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Nicholas J Pekas,1 Jason L Petersen,2,3 Monica Sathyanesan,1,2 Samuel S Newton1,2 1Department of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermilion, SD, USA; 2Sioux Falls VA Health Care System, Sioux Falls, SD, USA; 3Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Vermillion, SD, USACorrespondence: Samuel S Newton Attn: Lee Medical Building, 414 E. Clark Street, Vermillion, SD 57069, USATel +1-605-658-6313Email Samuel.Sathyanesan@usd.eduIntroduction: Carbamoylated erythropoietin (CEPO) is a chemically engineered, nonhematopoietic derivative of erythropoietin (EPO) that retains its antidepressant and pro-cognitive 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.Keywords: carbamoylated erythropoietin, mimetic, antidepressant, innate repair receptor, erythropoietin receptor, nonhematopoietic

Flow cytometry analysis has stood the test of time as a powerful tool in the assessment of hematologic neoplasms. The role of flow cytometry has expanded to evaluate various nonhematologic neoplasms encountered in body cavity malignant effusions, lymph nodes, and other body sites. This review explores the use of routine antibody panels as well as specially designed multicolor antibody panels that have been investigated by different groups and reported in the literature for evaluating nonhematologic neoplasms. In this context, the limitations, pitfalls, future directions, and promising applications of flow cytometry analysis are also discussed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Erythropoietin (EPO) is the cytokine that regulates red blood cell production. Less understood is the nonerythroid action of EPO, includingmetabolic regulation of fat accumulation and glucose homeostasis.Although EPOtreatment increasedhematocrit andimprovedglucose tolerance inmale andfemalemice,weobserveda gender difference in EPOeffects inweight control. EPOtreatment reduced diet-inducedweight gain from9.6±1.5 to 4.2± 1.4 g inmalemice (P < 0.001),while theweight gain in femalemicewas similar (4.7 ± 2.0 gwith PBS treatment and 3.3 ± 2.1 g with EPO treatment). EPO treatment also reduced weight gain in ovariectomized female mice, while the effect was abrogated with estradiol supplementation, suggesting that the sex-differential response to EPO was associatedwithestrogen.Furthermore,micewithtargeteddeletionofEPOreceptor inwhite adipose tissue exhibited sex-differentialphenotype inweight control and glucose sensitivity, and EPOreceptor gene expressionwas reduced in wild-type female mice, suggesting that white adipose tissue plays an integral role in mediating the metabolic effects of EPO. Our data provide evidence for a sex-differential response to EPO in weight control in mice and underscore the potential for gender specific EPO action beyond erythropoiesis. [ABSTRACT FROM AUTHOR]

Bone marrow mesenchymal stem cells (MSCs) have been shown to have immune modulatory effects. Despite efforts to identify these cells in vivo, to date, MSCs have been defined mainly by their in vitro cell characteristics. Here, we show that Lin"CD44hiScal~cKit+CD34~ cells make up ~0.5%-l% of murine whole bone marrow cells and yield nearly an equal amount of fibroblastic colony-forming units (CFU-F) as whole bone marrow. After transplantation into lethally irradiated recipients, Lin~CD44hiScal~cKit+ CD34~ cells engrafted in the bone marrow long-term and demonstrated characteristics of MSCs, including capacity to differentiate into osteoblasts and adipocytes. To examine whether Lin~CD44hiScal~cKit+CD34" cells have immune modulatory effects, in vitro coculture with acti- vated CD4+ T-cells resulted in decreased Thl7 cell differentiation by Lin~CD44hiScal~cKit+CD34" cells. Furthermore, serial infusions with Lin~CD44hlScal~ cKit+CD34~ cells reduced the progression to low-grade gastric dysplasia in mice infected with chronic Helico- bacterfelis (p = .038). This correlated with reduced gastric interleukin (IL)-17F, IL-22, and ROR-yt gene expression in responding mice (p < .05). These data suggest that bone marrow derived Lin~ CD44hiScal~cKit+CD34~ cells have characteristics of MSCs and reduce progression of early gastric tumorigenesis induced by chronic H.felis infection. The prevention of dysplastic changes may occur through inhibition of Thl7-dependent pathways. Stem Cells 2009;27:2301-2311 [ABSTRACT FROM AUTHOR]

Current theory indicates that mitochondria were obtained 1.5 billion years ago from an ancient prokaryote. The mitochondria provided the capacity for aerobic respiration, the creation of the eukaryotic cell, and eventually complex multicellular organisms. Recent reports have found that mitochondria play essential roles in aging and determining lifespan. A variety of heritable and acquired diseases are linked to mitochondrial dysfunction. We report here that mitochondria are more dynamic than previously considered: mitochondria or mtDNA can move between cells. The active transfer from adult stem cells and somatic cells can rescue aerobic respiration in mammalian cells with nonfunctional mitochondria. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) is the cytokine that regulates red blood cell production. Less understood is the nonerythroid action of EPO, including metabolic regulation of fat accumulation and glucose homeostasis. Although EPO treatment increased hematocrit and improved glucose tolerance in male and female mice, we observed a gender difference in EPO effects in weight control. EPO treatment reduced diet-induced weight gain from 9.6 ± 1.5 to 4.2 ± 1.4 g in male mice ( P < 0.001), while the weight gain in female mice was similar (4.7 ± 2.0 g with PBS treatment and 3.3 ± 2.1 g with EPO treatment). EPO treatment also reduced weight gain in ovariectomized female mice, while the effect was abrogated with estradiol supplementation, suggesting that the sex-differential response to EPO was associated with estrogen. Furthermore, mice with targeted deletion of EPO receptor in white adipose tissue exhibited sex-differential phenotype in weight control and glucose sensitivity, and EPO receptor gene expression was reduced in wild-type female mice, suggesting that white adipose tissue plays an integral role in mediating the metabolic effects of EPO. Our data provide evidence for a sex-differential response to EPO in weight control in mice and underscore the potential for gender specific EPO action beyond erythropoiesis.-Zhang, Y., Rogers, H. M., Zhang, X., Noguchi, C. T. Sex difference in mouse metabolic response to erythropoietin., (© FASEB.)

Erythropoietin (EPO) is the main regulator of red blood cell production. Since the 1990s, EPO has been used for the treatment of anemia associated with end-stage renal failure and chemotherapy. The erythropoietin receptors were found on other organs such as the brain, spinal cord, heart and skin. In addition, it has been shown that many tissues produce and locally release EPO in response to hypoxic, biochemical and physical stress. In cellular, animal and clinical studies, EPO protects tissues from ischemia and reperfusion injury, has antiapoptotic effects and improves regeneration after injury. In this article, we mainly review the nonhematopoietic effects and new possible clinical indications for EPO., (Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)