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1.
Neurol Neuroimmunol Neuroinflamm ; 11(3): e200223, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38588480

RESUMO

BACKGROUND AND OBJECTIVES: Optic neuritis is the most common optic neuropathy in young adults and a frequent manifestation of multiple sclerosis. Its clinical course is pertinent to the design of visual pathway neuroprotection trials. METHODS: This is a secondary analysis of longitudinal data from the TONE trial, which included 103 patients from 12 German academic tertiary centers with acute unilateral optic neuritis as a clinically isolated syndrome and baseline high-contrast visual acuity <0.5 decimal. Patients were randomized to 1,000 mg methylprednisolone i.v./d plus either erythropoietin (33,000 IU/d) or placebo (saline solution) for 3 days. They were followed up at standardized intervals with a battery of tests including high-contrast visual acuity, low-contrast letter acuity, contrast sensitivity, visual fields, visual evoked potentials, and retinal optical coherence tomography. At 6 months, participants answered a standardized questionnaire on vision-related quality of life (NEI-VFQ 25). We describe the disease course with mixed-effects piecewise linear models and calculate structure-function correlations using Pearson r. Because erythropoietin had no effect on the visual system, we use pooled (treatment-agnostic) data. RESULTS: Patients experienced initial rapid and then decelerating improvements of visual function with thinning of inner and thickening of outer retinal layers. At 6 months, visual parameters were positively correlated with inner and negatively correlated with outer retinal thickness changes. Peripapillary retinal nerve fiber layer thinning predominantly occurred in sectors without previous swelling. At 6 months, macular ganglion cell and inner plexiform layer thinning was weakly correlated with the P100 peak time (r = -0.11) and moderately correlated with the amplitude of visual evoked potentials (r = 0.35). Only functional outcomes were at least moderately correlated with vision-related quality of life. DISCUSSION: The longitudinal data from this large study cohort may serve as a reference for the clinical course of acute optic neuritis. The pattern of correlation between visual evoked potentials and inner retinal thinning may argue that the latter is mostly due to ganglion cell loss, rather than dysfunction. Visual pathway neuroprotection trials with functional outcomes are needed to confirm that candidate drugs will benefit patients' vision-related quality of life. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov, NCT01962571.


Assuntos
Eritropoetina , Neurite Óptica , Adulto Jovem , Humanos , Qualidade de Vida , Potenciais Evocados Visuais , Neurite Óptica/tratamento farmacológico , Progressão da Doença , Eritropoetina/uso terapêutico
2.
PeerJ ; 12: e17123, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38560469

RESUMO

Background: The purpose of the present study was to investigate the effect of erythropoietin (EPO) on lung ischemia-reperfusion injury (LIRI). Methods: Sprague Dawley rats and BEAS-2B cells were employed to construct an ischemia-reperfusion (I/R)-induced model in vivo and in vitro, respectively. Afterward, I/R rats and tert-butyl hydroperoxide (TBHP)-induced cells were treated with different concentrations of EPO. Furthermore, 40 patients with LIRI and healthy controls were enrolled in the study. Results: It was observed that lung tissue damage, cell apoptosis and the expression of BAX and caspase-3 were higher in the LIRI model in vivo and in vitro than in the control group, nevertheless, the Bcl-2, FGF23 and FGFR4 expression level was lower than in the control group. EPO administration significantly reduced lung tissue damage and cell apoptosis while also up-regulating the expression of FGF23 and FGFR4. Rescue experiments indicated that EPO exerted a protective role associated with the FGF23/FGFR4/p-ERK1/2 signal pathway. Notably, the expression of serum EPO, FGF23, FGFR4 and Bcl-2 was decreased in patients with LIRI, while the expression of caspase-3 and BAX was higher. Conclusion: EPO could effectively improve LIRI, which might be related to the activation of the FGF23/FGFR4/p-ERK1/2 signaling pathway.


