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1.
Sci Rep ; 12(1): 18565, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329181

RESUMO

Cytokine receptor-like factor 3 (CRLF3) is a conserved but largely uncharacterized orphan cytokine receptor of eumetazoan animals. CRLF3-mediated neuroprotection in insects can be stimulated with human erythropoietin. To identify mechanisms of CRLF3-mediated neuroprotection we studied the expression and proapoptotic function of acetylcholinesterase in insect neurons. We exposed primary brain neurons from Tribolium castaneum to apoptogenic stimuli and dsRNA to interfere with acetylcholinesterase gene expression and compared survival and acetylcholinesterase expression in the presence or absence of the CRLF3 ligand erythropoietin. Hypoxia increased apoptotic cell death and expression of both acetylcholinesterase-coding genes ace-1 and ace-2. Both ace genes give rise to single transcripts in normal and apoptogenic conditions. Pharmacological inhibition of acetylcholinesterases and RNAi-mediated knockdown of either ace-1 or ace-2 expression prevented hypoxia-induced apoptosis. Activation of CRLF3 with protective concentrations of erythropoietin prevented the increased expression of acetylcholinesterase with larger impact on ace-1 than on ace-2. In contrast, high concentrations of erythropoietin that cause neuronal death induced ace-1 expression and hence promoted apoptosis. Our study confirms the general proapoptotic function of AChE, assigns a role of both ace-1 and ace-2 in the regulation of apoptotic death and identifies the erythropoietin/CRLF3-mediated prevention of enhanced acetylcholinesterase expression under apoptogenic conditions as neuroprotective mechanism.


Assuntos
Acetilcolinesterase , Eritropoetina , Animais , Humanos , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Eritropoetina/genética , Eritropoetina/farmacologia , Eritropoetina/metabolismo , Neurônios/metabolismo , Receptores da Eritropoetina/genética , Receptores da Eritropoetina/metabolismo , Insetos/metabolismo , Hipóxia/metabolismo , Receptores de Citocinas/metabolismo
2.
Biomed Pharmacother ; 156: 113944, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36411630

RESUMO

BACKGROUND: Inflammatory Bowel Disease (IBD) is recognized as a group of chronic inflammatory disorders, localized in the gastrointestinal tract, which does not have a cure known. Indeed, the pharmacological approaches, commonly used, demonstrate significant toxicity, which highlights the need of investigating new possible treatments. Erythropoietin (EPO) is clinically used in anemic patients, with chronic renal insufficiency, due to its erythropoietic effect. However, it has also been described other non-erythropoietic effects, such as an anti-inflammatory role. There is already preclinical evidence about its anti-inflammatory effect in the IBD context, namely in an acute model of colitis in mice. Therefore, it is relevant to ascertain its anti-inflammatory effect in a chronic model, but mainly its hematopoietic side effect, during chronic treatment. AIM: This experiment aims to evaluate the efficacy and safety of EPO treatment in a chronic 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rodents. METHODS: The induction of chronic colitis consistedofn five weekly intrarectal administrations of 1% TNBS, and then mice were treated daily with 500 IU/Kg or 1000 IU/Kg of EPO, through intraperitoneal injections, for 14 days. RESULTS: EPO demonstrated a significant anti-inflammatory effect, translated by a significant reduction of the concentration oftumorr necrosis factor-α, fecal calprotectin, and fecal hemoglobin. Moreover, it has also been demonstrated to be safe, considering the cardiovascular system, in terms of extraintestinal manifestations, namely at renal and hepatic functions. CONCLUSIONS: EPO demonstrated to be a promising pharmacological approach to be considered in the management of IBD, being an interesting target for drug repositioning.


