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Erythropoietin (EPO) is an evolutionarily conserved hormone well documented for its erythropoietic role via binding the homodimeric EPO receptor (EPOR) 2 . In past decades, evidence has proved that EPO acts far beyond erythropoiesis. By binding the tissue-protective receptor (TPR), EPO suppresses proinflammatory cytokines, protects cells from apoptosis and promotes wound healing. Very recently, new data revealed that TPR is widely expressed on a variety of immune cells, and EPO could directly modulate their activation, differentiation and function. Notably, nonerythropoietic EPO derivatives, which mimic the structure of helix B within EPO, specifically bind TPR and show great potency in tissue protection and immune regulation. These small peptides prevent the cardiovascular side effects of EPO and are promising as clinical drugs. This review briefly introduces the receptors and tissue-protective effects of EPO and its derivatives and highlights their immunomodulatory functions and application prospects.

Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in mammalian brain. In clinical settings, recombinant EPO treatment has revealed a remarkable improvement of cognition, but underlying mechanisms have remained obscure. Here, we show with a novel line of reporter mice that cognitive challenge induces local/endogenous hypoxia in hippocampal pyramidal neurons, hence enhancing expression of EPO and EPO receptor (EPOR). High-dose EPO administration, amplifying auto/paracrine EPO/EPOR signaling, prompts the emergence of new CA1 neurons and enhanced dendritic spine densities. Single-cell sequencing reveals rapid increase in newly differentiating neurons. Importantly, improved performance on complex running wheels after EPO is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. This suggests a model of neuroplasticity in form of a fundamental regulatory circle, in which neuronal networks—challenged by cognitive tasks—drift into transient hypoxia, thereby triggering neuronal EPO/EPOR expression. EPO treatment improves cognition, but underlying mechanisms were unknown. Here the authors describe a regulatory loop in which brain networks challenged by cognitive tasks drift into functional hypoxia that drives—via neuronal EPO synthesis—neurodifferentiation and dendritic spine formation.

Erythropoietin is a cytokine that binds to the Erythropoietin receptor and regulates the formation of erythroid cells during erythropoiesis in the bone marrow. However, many other organs and tissues express Erythropoietin and its receptor, such as the Nervous System, which principally regulates tissue protection. In the Central Nervous System, Erythropoietin is principally expressed by astrocytes, while neurons mainly express Erythropoietin receptors. Moreover, Erythropoietin acts as a pleiotropic molecule with neuroprotective effects, and its mechanisms of signal transduction pathways are defined, and there is a growing interest in its therapeutic potential. This review focuses on the role of Erythropoietin and its relationship with HIF1, PI3/Akt, GSK3B, JAK/STAT, and MAPKs signaling pathways that leads to cell survival after injury in the Central Nervous System. Knowledge of these signaling systems comprehensively could better guide EPO treatment to restoring different SNC alterations mediated by different insults.

Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.

Chemoresistance is the crux of clinical treatment failure of small‐cell lung cancer (SCLC). Cancer stem cells play a critical role in therapeutic resistance of malignant tumors. Studies have shown that the role of erythropoietin‐producing hepatocellular A2 (EphA2) in tumors is complex. This study aimed to test the hypothesis that ligand‐independent activation of EphA2 modulates chemoresistance by enhancing stemness in SCLC. We verified that EphA2 was activated in chemoresistance sublines in a ligand‐independent manner rather than a ligand‐dependent manner. Ligand‐independent EphA2 enhanced the expression of stemness‐associated biomarkers (CD44, Myc, and SOX2), accelerated epithelial–mesenchymal transition (EMT) and reinforced self‐renewal to drive the chemoresistance of SCLC, while the P817H mutant EphA2 neutralized intrinsic function. Co‐immunoprecipitation (co‐IP) and GST‐pull down experiments were conducted to verify that EphA2 directly interacted with PRMT1. Moreover, EphA2 increased the expression and activity of PRMT1. Whereafter, PRMT1 interacted with and methylated SOX2 to induce stemness and chemoresistance in SCLC. Pharmacological inhibition of EphA2 showed a synergistic anti‐tumor effect with chemotherapy in preclinical models, including patient‐derived xenograft (PDX) models. These findings highlight, for the first time, that the EphA2/PRMT1/SOX2 pathway induces chemoresistance in SCLC by promoting stemness. EphA2 is a potential therapeutic target in SCLC treatment. This study showed that ligand‐independent EphA2 induces chemoresistance in SCLC. Ligand‐independent EphA2 directly interacted with PRMT1, which augmented stemness to promote chemoresistance in SCLC while methylating SOX2 at R43. Finally, inhibition of EphA2 confirmed the anti‐tumor effect both in vitro and in vivo experiments.

Recombinant human erythropoietin (rh-EPO) has been shown to stimulate neurogenesis and angiogenesis, both of which play crucial roles in the repair of brain injuries. Previously, we observed that rh-EPO treatment effectively reduced brain damage and enhanced angiogenesis in a neonatal rat model of periventricular white matter damage (PWMD). The objective of this research is to investigate the specific mechanism through which rh-EPO regulates angiogenesis following PWMD in premature neonates. We conducted experiments utilizing a neonatal PWMD model. Following rh-EPO treatment, the levels of erythropoietin receptor (EPOR) were found to be increased in the damaged brain of rats. Although the total amount of extracellular signal-regulated kinase (ERK), a downstream protein in the EPO signaling pathway, remained unchanged, there was clear upregulation of phosphorylated ERK1 (p-ERK1) levels. The increase in levels of p-ERK1 was inhibited by an ERK kinase inhibitor, while the total amount of ERK remained unchanged. Conversely, the levels of EPOR were not affected by the inhibitor. Notably, the introduction of rh-EPO led to a significant increase in the frequency of angiogenesis-related cells and the expression levels of angiogenic factors. However, these effects were nullified when the ERK pathway was blocked. These findings indicate that rh-EPO enhances angiogenic responses through the EPOR-ERK1 pathway in a neonatal PWMD model.

