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Diabetes Mellitus (DM) is a complex metabolic disorder associated with multiple microvascular complications leading to nephropathy, retinopathy, and neuropathy. Mounting evidence suggests that red blood cell (RBC) alterations are both a cause and consequence of disturbances related to DM-associated complications. Importantly, a significant proportion of DM patients develop varying degrees of anemia of confounding etiology, leading to increased morbidity. In chronic hyperglycemia, RBCs display morphological, enzymatic, and biophysical changes, which in turn prime them for swift phagocytic clearance from circulation. A multitude of endogenous factors, such as oxidative and dicarbonyl stress, uremic toxins, extracellular hypertonicity, sorbitol accumulation, and deranged nitric oxide metabolism, have been implicated in pathological RBC changes in DM. This review collates clinical laboratory findings of changes in hematology indices in DM patients and discusses recent reports on the putative mechanisms underpinning shortened RBC survival and disturbed cell membrane architecture within the diabetic milieu. Specifically, RBC cell death signaling, RBC metabolism, procoagulant RBC phenotype, RBC-triggered endothelial cell dysfunction, and changes in RBC deformability and aggregation in the context of DM are discussed. Understanding the mechanisms of RBC alterations in DM provides valuable insights into the clinical significance of the crosstalk between RBCs and microangiopathy in DM. [ABSTRACT FROM AUTHOR]

Background and Objectives: Abundant clinical evidence supports the safety of red blood cell (RBC) concentrates for transfusion irrespective of storage age, but still, less is known about how recipient characteristics may affect post‐transfusion RBC recovery and function. Septic patients are frequently transfused. We hypothesized that the recipient environment in patients with septicaemia would blunt the increase in post‐transfusion blood haemoglobin (Hb). The main objective was to compare the post‐transfusion Hb increment in hospitalized patients with or without a positive blood culture. Materials and Methods: A retrospective cohort study using data from the Transfusion Research, Utilization, Surveillance, and Tracking database (TRUST) was performed. All adult non‐trauma in‐patients transfused between 2010 and 2017 with ≥1 RBC unit, and for whom both pre‐ and post‐transfusion complete blood count and pre‐transfusion blood culture data were available were included. A general linear model with binary blood culture positivity was fit for continuous Hb increment after transfusion and was adjusted for patient demographic parameters and transfusion‐related covariates. Results: Among 210,263 admitted patients, 6252 were transfused: 596 had positive cultures, and 5656 had negative blood cultures. A modelled Hb deficit of 1.50 g/L in blood culture‐positive patients was found. All covariates had a significant effect on Hb increment, except for the age of the transfused RBC. Conclusion: Recipient blood culture positivity was associated with a statistically significant but modestly lower post‐transfusion Hb increment in hospitalized patients. In isolation, the effect is unlikely to be clinically significant, but it could become so in combination with other recipient characteristics. [ABSTRACT FROM AUTHOR]

