In light of the present therapeutic situation in COVID-19, any measure to improve course and outcome of seriously affected individuals is of utmost importance. We recap here evidence that supports the use of human recombinant erythropoietin (EPO) for ameliorating course and outcome of seriously ill COVID-19 patients. This brief expert review grounds on available subject-relevant literature searched until May 14, 2020, including Medline, Google Scholar, and preprint servers. We delineate in brief sections, each introduced by a summary of respective COVID-19 references, how EPO may target a number of the gravest sequelae of these patients. EPO is expected to: (1) improve respiration at several levels including lung, brainstem, spinal cord and respiratory muscles; (2) counteract overshooting inflammation caused by cytokine storm/ inflammasome; (3) act neuroprotective and neuroregenerative in brain and peripheral nervous system. Based on this accumulating experimental and clinical evidence, we finally provide the research design for a double-blind placebo-controlled randomized clinical trial including severely affected patients, which is planned to start shortly.

/pdf/erythropoietin-as-candidate-for-supportive-treatment-of-3k9e4f2g74.pdf

Erythropoietin as candidate for supportive treatment of severe COVID-19.

As major complications of chemoradiotherapy, myelosuppression and hematopoietic‐system damage severely affect immunologic function and can delay or even terminate treatment for cancer patients. Although several specific cytokines have been used for hematopoiesis recovery, their effect is limited, and they may increase the risk of tumor recurrence. In this study, osteogenic growth peptide functionalized tetrahedral framework nucleic‐acid nanostructures (OGP‐tFNAs) are prepared; they combine the positive hematopoiesis stimulating effect of OGP and the drug carrying function of tFNAs. The potential of OGP‐tFNAs for hematopoietic stimulation and microenvironment regulation is investigated. It is shown that OGP‐tFNAs can protect bone marrow stromal cells from 5‐fluorouracil (5‐FU)‐induced DNA damage and apoptosis. OGP‐tFNAs pretreatment activates the extracellularly regulated protein kinase signal and downregulates apoptosis‐related proteins. OGP‐tFNAs also alleviate the chemotherapy‐induced inhibition of hematopoiesis‐related cytokine expression, which is crucial for hematopoiesis reconstitution. In conclusion, OGP‐tFNAs can protect hematopoietic cells and their microenvironment from chemotherapy‐induced injuries and myelosuppression, while promoting hematopoiesis regeneration.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202202058

Myelosuppression Alleviation and Hematopoietic Regeneration by Tetrahedral‐Framework Nucleic‐Acid Nanostructures Functionalized with Osteogenic Growth Peptide

The role of CD71 + erythroid cells in the regulation of the immune response.

Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is produced in the kidney during the adult life and acts both as a peptide hormone and hematopoietic growth factor (HGF), stimulating bone marrow erythropoiesis. EPO production is activated by hypoxia and is regulated via an oxygen-sensitive feedback loop. EPO acts via its homodimeric erythropoietin receptor (EPO-R) that increases cell survival and drives the terminal erythroid maturation of progenitors BFU-Es and CFU-Es to billions of mature RBCs. This pathway involves the activation of multiple erythroid transcription factors, such as GATA1, FOG1, TAL-1, EKLF and BCL11A, and leads to the overexpression of genes encoding enzymes involved in heme biosynthesis and the production of hemoglobin. The detection of a heterodimeric complex of EPO-R (consisting of one EPO-R chain and the CSF2RB β-chain, CD131) in several tissues (brain, heart, skeletal muscle) explains the EPO pleotropic action as a protection factor for several cells, including the multipotent MSCs as well as cells modulating the innate and adaptive immunity arms. EPO induces the osteogenic and endothelial transdifferentiation of the multipotent MSCs via the activation of EPO-R signaling pathways, leading to bone remodeling, induction of angiogenesis and secretion of a large number of trophic factors (secretome). These diversely unique properties of EPO, taken together with its clinical use to treat anemias associated with chronic renal failure and other blood disorders, make it a valuable biologic agent in regenerative medicine for the treatment/cure of tissue de-regeneration disorders.

Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine

Currently there are approximately 291,000 people suffering from a spinal cord injury (SCI) in the United States. SCI is associated with traumatic changes in mobility and neuralgia, as well as many other long-term chronic health complications, including metabolic disorders, diabetes mellitus, non-alcoholic steatohepatitis, osteoporosis, and elevated inflammatory markers. Due to medical advances, patients with SCI survive much longer than previously. This increase in life expectancy exposes them to novel neurological complications such as memory loss, cognitive decline, depression, and Alzheimer's disease. In fact, these usually age-associated disorders are more prevalent in people living with SCI. A common factor of these disorders is the reduction in hippocampal neurogenesis. Inflammation, which is elevated after SCI, plays a major role in modulating hippocampal neurogenesis. While there is no clear consensus on the mechanism of the decline in hippocampal neurogenesis and cognition after SCI, we will examine in this review how SCI-induced inflammation could modulate hippocampal neurogenesis and provoke age-associated neurological disorders. Thereafter, we will discuss possible therapeutic options which may mitigate the influence of SCI associated complications on hippocampal neurogenesis.

/pdf/the-potential-role-of-inflammation-in-modulating-endogenous-3vofeuq7s0.pdf

The Potential Role of Inflammation in Modulating Endogenous Hippocampal Neurogenesis After Spinal Cord Injury.