Assuntos
Eritropoetina , Traumatismo por Reperfusão , Animais , Humanos , Ratos , Proteína X Associada a bcl-2/metabolismo , Caspase 3/genética , Epoetina alfa/metabolismo , Eritropoetina/farmacologia , Isquemia , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais
4.
CNS Neurosci Ther ; 30(3): e14676, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38488446

RESUMO

AIM: To explore the neuroprotective effects of ARA290 and the role of ß-common receptor (ßCR) in a mouse model of middle cerebral artery occlusion (MCAO). METHODS: This study included male C57BL/6J mice that underwent MCAO and reperfusion. The neuroprotective effect of ARA290 on MCAO-induced brain injury was investigated using neurological function tests (Longa and modified neurological severity score). Cerebral infarction was examined by 2, 3, 5-triphenyl tetrazolium chloride staining, neuronal apoptosis was assessed by immunofluorescence staining, blood parameters were measured using a flow cytometry-based automated hematology analyzer, liquid chromatography with tandem mass spectrometry was used to identify the serum metabolomics signature, inflammatory cytokines and liver index were detected by commercially available kits, and the protein levels of the erythropoietin (EPO) receptor and ßCR were measured by western blot. RESULTS: ARA290 exerted a qualitatively similar neuroprotective effect after MCAO as EPO. ARA290 significantly reduced neuronal apoptosis and the level of inflammatory cytokines in the brain tissue. However, ARA290's neuroprotective effect was significantly suppressed following the injection of siRNA against ßCR. CONCLUSION: ARA290 provided a neuroprotective effect via ßCR in cerebral ischemic mice without causing erythropoiesis. This study provides novel insights into the role of ARA290 in ischemic stroke intervention.


Assuntos
Isquemia Encefálica , Eritropoetina , AVC Isquêmico , Fármacos Neuroprotetores , Oligopeptídeos , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Camundongos , Masculino , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Camundongos Endogâmicos C57BL , Eritropoetina/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Peptídeos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Citocinas , Encéfalo , Isquemia Encefálica/tratamento farmacológico
5.
J Psychopharmacol ; 38(4): 362-374, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38519416

RESUMO

BACKGROUND: Persistent cognitive impairment is frequent across bipolar disorder (BD) and major depressive disorder (MDD), highlighting an urgent need for pro-cognitive treatments. AIM: This study investigated effects of erythropoietin (EPO) on cognitive impairment and dorsal prefrontal cortex (dPFC) activity in affective disorders. METHODS: In this randomized, double-blinded, placebo-controlled trial, cognitively impaired patients with remitted BD or MDD received 1 weekly recombinant human EPO (40,000 IU/mL) or saline infusion for a 12-week period. Assessments were conducted at baseline, after 2 weeks of treatment (week 3), immediately after treatment (week 13) and at 6-months follow-up. Participants underwent functional MRI during performance on a n-back working memory (WM) task at baseline and week 3, and for a subgroup 6 weeks post-treatment (week 18). The primary outcome was a cognitive composite score at week 13, whereas secondary outcomes comprised sustained attention and functioning. WM-related dPFC activity was a tertiary outcome. RESULTS: Data were analysed for 101 of the 103 included patients (EPO, n = 58; saline, n = 43). There were no effects of EPO over saline on any cognitive or functional outcomes or on WM-related dPFC activity. CONCLUSIONS: The absence of treatment-related changes in cognition and neural activity was unexpected and contrasts with multiple previous preclinical and clinical studies. It is possible that the lack of effects resulted from a recent change in the manufacturing process for EPO. Nevertheless, the findings support the validity of dPFC target engagement as a biomarker model for pro-cognitive effects, according to which treatments that do not improve cognition should not modulate dPFC activity. TRIAL REGISTRATIONS: EudraCT no.: 2016-004023-24; ClinicalTrials.gov identifier: NCT03315897.


Assuntos
Disfunção Cognitiva , Transtorno Depressivo Maior , Eritropoetina , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Transtornos do Humor/tratamento farmacológico , Eritropoetina/farmacologia , Eritropoetina/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Cognição , Córtex Pré-Frontal , Resultado do Tratamento , Método Duplo-Cego
6.
Neurosurg Rev ; 47(1): 132, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38546884