Previous studies have shown that pharmacological inhibition of the phosphoinositol-3 (PI3) kinase disrupts the activation of mast cells. Through phosphoinositide-dependent kinase PDK1, PI3 kinase activates the serum- and glucocorticoid-inducible kinase 3 (SGK3). The present study explored the role of SGK3 in mast cell function. Mast cells were isolated and cultured from bone marrow (BMMCs) of gene-targeted mice lacking SGK3 ([sgk3.sup.-/-]) and their wild-type littermates ([sgk3.sup.+/+]). BMMC numbers in the ear conch were similar in both genotypes. Stimulation with IgE and cognate antigen triggered the release of intracellular [Ca.sup.2+] and entry of extracellular [Ca.sup.2+]. Influx of extracellular [Ca.sup.2+] but not [Ca.sup.2+] release from intracellular stores was significantly blunted in [sgk3.sup.-/-] BMMCs compared with [sgk3.sup.+/+] BMMCs. Antigen stimulation further led to a rapid increase of a [K.sup.+]-selective conductance in [sgk3.sup.+/+] BMMCs, an effect again blunted in [sgk3.sup.-/-] BMMCs. In contrast, the [Ca.sup.2+] ionophore ionomycin activated [K.sup.+] currents to a similar extent in [sgk3.sup.-/-] and in [sgk3.sup.+/+] BMMCs. [beta]-Hexosaminidase release, triggered by antigen stimulation, was also significantly decreased in [sgk3.sup.-/-] BMMCs. IgE-dependent anaphylaxis measured as a sharp decrease in body temperature upon injection of DNP-HSA antigen was again significantly blunted in [sgk3.sup.-/-] compared with [sgk3.sup.+/+] mice. Serum histamine levels measured 30 rain after induction of an anaphylactic reaction were significantly lower in [sgk3.sup.-/-] than in [sgk3.sup.+/+] mice. In conclusion, both in vitro and in vivo function of BMMCs are impaired in gene targeted mice lacking SGK3. Thus SGK3 is critical for proper mast cell function. allergy; anaphylaxis; calcium ion channels; degranulation; potassium ion channels; [K.sub.ca] 3.1; phosphoinositol-3 kinase doi: 10.1152/ajpcell.00539.2009.

Abstract Background Nitric oxide (NO) is a multifunctional signaling molecule that regulates important cellular events in inflammation including leukocyte recruitment. Previous studies have shown that pharmacological inhibition of NO synthesis induces leukocyte recruitment in various in vitro and animal models. However, it is not known whether NO modulation has similar effects on leukocyte-endothelial cell interactions within the human microvasculature. The present study explored the effect of systemic L-NAME treatment on leukocyte recruitment in the SCID-hu mouse model. Methods Human skin xenografts were transplanted in SCID mice to study human leukocyte dynamics in human vasculature. Early events of human leukocyte recruitment in human vasculature were studied using intravital microscopy. NO synthesis was pharmacologically inhibited using NG-nitro-L-arginine methyl ester (L-NAME). Immunohistochemical analysis was performed to elucidate E-selectin expression in human xenograft skin. Human neutrophil-endothelial cell interactions were also studied in an in vitro flow chamber assay system. P- and E-selectin expression on cultured human umbilical vein endothelial cells (HUVECs) was measured using ELISA. Platelet-activating factor (PAF) synthesis was detected using a TLC-based assay. Results L-NAME treatment significantly enhanced the rolling and adhesion of human leukocytes to the human vasculature. Functional blocking of P- and E-selectins significantly inhibited rolling but not adhesion induced by inhibition of NO synthesis. Systemic L-NAME treatment enhanced E-selectin expression in human xenograft skin. L-NAME treatment significantly enhanced P- and E-selectin expression on HUVECs. L-NAME treatment did not significantly modify neutrophil rolling or adhesion to HUVECs indicating that L-NAME−induced subtle P- and E-selectin expression was insufficient to elicit dynamic neutrophil-HUVEC interactions in vitro. Moreover, synthesis of endothelial-derived PAF was not significantly modified by L-NAME treatment. These results point to the accelerated leukocyte recruitment in human vasculature following suppression of NO synthesis, effects that are mediated by P- and E-selectins. The findings are, however, not supported by the in vitro data. Conclusion Inhibition of endogenous NO triggers early events of human leukocyte recruitment in human vasculature, involving complex cellular or molecular mechanisms in addition to P- and E-selectin-mediated leukocyte rolling.

