnicas Biosensibles , Sistemas CRISPR-Cas , Doping en los Deportes , Interacciones Hidrofóbicas e Hidrofílicas , Dispositivos Laboratorio en un Chip , Sistemas CRISPR-Cas/genética , Doping en los Deportes/prevención & control , Animales , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Ratones , Humanos , Eritropoyetina/genética , Eritropoyetina/análisis , Diseño de Equipo , Proteínas Asociadas a CRISPR/genética , Proteínas Bacterianas , EndodesoxirribonucleasasRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Jian-Pi-Yi-Shen (JPYS) formula is an effective herbal therapy against renal injury, and JPYS has been clinically applied to ameliorate chronic kidney disease (CKD) and CKD-associated anemia. Increasing evidence supports the link between renal fibrosis and anemia in CKD. JPYS possessed anti-fibrosis effects in experimental CKD. Nevertheless, research on the mechanisms of JPYS in ameliorating renal anemia (RA) through suppressing renal fibrosis remains to be clarified. AIM OF THE STUDY: Our study here was carried out to investigate the mechanisms of JPYS in protecting against RA. MATERIALS AND METHODS: An adenine-induced anemia model in rats with CKD at three different time points was established, and bio-samples taken from each group were analyzed. Biochemical analysis was employed to detect kidney function and hematological parameters. Masson staining was used to evaluate renal fibrosis of rats. Western blot and immunohistochemistry were utilized to evaluate the expressions of fibrotic markers, erythropoietin (EPO) and hypoxia inducible factor-2α (HIF-2α) in the kidneys of rats. Subsequently, transcriptomic analysis was conducted to disclose the possible mechanisms of JPYS in treating RA. Finally, the expression levels of key targets were analyzed and validated by using Western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS: JPYS treatment improved kidney function, suppressed renal fibrosis and enhanced hematological parameters in CKD rats. Moreover, JPYS treatment restored the increased expression levels of fibrotic markers and the declined EPO with time dependence. In parallel, data indicated JPYS treatment stimulated the translocation of HIF-2α into nucleus in the renal interstitium and thus promoted the expression of EPO. Transcriptomic profiling disclosed that activations of both nuclear factor kappa B (NF-κB) and transforming growth factor-ß (TGF-ß)/Smad pathways were closely associated with RA. Ultimately, experimental validation results presented that the increased expressions of target proteins from the above-mentioned two pathways in the kidneys were decreased significantly after JPYS treatment. CONCLUSION: Our findings suggest that JPYS may improve RA by alleviating renal fibrosis, and the mechanisms of which involve in inhibiting the NF-κB and TGF-ß/Smad pathways.