Assuntos
Colite , Eritropoetina , Doença Enxerto-Hospedeiro , Doenças Inflamatórias Intestinais , Camundongos , Animais , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/induzido quimicamente , Ácido Trinitrobenzenossulfônico , Colite/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Crônica , Eritropoetina/uso terapêutico
3.
Biomed Pharmacother ; 156: 113971, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36411647

RESUMO

BACKGROUND AND AIM: Gentamycin-induced nephrotoxicity is related to stimulation of oxidative stress and inflammatory cascades leading to apoptotic renal damage. Heme oxygenase-1 (HO-1) induction considered to be an adaptive response against oxidative tissue damage. Our study aimed to investigate the possible nephroprotective role of HO-1 inducers (hemin and erythropoietin (EPO)) and elucidate their potential underlying molecular mechanisms by assessing their antioxidant, anti-apoptotic, and anti-inflammatory properties. METHODS: Kidney function markers (urea and creatinine), lipid peroxidation and antioxidant markers (MDA and GPx), inflammation and apoptotic markers (IL-6 and Bcl-2), and the relative gene expression levels of Nrf2 and HO-1 were assessed. Histopathological changes of the kidney were examined. RESULTS: Nephrotoxic rats pretreated with hemin showed significant decrease in serum level of urea, creatinine, and MDA, compared to non-treated group. The kidney tissues also showed significant elevation of Bcl2 level, but significant decrease of IL-6, compared to non-treated group. Moreover, hemin pre-treatment significantly upregulated gene expression of Nrf2 and HO-1 in kidney tissue to near the normal control group. On the other hand, pretreatment with EPO showed significant upregulation of HO-1 gene expression but didn't show significant difference in Nrf2 gene expression compared to control group. The histopathological examination of kidney supported the biochemical results. CONCLUSION: The current results proved that hemin rather than EPO, showed reno-protective effects in rats, which was mediated by activation of Nrf2 signaling pathway. This could be also attributed to the observed anti-inflammatory, antioxidant, and anti-apoptotic properties of hemin. In this regard, EPO showed lower potency.


Assuntos
Eritropoetina , Heme Oxigenase-1 , Ratos , Animais , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Hemina/farmacologia , Antioxidantes/farmacologia , Creatinina , Interleucina-6/farmacologia , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Transdução de Sinais , Eritropoetina/farmacologia , Ureia
4.
Drugs ; 82(16): 1565-1589, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36350500

RESUMO

Chronic kidney disease (CKD) affects approximately 10% of the worldwide population; anaemia is a frequent complication. Inadequate erythropoietin production and absolute or functional iron deficiency are the major causes. Accordingly, the current treatment is based on iron and erythropoiesis stimulating agents (ESAs). Available therapy has dramatically improved the management of anaemia and the quality of life. However, safety concerns were raised over ESA use, especially when aiming to reach near-to-normal haemoglobin levels with high doses. Moreover, many patients show hypo-responsiveness to ESA. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors (HIF-PHIs) were developed for the oral treatment of anaemia in CKD to overcome these concerns. They simulate the body's exposure to moderate hypoxia, stimulating the production of endogenous erythropoietin. Some molecules are already approved for clinical use in some countries. Data from clinical trials showed non-inferiority in anaemia correction compared to ESA or superiority for placebo. Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors may also have additional advantages in inflamed patients, improving iron utilisation and mobilisation and decreasing LDL-cholesterol. Overall, non-inferiority was also shown in major cardiovascular events, except for one molecule in the non-dialysis population. This was an unexpected finding, considering the lower erythropoietin levels reached using these drugs due to their peculiar mechanism of action. More data and longer follow-ups are necessary to better clarifying safety issues and further investigate the variety of pathways activated by HIF, which could have either positive or negative effects and could differentiate HIF-PHIs from ESAs.


Assuntos
Anemia , Eritropoetina , Hematínicos , Inibidores de Prolil-Hidrolase , Insuficiência Renal Crônica , Humanos , Inibidores de Prolil-Hidrolase/farmacologia , Inibidores de Prolil-Hidrolase/uso terapêutico , Qualidade de Vida , Anemia/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Eritropoetina/uso terapêutico , Hematínicos/uso terapêutico , Ferro , Prolil Hidroxilases
5.
Vnitr Lek ; 68(7): 438-443, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36402568