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 and its derivatives: from tissue protection to immune regulation

Background The tumor immune microenvironment is vital to kidney renal clear cell carcinoma (KIRC) progression, and immunotherapies have been shown to be effective in the management of KIRC. However, the prognostic genes associated with the tumor immune microenvironment in KIRC have not been fully identified. We obtained the KIRC RNA sequencing data and the clinical characteristics from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) database. We screened the gene modules associated with the tumor immune microenvironment based on the ESTIMATE algorithm and weighted gene coexpression network analysis (WGCNA). Univariate Cox analysis and the LASSO method were used to construct a prognostic model. Receiver Operating Characteristic (ROC) curve analysis was performed to evaluate the accuracy of our risk model. TIMER and Single-Sample Gene Set Enrichment Analysis (ssGSEA) were used to explore the correlation between prognostic genes and immune cell infiltration. Results Fifty-four genes in modules were significantly associated with the overall survival (OS) time of patients with KIRC. Furthermore, 12 hub genes were selected to construct the prognostic model. The prognostic model showed superior accuracy in both TCGA and ICGC cohorts using ROC curve analysis. Systematic analysis of immune cell infiltration revealed that nine genes were significantly correlated with levels of tumor-infiltrating immune cells. Conclusions Our findings indicated that the tumor immune microenvironment was an important determinant of KIRC outcomes and revealed potential biomarkers for predicting patient OS and for targeted immunotherapies.

/pdf/identification-and-verification-of-tumor-immune-3h2stobj.pdf

Identification and Verification of Tumor Immune Microenvironment-Related Prognostic Genes in Kidney Renal Clear Cell Carcinoma

Background Pneumonia is one of the most frequent but serious infectious complications post kidney transplantation. Severe pneumonia induces sustained immunosuppression, but few parameters concerning immune status are used to assess the severity of pneumonia. Myeloid-derived suppressor cells (MDSCs) are induced under infection and have the strong immunosuppressive capacity, but the correlation between MDSCs and pneumonia in kidney transplant recipients (KTRs) is unknown. Methods Peripheral blood MDSCs were longitudinally detected in 58 KTRs diagnosed with pneumonia using flow cytometry and in 29 stable KTRs as a control. The effectors of MDSCs were detected in the plasma. Spearman's rank correlation analysis was performed to determine the correlation between MDSCs and the severity of pneumonia as well as lymphopenia. Results The frequency of MDSCs and effectors, including arginase-1, S100A8/A9, and S100A12, were significantly increased in the pneumonia group compared with the stable group. CD11b+CD14+HLA-DRlow/−CD15− monocytic-MDSCs (M-MDSCs) were higher in the pneumonia group but showed no significant difference between the severe and non-severe pneumonia subgroups. CD11b+CD14−CD15+ low-density granulocytic-MDSCs (G-MDSCs) were specifically increased in the severe pneumonia subgroup and correlated with the severity of pneumonia as well as lymphopenia. During the study period of 2 weeks, the frequencies of MDSCs and G-MDSCs were persistently increased in the severe pneumonia subgroup. Conclusions MDSCs and G-MDSCs were persistently increased in KTRs with pneumonia. G-MDSCs were correlated with the severity of pneumonia and could thus be an indicator concerning immune status for assessing pneumonia severity.

The Expansion of Myeloid-Derived Suppressor Cells Correlates With the Severity of Pneumonia in Kidney Transplant Patients

Background Bicuspid aortic valve (BAV) is a congenital cardiac deformity, increasing the risk of developing calcific aortic valve disease (CAVD). The disturbance of hemodynamics can induce valvular calcification, but the mechanism has not been fully identified. Methods We constructed a finite element model (FEM) of the aortic valve based on the computed tomography angiography (CTA) data from BAV patients and tricuspid aortic valve (TAV) individuals. We analyzed the hemodynamic properties based on our model and investigated the characteristics of mechanical stimuli on BAV. Further, we detected the expression of Notch, NICD and Runx2 in valve samples and identified the association between mechanical stress and the Notch1 signaling pathway. Results Finite element analysis showed that at diastole phase, the equivalent stress on the root of BAV was significantly higher than that on the TAV leaflet. Correspondingly, the expression of Notch1 and NICH decreased and the expression of Runx2 elevated significantly on large BAV leaflet belly, which is associated with equivalent stress on leaflet. Our findings indicated that the root of BAV suffered higher mechanical stress due to the abnormal hemodynamic environment, and the disturbance of the Notch1/NICD/Runx2 signaling pathway caused by mechanical stimuli contributed to valvular calcification.

Abnormal mechanical stress on bicuspid aortic valve induces valvular calcification and inhibits Notch1/NICD/Runx2 signal

https://link.springer.com/content/pdf/10.1007/s42235-022-00191-3.pdf

Gangcheng Kong

Papers

Erythropoietin and its derivatives: from tissue protection to immune regulation

Identification and Verification of Tumor Immune Microenvironment-Related Prognostic Genes in Kidney Renal Clear Cell Carcinoma

The Expansion of Myeloid-Derived Suppressor Cells Correlates With the Severity of Pneumonia in Kidney Transplant Patients

Abnormal mechanical stress on bicuspid aortic valve induces valvular calcification and inhibits Notch1/NICD/Runx2 signal

A Novel Method to Improve the Physical Property and Biocompatibility of Decellularized Heart Valve Scaffold with Sericin and Polydopamine