The erythroid terminal differentiation program couples sequential cell divisions with progressive reductions in cell size. The erythropoietin receptor (EpoR) is essential for erythroblast survival, but its other functions are not well characterized. Here we use Epor −/− mouse erythroblasts endowed with survival signaling to identify novel non-redundant EpoR functions. We find that, paradoxically, EpoR signaling increases red cell size while also increasing the number and speed of erythroblast cell cycles. EpoR-regulation of cell size is independent of established red cell size regulation by iron. High erythropoietin (Epo) increases red cell size in wild-type mice and in human volunteers. The increase in mean corpuscular volume (MCV) outlasts the duration of Epo treatment and is not the result of increased reticulocyte number. Our work shows that EpoR signaling alters the relationship between cycling and cell size. Further, diagnostic interpretations of increased MCV should now include high Epo levels and hypoxic stress. Maturing erythroblasts become smaller with every cell division. Here, the authors show that Epo stimulation promotes cell division and also generates larger red cells, and that this occurs in mouse and human cells, suggesting that red cell size could be a diagnostic marker for hypoxic stress.

Acute kidney injury (AKI) is one of frequent complications of sepsis with high mortality. Mitochondria is the center of energy metabolism participating in the pathogenesis of sepsis-associated AKI, and SIRT1/PGC1-α signaling pathway plays a crucial role in the modulation of energy metabolism. Erythropoietin (EPO) exerts protective functions on chronic kidney disease. We aimed to assess the effects of EPO on cell damage and energy metabolism in a cell model of septic AKI. Renal tubular epithelial cells HK-2 were treated with LPS and human recombinant erythropoietin (rhEPO). Cell viability was detected by CCK-8 and mitochondrial membrane potential was determined using JC-1 fluorescent probe. Then the content of ATP, ADP and NADPH, as well as lactic acid, were measured for the assessment of energy metabolism. Oxidative stress was evaluated by detecting the levels of ROS, MDA, SOD and GSH. Pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, were measured with ELISA. Moreover, qRT-PCR and western blot were performed to detect mRNA and protein expressions. shSIRT1 was used to knockdown SIRT1, while EX527 and SR-18292 were applied to inhibit SIRT1 and PGC1-α, respectively, to investigate the regulatory mechanism of rhEPO on inflammatory injury and energy metabolism. In LPS-exposed HK-2 cells, rhEPO attenuated cell damage, inflammation and abnormal energy metabolism, as indicated by the elevated cell viability, the inhibited oxidative stress, cell apoptosis and inflammation, as well as the increased mitochondrial membrane potential and energy metabolism. However, these protective effects induced by rhEPO were reversed after SIRT1 or PGC1-α inhibition. EPO activated SIRT1/PGC1-α pathway to alleviate LPS-induced abnormal energy metabolism and cell damage in HK-2 cells. Our study suggested that rhEPO played a renoprotective role through SIRT1/PGC1-α pathway, which supported its therapeutic potential in septic AKI.

Cognitive functioning plays a significant role in determining an individual's quality of life, with cognitive decline being a major symptom of Alzheimer's disease (AD). Neurotrophic factors have been shown to reduce amyloid load and improve cognitive functioning in mouse models of AD; however, these studies have not examined whether combining two neurotrophic factors can enhance these benefits. Studies examining the neuroprotective properties of neurotrophic factors are also lacking. Here we investigate the neuroprotective potential of combining two neurotrophic factors, carbamoylated erythropoietin (CEPO) and insulin-like growth factor-1 (IGF-1), in AD. Male and female 5xFAD mice bred from both maternal and paternal origin were injected intraperitoneally with CEPO, IGF-1, CEPO+IGF-1, or vehicle starting at two months of age, before cognitive deficits are present, until nine months of age. Mouse behavior was analyzed using the open field and Morris Water Maze (MWM) tests at six and nine months of age to assess learning and memory. The brains were then removed to assess amyloid load and protein expression. We found that male 5xFAD mice showed behavioral deficits in the MWM starting at six months of age, and that CEPO and IGF-1 treatments, but not CEPO+IGF-1, could protect against those deficits. At nine months, the neurotrophic factor-treated male 5xFAD mice showed sustained improvement in the MWM test compared to the untreated 5xFAD mice. The female 5xFAD mice did not show behavioral deficits in the MWM until nine months. At this age, the neurotrophic factor-treated female 5xFAD mice did not show significantly different behavioral performance in the MWM test, indicating that these neurotrophic factors were ineffective at protecting against AD progression in female 5xFAD mice. We also perform a correlative neuroanatomical analysis of amyloid load. The data demonstrate a clear sex-specific difference in the neuroprotective effects of CEPO and IGF-1 in protecting against cognitive decline, with these neurotrophic factors being effective in male but not female mice. Our data also suggest that combining two neurotrophic factors may not be more effective than their individual treatment; however, more studies looking at different dosing and timing regimens should be pursued in the future.

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.