RESUMO

This systematic review aims to summarize the findings from all clinical randomized trials assessing the efficacy of potential neuroprotective agents in influencing the outcomes of acute spinal cord injuries (SCI). Following the PRISMA guidelines, we conducted comprehensive searches in four electronic databases (PubMed, Scopus, Cochrane Library, and Web of Science) up to September 5th, 2023. Our analysis included a total of 30 studies. We examined the effects of 15 substances/drugs: methylprednisolone, tirilazad mesylate, erythropoietin, nimodipine, naloxone, Sygen, Rho protein antagonist, granulocyte colony-stimulating factor, autologous macrophages, autologous bone marrow cells, vitamin D, progesterone, riluzole, minocycline, and blood alcohol concentration. Notable improvements in neurological outcomes were observed with progesterone plus vitamin D and granulocyte colony-stimulating factor. In contrast, results for methylprednisolone, erythropoietin, Sygen, Rho Protein, and Riluzole were inconclusive, primarily due to insufficient sample size or outdated evidence. No significant differences were found in the remaining evaluated drugs. Progesterone plus vitamin D, granulocyte colony-stimulating factor, methylprednisolone, Sygen, Rho Protein, and Riluzole may enhance neurological outcomes in acute SCI cases. It is worth noting that different endpoints or additional subgroup analyses may potentially alter the conclusions of individual trials. Therefore, certain SCI grades may benefit more from these treatments than others, while the overall results may remain inconclusive.


Assuntos
Eritropoetina , Fármacos Neuroprotetores , Traumatismos da Medula Espinal , Humanos , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Concentração Alcoólica no Sangue , Progesterona/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Metilprednisolona/uso terapêutico , Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Vitamina D/uso terapêutico
7.
BMC Oral Health ; 24(1): 391, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38539151

RESUMO

BACKGROUND: Tongue is complex muscular organ that may be affected by recurrent or chronic ulcerations and malignances that require effective treatment to enhance healing and tissue regeneration. So, this study aimed to evaluate the efficiency of erythropoietin (EPO) hydrogel as an anti-inflammatory and an inducer of neovascularization during healing of induced rats' tongue defects. METHODS: Thirty six rats were divided into three groups; Group I (negative control): tongues were left without ulceration and received no treatment, Group II (positive control): tongue defects were prepared on the tongues' dorsal surfaces, measuring (5 mm × 2 mm) using a tissue punch rotary drill for standardization, and left untreated, Group III (EPO group): tongue defects were prepared as in group II, then injected circumferentially around wound margins with a single high dose of EPO hydrogel of 5000 U/kg on the day of defect preparation. Animals were euthanized on seventh and fourteenth days after treatment, tongue specimens were collected, and paraffin blocks were prepared and processed for histological assessment by hematoxylin and eosin stain and immunohistochemical evaluation of anti-iNOS and anti-VEGF followed by histomorphometrical analysis and the relevant statistical tests. RESULTS: At both time points, the EPO treated group showed significantly enhanced tissue regeneration marked by the histologically better regenerated tissue with well developed, thick walled and well-organized blood vessels and significant reduction in defect depth compared to positive control group. EPO group also showed significant decrease in iNOS and significant increase in VEGF antibodies indicating its anti-inflammatory and neovascularization effects respectively. CONCLUSION: EPO treatment can significantly accelerate regeneration and filling of tongue defects by reducing tissue inflammation and enhancing neovascularization. Therefore, EPO could be a potential therapeutic strategy for accelerating healing of tongue ulcers. However, further investigations are required to optimize the dose and unravel any potential side effects before its clinical application.


Assuntos
Eritropoetina , Hidrogéis , Ratos , Animais , Hidrogéis/farmacologia , Eritropoetina/farmacologia , Eritropoetina/uso terapêutico , Cicatrização , Anti-Inflamatórios/farmacologia , Língua
8.
Anal Chem ; 96(13): 5307-5314, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38504497

RESUMO

Gene doping involves the misuse of genetic materials to alter an athlete's performance, which is banned at all times in both human and equine sports. Quantitative polymerase chain reaction (qPCR) assays have been used to control the misuse of transgenes in equine sports. Our laboratory recently developed and implemented duplex as well as multiplex qPCR assays for transgenes detection. To further advance gene doping control, we have developed for the first time a sensitive and definitive PCR-liquid chromatography high-resolution tandem mass spectrometry (PCR-LC-HRMS/MS) method for transgene detection with an estimated limit of detection of below 100 copies/mL for the human erythropoietin (hEPO) transgene in equine plasma. The method involved magnetic-glass-particle-based extraction of DNA from equine plasma prior to PCR amplification with 2'-deoxyuridine 5'-triphosphate (dUTP) followed by treatments with uracil DNA glycosylase and hot piperidine for selective cleavage to give small oligonucleotide fragments. The resulting DNA fragments were then analyzed by LC-HRMS/MS. The applicability of this method has been demonstrated by the successful detection of hEPO transgene in a blood sample collected from a gelding (castrated male horse) that had been administered the transgene. This novel approach not only serves as a complementary method for transgene detection but also paves the way for developing a generic PCR-LC-HRMS/MS method for the detection of multiple transgenes.