RESUMO

Anaemia is a very common complication of chronic kidney disease (CKD) and renal failure. The view of the treatment of anaemia has changed considerably since the introduction of ESAs (erythropoiesis-stimulating agents) into clinical practice, and the safety of this treatment is now prioritised over complete normalisation of haemoglobin (Hb) values. Iron administration is the mainstay of treatment in this group of patients, with intravenous administration proving to be both more effective and safer in both predialysis and dialysis patients. In addition to the long-used ESAs, a number of new agents developed to favourably influence erythropoiesis have recently been tested for the correction of anaemia. Among those with the greatest potential are the HIF-stabilizers (roxadustat, molidustat, vadadustat and daprodustat), which act through stimulation of erythropoiesis genes and thus represent a novel mechanism of action in the treatment of anaemia. In phase 3 clinical trials, these agents have shown the same efficacy in increasing Hb levels as ESAs, but much emphasis has recently been placed on their safety profile. They are orally administered agents and some of them are already approved and used in clinical practice. The first of these, roxadustat, is currently reimbursed also in the Czech Republic. Other molecules affecting anaemia, such as sotatercept, have also been confirmed to be effective in phase 1 and 2 clinical trials and are awaiting results from larger randomised trials.


Assuntos
Anemia , Eritropoetina , Hematínicos , Inibidores de Prolil-Hidrolase , Insuficiência Renal Crônica , Humanos , Inibidores de Prolil-Hidrolase/uso terapêutico , Insuficiência Renal Crônica/complicações , Anemia/tratamento farmacológico , Anemia/etiologia , Hematínicos/uso terapêutico
6.
Pediatr Int ; 64(1): e15330, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36321339

RESUMO

BACKGROUND: Iron deficiency during infancy is associated with poor neurological development, but iron overload causes severe complications. Appropriate iron supplementation is therefore vital. Reticulocyte hemoglobin content (RET-He) provides a real-time assessment of iron status and chracterezes hemoglobin synthesis in preterm infants. However, the existing literature lacks detailed reports assessing chronological changes in RET-He. The aim of this study was to assess the chronological changes in RET-He during oral iron dietary supplementation, and concomitant therapy with recombinant human erythropoietin (rHuEPO) in preterm very low birthweight infants. METHODS: Very low birthweight infants, admitted to our neonatal intensive care unit were analyzed retrospectively. Hemoglobin (Hb), reticulocyte percentage (Ret), mean corpuscular volume, RET-He, serum iron (Fe), and serum ferritin were recorded. Data at birth (T0), the initial day of rHuEPO therapy (T1), the initial day of oral iron supplementation (T2), 1-2 weeks (T3), 3-4 weeks (T4), 5-6 weeks (T5), and 7-8 weeks (T6) from the initial day of oral iron supplementation were extracted, and their changes over time were examined. RESULTS: Reticulocyte hemoglobin content was highest at birth and declined rapidly thereafter, especially after starting rHuEPO therapy. There was no upward trend in RET-He after the initiation of oral iron supplementation, with a slower increase during 5-6 weeks after the initiation of iron therapy. CONCLUSIONS: During the treatment of anemia of prematurity, low RET-He levels may be prolonged. Anemia of prematurity should therefore be assessed and treated on a case-by-case basis, while considering the iron metabolic capacity of preterm infants.


Assuntos
Anemia Ferropriva , Anemia , Eritropoetina , Doenças do Prematuro , Lactente , Recém-Nascido , Humanos , Reticulócitos/química , Anemia Ferropriva/etiologia , Estudos Retrospectivos , Recém-Nascido Prematuro , Hemoglobinas/análise , Anemia/complicações , Ferro
7.
Ren Fail ; 44(1): 1595-1603, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36190833

RESUMO

BACKGROUND: Aluminum accumulation is a well-described complication in dialysis patients. Improvements in hemodialysis technology have possibly eliminated the occurrence of aluminum overload. Limited evidence suggests that aluminum overload may decline in the era of aluminum removal from dialysis fluids, even with the use of aluminum binders. METHODS: We examined the data from January 2014 to June 1, 2020, identified through our electronic records, to evaluate the desferrioxamine (DFO) test results for aluminum overload. The presentation and treatment of aluminum overload were recorded. RESULTS: Ninety-nine dialysis patients were enrolled for the DFO test. Forty-seven patients (47.5%) were identified as DFO test positive for aluminum overload, of which 14 (14/47) patients had symptoms, including one patient with an unexplained fracture, eight patients with unexplained anemia despite high-dose erythropoiesis-stimulating agents, and five patients with hypercalcemia (serum calcium >11 mg dL-1). None of the patients with aluminum overload developed encephalopathy. Only four of the 47 patients had microcytic anemia. Patients requiring longer treatments (>10 months versus <10 months) had similar basal serum aluminum (p = 0.219) but had an increase in serum aluminum after DFO (p = 0.041). Furthermore, the treatments decreased erythropoietin doses in the aluminum overload group, with serum total alkaline phosphatase levels <60 U L-1 (p = 0.028). CONCLUSION: We concluded that aluminum overload existed in the reverse osmosis dialysis era. In light of non-obvious symptoms, such as anemia and bone turnover change, serum aluminum in dialysis patients should be monitored in countries using aluminum-based phosphate binders, despite reverse osmosis dialysis.


