Computational analysis of ligand-receptor interactions in wild-type and mutant erythropoietin complexes

Pekas, Nicholas J; Newton, Samuel S

doi:10.2147/aabc.s177206

Cited by 4 publications

(7 citation statements)

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“…One of angiogenic factors in our body is erythropoietin, and it is the body’s natural control mechanism for adjusting red blood cell count in response to the stressor. However, several important effects of EPO in the body are independent of its hematopoietic activity, and this is how EPO causes diabetic retinopathy changes [5, 6].…”

Section: Introductionmentioning

confidence: 99%

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Serum erythropoietin concentration and its correlation with stage of diabetic retinopathy

et al. 2019

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BackgroundErythropoietin (EPO) is one of the systemic angiogenic factors, and its role in ocular angiogenesis and in diabetic retinopathy (DR) is not yet fully understood. The latest research data reveal a possible correlation of higher erythropoietin concentrations in the blood and in the eye with the development of more advanced stages of DR.The main aim of this work was to examine the possible influence of serum concentrations of erythropoietin on the development of diabetic retinopathy in patients with diabetes mellitus type 2.MethodsThe research involved 90 patients examined at the University Eye Clinic of the Clinical Center of Vojvodina, Novi Sad, Serbia. The first group comprised 60 patients with diabetes mellitus lasting for 10 years or more, with diabetic retinopathy. The second, control group consisted of 30 healthy individuals. In the first group of 60 patients with diabetes, 30 of them had non-proliferative diabetic retinopathy (NPDR), and 30 had proliferative diabetic retinopathy (PDR). Laboratory EPO serum levels were determined, and they were correlated to the stage of DR. Concentration of EPO was assessed by ELISA method.ResultsThe highest average concentration of EPO in serum (9.95 mIU/ml) was determined in the group of people with diabetes with PDR. The lowest average concentration of EPO in the serum (6.90 mIU/ml) was found in the control group. The average concentration of EPO in serum in the group of patients with diabetes with NPDR was 7.00 mIU/ml. The EPO concentration in serum was elevated in the group of PDR, and it was directly proportional to the level of the clinical stadium of PDR, being significantly higher in the moderate and severe subgroup of PDR comparing to the control healthy subjects, NPDR and mild PDR (p = 0.007).ConclusionsSignificantly elevated serum concentration of EPO in the advanced stages of DR, and positive correlation between EPO serum concentration and clinical stages of PDR, suggest that erythropoietin represents an important growth factor from blood, which plays a significant role in retinal ischemia and angiogenesis in diabetic retinopathy, especially in the proliferative stage of this disease.

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Section: Introductionmentioning

confidence: 99%

“…Erythropoietin is a glycoprotein by its structure, which is composed of 166 amino acids. It is a pleiotropic cytokine, and a hormone with the function of circulatory growth factor [6, 8]. It is produced mainly in the kidneys, with only in a small part in the liver (10%); the primary stimulus for its releasing is tissue hypoxia.…”

Section: Introductionmentioning

confidence: 99%

Serum erythropoietin concentration and its correlation with stage of diabetic retinopathy

et al. 2019

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“…However, several important effects of EPO in the body are independent of its hematopoietic activity, and this is how EPO causes diabetic retinopathy changes (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…(7) Erythropoietin is a glycoprotein by its structure, which is composed of 166 amino acids. It is a pleiotropic cytokine, and a hormone with the function of circulatory growth factor (6,8). It is produced mainly in the kidneys, with only in a small part in the liver (10%); the primary stimulus for its releasing is tissue hypoxia.…”

Section: Introductionmentioning

confidence: 99%

“…By binding to its receptor, erythropoietin activates physiological signalling cascade (including JAK 2 kinase signaltransducing, and STAT signalling cascade), as a response to hypoxia. There are recently discovered naturally occurring EPO mutations at specific activation sites of EPO, and this is how attenuation or modelling of EPO signalling in hematopoiesis leads to anaemia and other pathologic conditions (6).…”

Section: Introductionmentioning

confidence: 99%

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Serum Erythropoietin Concentration And Its Correlation With Stage Of Diabetic Retinopathy