Abstract Background Gum Arabic (GA), a nonabsorbable nutrient from the exudate of Acacia senegal, exerts a powerful immunomodulatory effect on dendritic cells, antigen-presenting cells involved in the initiation of both innate and adaptive immunity. On the other hand GA degradation delivers short chain fatty acids, which in turn have been shown to foster the expression of foetal haemoglobin in erythrocytes. Increased levels of erythrocyte foetal haemoglobin are known to impede the intraerythrocytic growth of Plasmodium and thus confer some protection against malaria. The present study tested whether gum arabic may influence the clinical course of malaria. Methods Human erythrocytes were in vitro infected with Plasmodium falciparum in the absence and presence of butyrate and mice were in vivo infected with Plasmodium berghei ANKA by injecting parasitized murine erythrocytes (1 × 106) intraperitoneally. Half of the mice received gum arabic (10% in drinking water starting 10 days before the day of infection). Results According to the in vitro experiments butyrate significantly blunted parasitaemia only at concentrations much higher (3 mM) than those encountered in vivo following GA ingestion (in vivo experiments the administration of gum arabic slightly but significantly decreased the parasitaemia and significantly extended the life span of infected mice. Discussion GA moderately influences the parasitaemia and survival of Plasmodium-infected mice. The underlying mechanism remained, however, elusive. Conclusions Gum arabic favourably influences the course of murine malaria.

Abstract Background Premature death of Plasmodium-infected erythrocytes is considered to favourably influence the clinical course of malaria. Aurothiomalate has previously been shown to trigger erythrocyte death or eryptosis, which is characterized by cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing cells are rapidly cleared from circulating blood. The present study thus tested whether sodium aurothiomalate influences the intraerythrocytic parasite development in vitro and the clinical course of murine malaria in vivo. Methods Human erythrocytes were infected with Plasmodium falciparum BinH in vitro and mice were infected (intraperitoneal injection of 1 × 106 parasitized murine erythrocytes) with Plasmodium berghei ANKA in vivo. Results Exposure to aurothiomalate significantly decreased the in vitro parasitemia of P. falciparum-infected human erythrocytes without influencing the intraerythrocytic DNA/RNA content. Administration of sodium aurothiomalate in vivo (daily 10 mg/kg b.w. s.c. from the 8th day of infection) enhanced the percentage of phosphatidylserine-exposing infected and noninfected erythrocytes in blood. All nontreated mice died within 30 days of infection. Aurothiomalate-treatment delayed the lethal course of malaria leading to survival of more than 50% of the mice 30 days after infection. Conclusions Sodium aurothiomalate influences the survival of Plasmodium berghei-infected mice, an effect only partially explained by stimulation of eryptosis.

The average lifespan of circulating erythrocytes usually exceeds hundred days. Prior to that, however, erythrocytes may be exposed to oxidative stress in the circulation which could cause injury and trigger their suicidal death or eryptosis. Oxidative stress activates Ca2+‐permeable nonselective cation channels in the cell membrane, thus, stimulating Ca2+ entry and subsequent cell membrane scrambling resulting in phosphatidylserine exposure and activation of Ca2+‐sensitive K+ channels leading to K+ exit, hyperpolarization, Cl− exit, and ultimately cell shrinkage due to loss of KCl and osmotically driven water. While the mechanistic link between oxidative stress and anemia remains ill‐defined, several diseases such as diabetes, hepatic failure, malignancy, chronic kidney disease and inflammation have been identified to display both increased oxidative stress as well as eryptosis. Recent compelling evidence suggests that oxidative stress is an important perpetrator in accelerating erythrocyte loss in different systemic conditions and an underlying mechanism for anemia associated with these pathological states. In the present review, we discuss the role of oxidative stress in reducing erythrocyte survival and provide novel insights into the possible use of antioxidants as putative antieryptotic and antianemic agents in a variety of systemic diseases. This review highlights recent advances in elucidating the role of oxidative stress in influencing erythrocyte survival. The pro‐oxidative milieu present in different systemic diseases contributes to eryptosis, the suicidal death of erythrocytes, which consequently leads to anemia. Oxidative stress‐sensitive eryptosis may, thus, serve as a potential target in ameliorating anemia relevant to different clinical conditions. [ABSTRACT FROM AUTHOR]