Assuntos
Anemia , Eritropoetina , Fosfatase Alcalina , Alumínio/efeitos adversos , Compostos de Alumínio , Anemia/tratamento farmacológico , Cálcio , Desferroxamina/uso terapêutico , Humanos , Osmose , Fosfatos , Diálise Renal/efeitos adversos
8.
Front Immunol ; 13: 1010882, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211426

RESUMO

Hemolytic-uremic syndrome (HUS) can occur as a systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli and is characterized by microangiopathic hemolytic anemia and acute kidney injury. Hitherto, therapy has been limited to organ-supportive strategies. Erythropoietin (EPO) stimulates erythropoiesis and is approved for the treatment of certain forms of anemia, but not for HUS-associated hemolytic anemia. EPO and its non-hematopoietic analog pyroglutamate helix B surface peptide (pHBSP) have been shown to mediate tissue protection via an innate repair receptor (IRR) that is pharmacologically distinct from the erythropoiesis-mediating receptor (EPO-R). Here, we investigated the changes in endogenous EPO levels in patients with HUS and in piglets and mice subjected to preclinical HUS models. We found that endogenous EPO was elevated in plasma of humans, piglets, and mice with HUS, regardless of species and degree of anemia, suggesting that EPO signaling plays a role in HUS pathology. Therefore, we aimed to examine the therapeutic potential of EPO and pHBSP in mice with Stx-induced HUS. Administration of EPO or pHBSP improved 7-day survival and attenuated renal oxidative stress but did not significantly reduce renal dysfunction and injury in the employed model. pHBSP, but not EPO, attenuated renal nitrosative stress and reduced tubular dedifferentiation. In conclusion, targeting the EPO-R/IRR axis reduced mortality and renal oxidative stress in murine HUS without occurrence of thromboembolic complications or other adverse side effects. We therefore suggest that repurposing EPO for the treatment of patients with hemolytic anemia in HUS should be systematically investigated in future clinical trials.


Assuntos
Eritropoetina , Síndrome Hemolítico-Urêmica , Escherichia coli Shiga Toxigênica , Animais , Subunidade beta Comum dos Receptores de Citocinas , Eritropoetina/farmacologia , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Humanos , Camundongos , Oligopeptídeos , Receptores da Eritropoetina , Toxinas Shiga , Suínos
9.
Am J Hematol ; 97(11): 1404-1412, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36215667

RESUMO

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis.


Assuntos
Anemia , COVID-19 , Eritropoetina , Eritropoese/fisiologia , Hepcidinas , Humanos , Hipóxia , Inflamação , Ferro
10.
Ann Card Anaesth ; 25(4): 466-471, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36254912

RESUMO

Introduction: Preoperative anemia is an important and relatively common problem in patients undergoing cardiac surgery, and its treatment is crucial in improving postoperative outcomes. The use of recombinant erythropoietin is one of the suggested methods in this field. Therefore, in the present study, we sought to evaluate the effects of recombinant erythropoietin on hemoglobin (Hb) levels and blood transfusion needs in cardiac surgery in patients with preoperative anemia. Methods: This randomized nonblind clinical trial was performed on patients with mild-to-moderate anemia (Hb <12 g/dL in men and Hb <11 g/dL in women) undergoing cardiac surgery at a referral heart hospital (Tehran, Iran). The patients were randomly divided into two groups of 33 patients. In the intervention group, recombinant erythropoietin was administered at a dose of 500 IU/kg one to three days before surgery. Intra- and postoperative Hb levels and the need for blood transfusion were recorded during surgery and for 3 days afterward. Results: The use of packed red blood cells in the operating room was similar in the intervention and control groups (P = 0.156), but it was significantly lower in the intensive care unit in the intervention group (P = 0.030). The mean Hb, which was initially identical in the two groups (P > 0.05), showed a significantly lower decrease in the intervention group (P = 0.001). No significant differences were observed concerning other variables. Conclusions: The use of recombinant erythropoietin (500 IU/kg/day) one to three days before cardiac surgery in our anemic patients blunted a reduction in Hb levels and decreased blood transfusion needs.