Davidović

Babić

Jovanović

et al. 2019

Preprint

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Summary: Background: Erythropoietin (Epo) is one of systemic angiogenic factors, and its role in ocular angiogenesis and in diabetic retinopathy (DR) is not yet fully understood. Latest research data reveal possible correlation of higher EPO concentrations of erythropoietin in blood and in the eye, with more severe of stages of DR. The main aim of this work was to examine the possible influence of serum concentrations of erythropoietin on the development and stages of diabetic retinopathy in patients with diabetes mellitus type 2. Methods: The research involved 90 patients examined at University Eye Clinic in Clinical Center of Vojvodina in Novi Sad, Serbia. First group comprised of 60 patients with diabetes mellitus lasting 10 years or more, with diabetic retinopathy. Second, control group, consisted of 30 healthy individuals. In the first group of 60 diabetic patients, 30 of them had non-proliferative diabetic retinopathy (NPDR), and 30 had proliferative diabetic retinopathy (PDR). Laboratory EPO serum levels were determined, and they were correlated to the stage of DR. Concentration of EPO was assessed by ELISA method at the end of the study. Results: The highest average concentration of EPO in serum (9.95 mIU/ml) was determined in group of diabetics with PDR. The lowest average concentration of EPO in serum (6.90 mIU/ml) was found in control group. The average concentration of Epo in serum in group of diabetics with NPDR was 7.00 mIU/ml. EPO concentration in serum was elevated in group of PDR, and it was directly proportional to the level of clinical stadium of PDR, being significantly higher in moderate and severe subgroup of PDR comparing to control healthy subjects, NPDR and mild PDR (h=9.858, p=0.007). Conclusions: Significantly elevated serum concentration of EPO in advanced stages of DR, and positive correlation between EPO serum concentration and clinical stadium of PDR, suggest that erythropoietin presents one of the important growth factors from blood, which plays role in retinal ischemia and angiogenesis in diabetic retinopathy, especially in the proliferative stage of this disease. Keywords: diabetic retinopathy; erythropoietin; glycated hemoglobin; non-proliferative diabetic retinopathy; proliferative diabetic retinopathy.

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<p>Design and Development of a Behaviorally Active Recombinant Neurotrophic Factor</p>

Pekas¹,

Petersen²,

Sathyanesan³

et al. 2020

DDDT

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Introduction: Carbamoylated erythropoietin (CEPO) is a chemically engineered, nonhematopoietic derivative of erythropoietin (EPO) that retains its antidepressant and procognitive effects, which are attributed to the increased expression of neurotrophic factors like brain derived neurotrophic factor (BDNF), in the central nervous system. However, the chemical modification process which produces CEPO from erythropoietin (EPO) requires pure EPO as raw material, is challenging to scale-up and can also cause batch-to-batch variability. To address these key limitations while retaining its behavioral effects, we designed, expressed and analyzed a triple, glutamine, substitution recombinant mimetic of CEPO, named QPO. Methods and Materials: We employ a combination of computational structural biology, molecular, cellular and behavioral assays to design, produce, purify and test QPO. Results: QPO was shown to be a nonhematopoietic polypeptide with significant antidepressant-like and pro-cognitive behavioral effects in rodent assays while significantly upregulating BDNF expression in-vitro and in-vivo. The in-silico binding affinity analysis of QPO bound to the EPOR/EPOR homodimer receptor shows significantly decreased binding to Active Site 2, but not Active Site 1, of EPOR. Discussion: The results of the behavioral and gene expression analysis imply that QPO is a successful CEPO mimetic protein and potentially acts via a similar neurotrophic mechanism, making it a drug development target for psychiatric disorders. The decreased binding to Active Site 2 could imply that this active site is not involved in neuroactive signaling and could allow the development of a functional innate repair receptor (IRR) model. Substituting the three glutamine substitution residues with arginine (RPO) resulted in the loss of behavioral activity, indicating the importance of glutamine residues at those positions.

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Computational analysis of ligand-receptor interactions in wild-type and mutant erythropoietin complexes

Cited by 4 publications

References 20 publications

Serum erythropoietin concentration and its correlation with stage of diabetic retinopathy

Serum erythropoietin concentration and its correlation with stage of diabetic retinopathy

Serum Erythropoietin Concentration And Its Correlation With Stage Of Diabetic Retinopathy

<p>Design and Development of a Behaviorally Active Recombinant Neurotrophic Factor</p>

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