Assuntos
Doping nos Esportes , Eritropoetina , Cavalos , Animais , Humanos , Masculino , Espectrometria de Massas em Tandem/métodos , Doping nos Esportes/prevenção & controle , Cromatografia Líquida/métodos , Eritropoetina/genética , Transgenes , DNA , Reação em Cadeia da Polimerase
9.
Int J Med Sci ; 21(4): 703-713, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38464833

RESUMO

Background: Renal anaemia and left ventricular hypertrophy are the main complications of chronic kidney disease and are shared among dialysis patients. This retrospective study aimed to compare the efficacies of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat and recombinant human erythropoietin in reversing ventricular remodeling in dialysis patients with renal anaemia. Methods: A total of 204 participants underwent baseline examinations, including echocardiograms and laboratory tests, before being administered either treatment for at least 24 weeks from January 2018 to October 2021, after which follow-up examinations were conducted at 6 months. Propensity score matching based on key variables included age, gender, cardiovascular diseases, cardiovascular medications, dialysis course and the vascular access at baseline was performed to include populations with similar characteristics between groups. Results: In total, 136 patients were included with roxadustat or recombinant human erythropoietin. The left ventricular mass index after treatment with roxadustat and recombinant human erythropoietin both significantly decreased after 6 months, but there was no significant difference in the change in left ventricular mass index between the two groups. In addition, the left ventricular end-diastolic diameters and left ventricular wall thickness, systolic blood pressure, and diastolic blood pressure significantly decreased in the roxadustat group. Roxadustat and recombinant human erythropoietin also increased haemoglobin significantly, but there was no significant difference in the change in haemoglobin between the two groups. The results of multiple linear regression showed that the change in haemoglobin was independent factor affecting the improvement of left ventricular mass index. Conclusions: The increase of haemoglobin was associated with improving left ventricular hypertrophy in dialysis patients. However, the beneficial effects between roxadustat and recombinant human erythropoietin on left ventricular mass index did not show clear superiority or inferiority in six months.


Assuntos
Anemia , Eritropoetina , Insuficiência Renal Crônica , Humanos , Anemia/tratamento farmacológico , Anemia/etiologia , Eritropoetina/uso terapêutico , Glicina/uso terapêutico , Hemoglobinas/análise , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Isoquinolinas/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Estudos Retrospectivos , Remodelação Ventricular
10.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473816

RESUMO

The term 'gene doping' is used to describe the use of any unauthorized gene therapy techniques. We developed a test for five likely candidate genes for equine gene doping: EPO, FST, GH1, IGF1, and ILRN1. The test is based on real-time polymerase chain reaction (PCR) and includes separate screening and confirmation assays that detect different unique targets in each transgene. For doping material, we used nonviral (plasmid) and viral (recombinant adeno-associated virus) vectors carrying complementary DNA for the targeted genes; the vectors were accurately quantified by digital PCR. To reduce non-specific amplification from genomic DNA observed in some assays, a restriction digest step was introduced in the PCR protocol prior to cycling to cut the amplifiable targets within the endogenous genes. We made the screening stage of the test simpler and faster by multiplexing PCR assays for four transgenes (EPO, FST, IGF1, and ILRN1), while the GH1 assay is performed in simplex. Both stages of the test reliably detect at least 20 copies of each transgene in a background of genomic DNA equivalent to what is extracted from two milliliters of equine blood. The test protocol was documented and tested with equine blood samples provided by an official doping control authority. The developed tests will form the basis for screening official horseracing samples in Australia.