Assuntos
Anemia , Procedimentos Cirúrgicos Cardíacos , Eritropoetina , Anemia/tratamento farmacológico , Transfusão de Sangue , Eritropoetina/uso terapêutico , Feminino , Hemoglobinas , Humanos , Irã (Geográfico) , Masculino , Proteínas Recombinantes/uso terapêutico
11.
Life Sci ; 310: 121124, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36306536

RESUMO

AIMS: While elevated hepcidin levels with inflammation have been postulated as a putative mechanism hindering effective erythropoiesis after intravenous (IV) iron therapy in anemic patients undergoing surgery, little is known about the concomitant changes in other major regulators affecting erythropoiesis. This study investigated the activities of relevant regulators after iron replenishment in a rat model of iron deficiency anemia with inflammation. MAIN METHODS: Inflammation was induced by administration of complete Freund's adjuvant (CFA) in male Sprague-Dawley rats. After 2 weeks of CFA treatment, the rats received IV iron (CFA­iron) or saline (CFA-saline). The control group received saline instead of CFA and iron (saline-saline). At 1, 3, and 10 days after iron or saline treatment, inflammatory cytokines, oxidative markers, iron profiles, hepcidin, erythropoietin (EPO), erythroferrone (ERFE), fibroblast growth factor 23 (FGF 23), and expression of mRNA and proteins in the liver involved in hepcidin signaling pathways were measured. KEY FINDINGS: CFA treatment and iron restriction decreased hemoglobin and serum iron levels, significantly increasing inflammatory and oxidative markers. Iron supplementation did not restore hemoglobin levels despite improved iron profiles. CFA injections increased hepcidin and FGF 23 levels and decreased EPO and ERFE levels, which further intensified after iron supplementation with concomitantly elevated levels of oxidative stress and inflammatory markers. SIGNIFICANCE: Under inflammatory conditions, IV iron administration exacerbated inflammatory and oxidative stress and did not resolve anemia, even under iron deficiency conditions. Iron therapy exerted adverse influences on the changes in key regulators toward impeding erythropoiesis that was already impeded by inflammation.


Assuntos
Anemia Ferropriva , Anemia , Eritropoetina , Deficiências de Ferro , Masculino , Ratos , Animais , Hepcidinas/metabolismo , Eritropoese , Ferro/metabolismo , Ratos Sprague-Dawley , Eritropoetina/farmacologia , Anemia Ferropriva/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/complicações , Hemoglobinas , Biomarcadores , Suplementos Nutricionais
12.
Kidney360 ; 3(9): 1511-1528, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36245647

RESUMO

Background: Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin by stimulating erythropoietin synthesis and improving iron availability through facilitation of iron uptake and/or release from stores. In this exploratory analysis, we assessed the effect of roxadustat treatment on laboratory parameters related to iron metabolism in patients with anemia of chronic kidney disease (CKD). Methods: Data were pooled from pivotal, randomized, phase 3 roxadustat trials: three placebo-controlled, double-blind trials in nondialysis-dependent (NDD) CKD and three open-label, active-comparator (epoetin alfa) trials in dialysis-dependent (DD) CKD. In this exploratory analysis, mean changes from baseline in hemoglobin, iron parameters, and hepcidin, and intravenous (iv) iron use were evaluated. Pooled results in NDD CKD and DD CKD patients are reported. Results: Overall, 4277 patients with NDD CKD and 3890 patients with DD CKD were evaluated. Hemoglobin increases with roxadustat treatment were accompanied by increases in serum iron and total iron-binding capacity (TIBC) and decreases in serum ferritin and hepcidin from baseline through week 52. With epoetin alfa, the hemoglobin increase was accompanied by decreases in serum ferritin and hepcidin, but serum iron decreased, and there was no change in TIBC. With placebo, there were no changes in hemoglobin, iron parameters, or hepcidin. During treatment, iv iron use was reduced with roxadustat versus placebo and epoetin alfa. Conclusions: In patients with NDD CKD and DD CKD, roxadustat treatment is associated with increases in serum iron and TIBC, accompanied by reduced hepcidin and indicative of improved iron kinetics. Patients treated with roxadustat achieved target hemoglobin levels with less iv iron use versus comparators. Practitioners treating patients with anemia of CKD with roxadustat should consider its unique effects when interpreting iron parameters.