Assuntos
Eritropoetina , Animais , Cavalos/genética , Eritropoetina/genética , Austrália , Plasmídeos , DNA/genética , Reação em Cadeia da Polimerase em Tempo Real
11.
Sci Adv ; 10(10): eadl2097, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38457493

RESUMO

Janus kinase 2 (JAK2) mediates type I/II cytokine receptor signaling, but JAK2 is also activated by somatic mutations that cause hematological malignancies by mechanisms that are still incompletely understood. Quantitative superresolution microscopy (qSMLM) showed that erythropoietin receptor (EpoR) exists as monomers and dimerizes upon Epo stimulation or through the predominant JAK2 pseudokinase domain mutations (V617F, K539L, and R683S). Crystallographic analysis complemented by kinase activity analysis and atomic-level simulations revealed distinct pseudokinase dimer interfaces and activation mechanisms for the mutants: JAK V617F activity is driven by dimerization, K539L involves both increased receptor dimerization and kinase activity, and R683S prevents autoinhibition and increases catalytic activity and drives JAK2 equilibrium toward activation state through a wild-type dimer interface. Artificial intelligence-guided modeling and simulations revealed that the pseudokinase mutations cause differences in the pathogenic full-length JAK2 dimers, particularly in the FERM-SH2 domains. A detailed molecular understanding of mutation-driven JAK2 hyperactivation may enable novel therapeutic approaches to selectively target pathogenic JAK2 signaling.


Assuntos
Eritropoetina , Janus Quinase 2 , Inteligência Artificial , Eritropoetina/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Mutação , Receptores da Eritropoetina/genética , Transdução de Sinais/genética , Humanos
12.
J Investig Med High Impact Case Rep ; 12: 23247096241231649, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38353220

RESUMO

Jehovah's Witnesses is a Christian denomination widely recognized for their steadfast refusal of blood transfusions, even when facing severe anemia. We describe a unique case of a 42-year-old Jehovah's Witness woman with severe iron deficiency anemia. She necessitated surgical correction of a malpositioned gastric band within the context of a complex necrotizing aspiration pneumonia secondary to esophageal obstruction. Medical management of this severe anemia has been a challenge as traditional approaches, like a blood transfusion, are not possible. Instead, a multifaceted approach has been described with intravenous iron infusions, recombinant human erythropoietin, vitamin B12, folate, and vitamin C administration. We emphasize the lack of consensus on guideline protocols regarding management of severe anemia for Jehovah's Witness patients and the subsequent need for more investigation into that matter. It also underscores the significance of respecting patient autonomy through close collaboration between patients and their health care providers to ensure effective patient-centered care.


Assuntos
Anemia , Eritropoetina , Testemunhas de Jeová , Laparoscopia , Abscesso Pulmonar , Feminino , Humanos , Adulto , Anemia/etiologia , Anemia/terapia , Transfusão de Sangue
13.
Exp Clin Transplant ; 22(Suppl 1): 323-331, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38385419

RESUMO

OBJECTIVES: Posttransplant anemia might be associated with cardiovascular morbidity and increased mortality. To our knowledge, the debate on anemia correction has neither been revisited nor decided definitively. We aimed to assess the effects of full correction of posttransplant anemia on the cardiovascular system and quality of life among renal transplant recipients with stable graft function who were using erythropoietin-stimulating agents. MATERIALS AND METHODS: We enrolled 247 kidney recipients with stable graft function to be assessed for anemia. Eligible patients were randomized to achieve targeted hemoglobin of 11 to 12 g/dL (group 1, n = 183) or of 13 to 15 g/dL (group 2, n = 64) with the use of erythropoietin-stimulating agents. Patients underwent monthly clinical and laboratory evaluations of kidney graft function. Quality of life and echocardiography were assessed at study start and at 12 months. RESULTS: The 2 groups were comparable regarding pretransplant characteristics. In group 2, we observed comparable posttransplant complications (P > .05) but better graft function at 6 months and better cardiac indexes at 1 year of the study (P < .05). At 12 months, quality of life had improved after full correction of posttransplant anemia in the renal transplant recipients who received erythropoietinstimulating agents. CONCLUSIONS: Full correction of posttransplant anemia in renal transplant recipients was associated with improved quality of life and cardiac indexes without an effect on cardiovascular comorbidity.