Assuntos
Anemia , Eritropoetina , Inibidores de Prolil-Hidrolase , Insuficiência Renal Crônica , Humanos , Anemia/tratamento farmacológico , Epoetina alfa/metabolismo , Eritropoetina/metabolismo , Ferritinas/uso terapêutico , Glicina/análogos & derivados , Hemoglobinas/análise , Hepcidinas , Ferro/uso terapêutico , Isoquinolinas , Inibidores de Prolil-Hidrolase/uso terapêutico , Diálise Renal , Insuficiência Renal Crônica/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase III como Assunto
14.
EMBO J ; 41(22): e111038, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36215698

RESUMO

Impaired clearance of beta-amyloid (Aß) is a primary cause of sporadic Alzheimer's disease (AD). Aß clearance in the periphery contributes to reducing brain Aß levels and preventing Alzheimer's disease pathogenesis. We show here that erythropoietin (EPO) increases phagocytic activity, levels of Aß-degrading enzymes, and Aß clearance in peripheral macrophages via PPARγ. Erythropoietin is also shown to suppress Aß-induced inflammatory responses. Deletion of EPO receptor in peripheral macrophages leads to increased peripheral and brain Aß levels and exacerbates Alzheimer's-associated brain pathologies and behavioral deficits in AD-model mice. Moreover, erythropoietin signaling is impaired in peripheral macrophages of old AD-model mice. Exogenous erythropoietin normalizes impaired EPO signaling and dysregulated functions of peripheral macrophages in old AD-model mice, promotes systemic Aß clearance, and alleviates disease progression. Erythropoietin treatment may represent a potential therapeutic approach for Alzheimer's disease.


Assuntos
Doença de Alzheimer , Eritropoetina , Animais , Camundongos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Eritropoetina/farmacologia , Eritropoetina/uso terapêutico , Encéfalo/metabolismo , Macrófagos/metabolismo , Camundongos Transgênicos , Modelos Animais de Doenças
15.
Eur J Clin Pharmacol ; 78(12): 1867-1875, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36195739

RESUMO

PURPOSE: Anemia of chronic kidney disease (CKD) has traditionally been treated with recombinant human erythropoietin (rhEPO). Recently, daprodustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor, has also been shown to increase hematocrit. It remains unclear whether daprodustat or rhEPO should be the treatment of choice for anemia of CKD. We aimed to assess the efficacy and cardiovascular safety of daprodustat versus rhEPO in CKD patients. METHODS: Online databases were queried in April 2022 for articles comparing the efficacy and safety of daprodustat in DD-CKD and NDD-CKD subgroups. Results from trials were pooled using a random-effects model. RESULTS: Data on 8245 CKD patients from eight clinical trials were included. Our results show that in comparison to rhEPO, daprodustat maintained the same efficacy in increasing hemoglobin levels in both the DD-CKD (MD: 0.10; 95% CI [- 0.13,0.34]; p = 0.50) and NDD-CKD (MD: - 0.01; 95% CI [- 0.38,0.35]; p = 0.95) subgroups. Daprodustat significantly lowered hepcidin levels and significantly increased TIBC in both subgroups. Additionally, daprodustat significantly reduced the incidence of major adverse cardiovascular events (MACE) (RR: 0.89; 95% CI: 0.89-0.98; p = 0.02) and its myocardial infarction (MI) component (RR: 0.74; 95% CI: 0.59-0.92; p = 0.006) in the DD-CKD subgroup. CONCLUSION: Daprodustat has similar efficacy compared to rhEPO for the treatment of anemia of CKD. On treatment, the reduced experience of MACE was reported in DD-CKD patients as compared to rhEPO. Furthermore, effects on iron metabolism varied by parameter, with daprodustat being superior to rhEPO in some cases and inferior in others.