Assuntos
Anemia , Eritropoetina , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Estudos Prospectivos , Qualidade de Vida , Anemia/diagnóstico , Anemia/tratamento farmacológico , Anemia/etiologia , Eritropoetina/efeitos adversos , Transplantados
14.
Int J Mol Sci ; 25(3)2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38338786

RESUMO

In vivo iron levels can be adjusted through intestinal iron absorption to be maintained at a suitable level; however, optimal iron levels in hemodialysis (HD) patients are unclear. In this study, we investigated total body iron (TBI), calculated as the sum of red blood cell (RBC) iron and iron stores, during courses of low-dose oral iron replacement therapy, and evaluated in vivo iron sufficiency and its indicators in HD patients. We analyzed data on 105 courses of low-dose iron replacement therapy administered to 83 patients on maintenance HD over 7 months. We evaluated changes in TBI, RBC iron, and iron stores from the initiation of treatment to month 7 in two groups of patients, namely, iron-therapy responders and non-responders. TBI showed significant increases until month 4 and plateaued thereafter in iron-therapy responders, and tended to increase and then reached a similar plateau in non-responders (month 7: 1900 ± 447 vs. 1900 ± 408 mg). Steady-state TBI was strongly correlated with body surface area (y = 1628.6x - 791.91, R2 = 0.88, p < 0.001). We observed constant TBI during oral iron replacement therapy suggesting the activation of a "mucosal block". The results suggest that body surface area has utility for estimating the required TBI with regression equations.


Assuntos
Anemia Ferropriva , Eritropoetina , Falência Renal Crônica , Humanos , Ferro/metabolismo , Estudos Retrospectivos , Ferritinas , Diálise Renal/efeitos adversos , Anemia Ferropriva/tratamento farmacológico , Eritropoetina/metabolismo , Falência Renal Crônica/etiologia , Hemoglobinas/metabolismo
15.
Methods Mol Biol ; 2755: 249-264, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38319583

RESUMO

Cellular and tissue adaptations to oxygen deprivation (hypoxia) are necessary for both normal physiology and disease. Responses to hypoxia are initiated by the cellular oxygen sensors prolyl-4-hydroxylase domain (PHD) proteins 1-3 and factor inhibiting HIF (FIH). These enzymes regulate the transcription factor hypoxia-inducible factor (HIF) in a hypoxia-sensitive manner. FIH also regulates proteins outside the HIF pathway, including the deubiquitinase OTUB1. Numerous preclinical analyses have demonstrated that treatment with HIF hydroxylase inhibitors is beneficial and protective in many hypoxia-associated diseases. However, clinically available HIF hydroxylase inhibitors increase erythropoietin (EPO) gene expression and red blood cell production, which can be detrimental in hypoxia-associated conditions, such as ischemia/reperfusion injury of the heart or chronic inflammation. Our understanding of the relevance of FIH in (patho)physiology is only in its infancy, but FIH activity does not govern erythropoietin expression. Therefore, it is of prime interest to assess the relevance of FIH activity in (patho)physiology in detail, as it may contribute to developing novel therapeutic options for treating hypoxia-associated diseases that do not affect Epo regulation. Here, we describe specific protocols for two different methods to assess FIH enzymatic activity within cells, using a HIF-dependent firefly luciferase-reporter gene and an oxomer-dependent assay. Oxomers are oxygen-dependent stable protein oligomers formed by FIH, for example, with the deubiquitinase OTUB1. Oxomer formation directly depends on FIH activity, providing a suitable cellular readout for an easy-to-use analysis of FIH enzymatic activity in cellulo. These techniques permit an analysis of FIH activity toward HIF and outside the HIF pathway, allowing the investigation of FIH activity under different (patho)physiological conditions and assessment of novel (putative) inhibitors.


Assuntos
Eritropoetina , Humanos , Genes Reporter , Eritropoetina/genética , Oxigenases de Função Mista , Hipóxia , Oxigênio , Enzimas Desubiquitinantes
16.
Transfusion ; 64(3): 510-516, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38351735

RESUMO

BACKGROUND: Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with ABO major incompatibility is characterized by transfusion dependent anemia. No standard treatment existed for PRCA following allo-HSCT yet. STUDY DESIGN AND METHODS: We conducted a retrospective study, and reported our experience with the use of avatrombopag and lower dose rituximab to treat five patients with PRCA subsequent to major ABO-incompatible allo-HSCT. RESULTS: Five cases of PRCA were identified from 72 patients who underwent allo-HSCT with major or bidirectional ABO mismatch. Cumulative incidence at Day +60 was 6.9% (5/72) at our center. All donor and recipient blood groups were A+  and O+ , respectively. In the first three cases we reported, patients received erythropoietin, plasma exchange, and donor lymphocyte infusion, but none of them had any effect. After 4 weeks of treatment with low dose rituximab (100 mg/week) combined with avatrombopag (40 mg/day), favorable outcomes were obtained. According to the aforementioned experience, Cases 4 and 5 were administered low-dose rituximab and avatrombopag in 3 months after transplantation, and erythroid response was observed on 3 weeks after treatment. Our patients tolerated low-dose rituximab and avatrombopag well and experienced rapid efficacy, with a median duration of 3 weeks. Furthermore, no severe infection or thrombocytosis necessitated a dose adjustment. CONCLUSION: Low-dose rituximab and avatrombopag may be an effective treatment for patients with PRCA after major ABO-incompatible allo-HSCT. The patients should be treated at least 90 days post transplantation if conventional erythropoietin therapy fails.


Assuntos
Eritropoetina , Transplante de Células-Tronco Hematopoéticas , Aplasia Pura de Série Vermelha , Tiazóis , Tiofenos , Humanos , Rituximab/uso terapêutico , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Aplasia Pura de Série Vermelha/tratamento farmacológico , Sistema ABO de Grupos Sanguíneos , Incompatibilidade de Grupos Sanguíneos
17.
Diabetes Obes Metab ; 26(5): 1723-1730, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38326092

RESUMO

AIMS: To analyse the changes in erythropoietic and estimated fluid volume parameters after the initiation of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). METHODS: This was a post-hoc analysis of the PROCEED trial, which evaluated the effect of 24-week ipragliflozin treatment on endothelial dysfunction in patients with T2DM and CKD. We evaluated the changes in erythropoietic and estimated fluid volume parameters from baseline to 24 weeks post-treatment in 53 patients who received ipragliflozin (ipragliflozin group) and 55 patients with T2DM and CKD without sodium-glucose co-transporter 2 inhibitors (control group), a full analysis set of the PROCEED trial. RESULTS: The increases in haemoglobin [estimated group difference, 0.5 g/dl; 95% confidence interval (CI), 0.3-0.8; p < .001], haematocrit (estimated group difference, 2.2%; 95% CI, 1.3-3.1; p < .001) and erythropoietin (estimated log-transformed group difference, 0.1; 95% CI, 0.01-0.3; p = .036) were significantly greater in the ipragliflozin group than those in the control group. Ipragliflozin treatment was significantly associated with an increase in erythropoietin, independent of the corresponding change in haemoglobin (ß = 0.253, p < .001) or haematocrit (ß = 0.278, p < .001). Reductions in estimated plasma volume (estimated group difference, -7.94%; 95% CI, -11.6 to -4.26%; p < .001) and estimated extracellular volume (estimated group difference, -181.6 ml; 95% CI, -275.7 to -87.48 ml; p < .001) were significantly greater in the ipragliflozin group than those in the control group. CONCLUSIONS: Erythropoiesis was enhanced and estimated fluid volumes were reduced by ipragliflozin in patients with T2DM and CKD. CLINICAL TRIAL: PROCEED trial (registration number: jRCTs071190054).


Assuntos
Diabetes Mellitus Tipo 2 , Eritropoetina , Glucosídeos , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Simportadores , Tiofenos , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Eritropoese , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamente , Eritropoetina/uso terapêutico , Glucose/uso terapêutico , Hemoglobinas/uso terapêutico , Simportadores/uso terapêutico , Sódio , Hipoglicemiantes/uso terapêutico
18.
J Intern Med ; 295(5): 620-633, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38343089

RESUMO

BACKGROUND: Left ventricular hypertrophy (LVH) is highly prevalent in haemodialysis (HD) patients and is associated with an increased risk of death. Roxadustat and recombinant human erythropoietin (rHuEPO, abbreviated as EPO) are the main treatment strategies for renal anaemia in HD patients, but it has not been clear whether there is a difference in their effect on LVH. METHODS: In this multi-centre, prospective, randomized trial of 12-month duration, study participants were randomized in a 1:1 ratio to the roxadustat group or the EPO group. The doses of both treatment regimens were adjusted so that the patients had a haemoglobin level of 10.0-12.0 g per dL. The primary study endpoint was the change from baseline to 12 months in the left ventricular mass index (LVMI, g/m2) measured by echocardiography. RESULTS: In total, 114 patients were enrolled. The mean age was 50 years, and the median dialysis duration was 33 months. Sixty-one patients were men, and 24 were diabetic. LVMI decreased from 116.18 ± 27.84 to 110.70 ± 25.74 g/m2 in the roxadustat group. However, it increased from 109.35 ± 23.41 to 114.99 ± 28.46 g/m2 in the EPO group, with a significant difference in the change in LVMI between the two groups [-5.48 (-11.60 to 0.65) vs. 5.65 (0.74 to 10.55), p < 0.05]. Changes in left ventricular mass, end-diastolic volume and 6-min walk test seemed superior in the roxadustat group. There were no significant differences in other cardiac geometry, biochemical parameters and major adverse cardiovascular events between the two groups. CONCLUSIONS: Compared to EPO, roxadustat is more helpful in the regression of LVH in HD patients.