Assuntos
Anemia , Barbitúricos , Insuficiência Renal Crônica , Humanos , Anemia/tratamento farmacológico , Anemia/etiologia , Eritropoetina/uso terapêutico , Prolina Dioxigenases do Fator Induzível por Hipóxia , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Barbitúricos/uso terapêutico
16.
Int J Mol Sci ; 23(19)2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-36233351

RESUMO

Erythropoietin (EPO) is a pleiotropic cytokine that classically drives erythropoiesis but can also induce bone loss by decreasing bone formation and increasing resorption. Deletion of the EPO receptor (EPOR) on osteoblasts or B cells partially mitigates the skeletal effects of EPO, thereby implicating a contribution by EPOR on other cell lineages. This study was designed to define the role of monocyte EPOR in EPO-mediated bone loss, by using two mouse lines with conditional deletion of EPOR in the monocytic lineage. Low-dose EPO attenuated the reduction in bone volume (BV/TV) in Cx3cr1Cre EPORf/f female mice (27.05%) compared to controls (39.26%), but the difference was not statistically significant. To validate these findings, we increased the EPO dose in LysMCre model mice, a model more commonly used to target preosteoclasts. There was a significant reduction in both the increase in the proportion of bone marrow preosteoclasts (CD115+) observed following high-dose EPO administration and the resulting bone loss in LysMCre EPORf/f female mice (44.46% reduction in BV/TV) as compared to controls (77.28%), without interference with the erythropoietic activity. Our data suggest that EPOR in the monocytic lineage is at least partially responsible for driving the effect of EPO on bone mass.


Assuntos
Eritropoetina , Receptores da Eritropoetina , Animais , Eritropoetina/metabolismo , Eritropoetina/farmacologia , Feminino , Camundongos , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Receptores da Eritropoetina/genética , Receptores da Eritropoetina/metabolismo , Transdução de Sinais
17.
Bull Exp Biol Med ; 173(5): 633-635, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36210409

RESUMO

We studied the effect of preconditioning of human bone marrow mononuclear cells with erythropoietin on the immunophenotype of immunocompetent cells and paracrine activity of mouse splenocytes. The expression of erythropoietin receptors on immunocompetent human bone marrow cells was shown to change after a short-term (60 min) exposure to erythropoietin. The number of T helpers carrying erythropoietin receptors decreased and the number of T suppressors, B lymphocytes, and monocytes carrying erythropoietin receptors increased. The presence of 30% conditioned medium from human bone marrow mononuclear cells or 33.4 U/ml of erythropoietin reduced apoptosis/necrosis, increased intracellular activity of NADPH-dependent oxidoreductases of splenocytes, and did not affect oxidative phosphorylation (did not enhance lactate production and glucose uptake by cells).


Assuntos
Medula Óssea , Eritropoetina , Animais , Medula Óssea/metabolismo , Células da Medula Óssea , Meios de Cultivo Condicionados/metabolismo , Eritropoetina/metabolismo , Eritropoetina/farmacologia , Glucose/metabolismo , Humanos , Lactatos/metabolismo , Camundongos , NADP/metabolismo , Oxirredutases , Receptores da Eritropoetina/genética , Receptores da Eritropoetina/metabolismo , Baço
18.
Anal Chim Acta ; 1233: 340492, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36283781

RESUMO

Glycosylation is one of the most important post-translational modifications. However, the characterizations of glycopeptides, especially the negatively charged sialoglycopeptides that are associated with various diseases, remain challenging, due to the co-existence with high abundant peptides and the low ionization efficiency of sialoglycopeptides resulting from the carboxyl groups. Therefore, it is essential to develop an efficient enrichment method for sialoglycopeptides. Here, we present a novel derivatization-based enrichment method that can (i) identify linkage isomers of sialic acids by generating mass difference, (ii) unify the net charge of peptides into zero, and (iii) introduce positive charges to sialoglycopeptides by conjugating quaternary ammonium with sialic acid. The derivatization, termed derivatization of sialylated glycopeptides plus (DOSG+), enables efficient enrichment through electrostatic interaction using weak cation exchange (WCX) media. DOSG+ -based WCX enrichment was validated and optimized with samples derived from bovine fetuin. Peptides were removed efficiently (recovery rate <1%). The signal intensity of a selected model sialoglycopeptide was increased by ∼30% (suggesting recovery rate >100%). The method was employed on human alpha-1 acid glycoprotein (AGP), and recombinant human erythropoietin (EPO), demonstrating the application of DOSG+ -based WCX enrichment on complexed N-linked and O-linked sialoglycopeptides. The method is simple, efficient, and targets small-scale sialoglycopeptide enrichment.