Assuntos
Anemia , Eritropoetina , Falência Renal Crônica , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Estudos Prospectivos , Diálise Renal/efeitos adversos , Anemia/etiologia , Anemia/complicações , Eritropoetina/uso terapêutico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/etiologia , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia
19.
J Vet Med Sci ; 86(4): 368-373, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38383003

RESUMO

Here we report a case series of two dogs diagnosed as renal interstitial cell tumor (RICT) accompanied by elevated serum erythropoietin level and marked polycythemia. RICT is a rare tumor in dogs, originating from renal interstitial cells. While several renal tumors such as renal lymphoma, adenocarcinoma, carcinoma, sarcoma, fibrosarcoma and nephroblastoma may cause polycythemia, polycythemia caused by RICT has never been reported in dogs. The tumors in both dogs were solitary and lied within cortex or cortico-medullary junction. Histopathology revealed spindle-shaped cells suggesting mesenchymal origin, with no mitotic figures suggesting that the tumors in both dogs were benign. Following surgical removal of the affected kidney, serum erythropoietin level and polycythemia normalized in both dogs.


Assuntos
Doenças do Cão , Eritropoetina , Neoplasias Renais , Tumor de Células de Leydig , Policitemia , Masculino , Cães , Animais , Policitemia/veterinária , Policitemia/complicações , Tumor de Células de Leydig/veterinária , Doenças do Cão/etiologia , Doenças do Cão/cirurgia , Neoplasias Renais/veterinária
20.
J Mol Cell Cardiol ; 188: 90-104, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38382296

RESUMO

The role of erythropoietin (EPO) has extended beyond hematopoiesis to include cytoprotection, inotropy, and neurogenesis. Extra-renal EPO has been reported for multiple tissue/cell types, but the physiological relevance remains unknown. Although the EPO receptor is expressed by multiple cardiac cell types and human recombinant EPO increases contractility and confers cytoprotection against injury, whether the heart produces physiologically meaningful amounts of EPO in vivo is unclear. We show a distinct circadian rhythm of cardiac EPO mRNA expression in adult mice and increased mRNA expression during embryogenesis, suggesting physiological relevance to cardiac EPO production throughout life. We then generated constitutive, cardiomyocyte-specific EPO knockout mice driven by the Mlc2v promoter (EPOfl/fl:Mlc2v-cre+/-; EPOΔ/Δ-CM). During cardiogenesis, cardiac EPO mRNA expression and cellular proliferation were reduced in EPOΔ/Δ-CM hearts. However, in adult EPOΔ/Δ- CM mice, total heart weight was preserved through increased cardiomyocyte cross-sectional area, indicating the reduced cellular proliferation was compensated for by cellular hypertrophy. Echocardiography revealed no changes in cardiac dimensions, with modest reductions in ejection fraction, stroke volume, and tachycardia, whereas invasive hemodynamics showed increased cardiac contractility and lusitropy. Paradoxically, EPO mRNA expression in the heart was elevated in adult EPOΔ/Δ-CM, along with increased serum EPO protein content and hematocrit. Using RNA fluorescent in situ hybridization, we found that Epo RNA colocalized with endothelial cells in the hearts of adult EPOΔ/Δ-CM mice, identifying the endothelial cells as a cell responsible for the EPO hyper-expression. Collectively, these data identify the first physiological roles for cardiomyocyte-derived EPO. We have established cardiac EPO mRNA expression is a complex interplay of multiple cell types, where loss of embryonic cardiomyocyte EPO production results in hyper-expression from other cells within the adult heart.


Assuntos
Células Endoteliais , Eritropoetina , Animais , Camundongos , Hiperplasia , Hibridização in Situ Fluorescente , Miócitos Cardíacos , RNA , RNA Mensageiro/genética
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