Assuntos
Compostos de Amônio , Eritropoetina , Bovinos , Animais , Humanos , Glicopeptídeos/química , Sialoglicoproteínas/química , Ácido N-Acetilneuramínico , Ácidos Siálicos , Peptídeos , Cátions , Fetuínas
19.
Ren Fail ; 44(1): 1801-1810, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36305202

RESUMO

INTRODUCTION: We examined the combined effect of erythropoietin (EPO) hyporesponsiveness and low handgrip strength (HGS) on the prognosis of patients undergoing hemodialysis (HD). METHODS: We recruited patients with chronic kidney disease (CKD) Stage 5, who were undergoing HD at our dialysis clinic between January 2015 and March 2015 (n = 182). Patients of ≥20 years of age and who had been undergoing HD for ≧3 months at enrollment were eligible for inclusion. Seven patients treated with epoetin-ß pegol were excluded. First, the erythropoietin resistance index (ERI) and HGS were measured. The patients were stratified by the ERI of 9.44 (U/kg/week/g/dL), and by the HGS of 28 kg for men and 18 kg for women. We then observed death and cardiovascular disease (CVD), composite endpoint (deaths or CVD) for a median of 2 years. RESULTS: A total of 175 patients (male, n = 122; female, n = 53; age, 34-92 years) were included in the analysis. During the observation period of 24 months, 57 events (14 deaths and 43 CVD) were observed. High ERI and low HGS were associated with a high incidence of endpoints compared to low ERI and high HGS. Among the four groups classified by ERI and HGS values, the highest risk group was the high ERI/low HGS group (HR: 4.20 95% CI 2.12-8.33). CONCLUSIONS: EPO hyporesponsiveness combined with low HGS were found to be significant predictors of a poor outcome, and the synergistic effects of the two factors had stronger predictive ability than either single factor.


Assuntos
Doenças Cardiovasculares , Eritropoetina , Hematínicos , Falência Renal Crônica , Humanos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Hematínicos/farmacologia , Hematínicos/uso terapêutico , Força da Mão , Eritropoese , Estudos Prospectivos , Diálise Renal/efeitos adversos , Eritropoetina/uso terapêutico , Eritropoetina/farmacologia , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Prognóstico , Doenças Cardiovasculares/etiologia
20.
J Nanobiotechnology ; 20(1): 461, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36307805

RESUMO

BACKGROUND: Traumatic peripheral nerve injury (TPNI) is a major medical problem with no universally accepted pharmacologic treatment. We hypothesized that encapsulation of pro-angiogenic erythropoietin (EPO) in amphiphilic PLGA-PEG block copolymers could serve as a local controlled-release drug delivery system to enhance neurovascular regeneration after nerve injury. METHODS: In this study, we synthesized an EPO-PLGA-PEG block copolymer formulation. We characterized its physiochemical and release properties and examined its effects on functional recovery, neural regeneration, and blood vessel formation after sciatic nerve crush injury in mice. RESULTS: EPO-PLGA-PEG underwent solution-to-gel transition within the physiologically relevant temperature window and released stable EPO for up to 18 days. EPO-PLGA-PEG significantly enhanced sciatic function index (SFI), grip strength, and withdrawal reflex post-sciatic nerve crush injury. Furthermore, EPO-PLGA-PEG significantly increased blood vessel density, number of junctions, and myelinated nerve fibers after injury. CONCLUSION: This study provides promising preclinical evidence for using EPO-PLGA-PEG as a local controlled-release treatment to enhance functional outcomes and neurovascular regeneration in TPNI.


Assuntos
Lesões por Esmagamento , Eritropoetina , Traumatismos dos Nervos Periféricos , Neuropatia Ciática , Camundongos , Animais , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Preparações de Ação Retardada/farmacologia , Regeneração Nervosa , Neuropatia Ciática/tratamento farmacológico , Eritropoetina/farmacologia , Eritropoetina/química , Eritropoetina/uso terapêutico , Lesões por Esmagamento/tratamento farmacológico
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