Correction: Effects of aluminum chloride and coenzyme Q10 on the molecular structure of lipids and the morphology of the brain hippocampus cells

Correction for ‘Effects of aluminum chloride and coenzyme Q10 on the molecular structure of lipids and the morphology of the brain hippocampus cells’ by Abdu Saeed et al., RSC Adv., 2021, 11, 29925–29933, DOI: 10.1039/D1RA03786B.

The authors regret that the name of one of the authors (Naeem F. Qusty) was shown incorrectly in the original article. In addition, the author contributions were incorrectly given. The corrected author list and contributions are as shown here.     

CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin

CD163 mediates the internalization of hemoglobin-haptoglobin (Hb-Hp) complexes by macrophages. Because Hp binding capacity is exhausted during severe hemolysis, an Hp-independent Hb-clearance pathway is presumed to exist. We demonstrate that Hb interacts efficiently with CD163 in the absence of Hp. Not only is Hb internalized into an endosomal compartment by CD163 as a result of active receptor-dependent endocytosis; it also inhibits the uptake of Hb-Hp complexes, suggesting a common receptor-binding site. Free Hb further induces heme oxygenase mRNA expression in CD163+ HEK293 cells, but not in CD163- cells. Additional evidence for Hp-independent Hb-CD163 interaction is provided by the demonstration that CD163 mediates the uptake of alpha alpha-DBBF crosslinked Hb, a chemically modified Hb that forms minimal Hp complexes. Moreover, certain modifications to Hb, such as polymerization or the attachment of specific functional groups (3 lysyl residues) to the beta-Cys93 can reduce or enhance this pathway of uptake. In human macrophages, Hp-complex formation critically enhances Hb uptake at low (1 microg/mL), but not at high (greater than 100 microg/mL), ligand concentrations, lending support for a concentration-dependent biphasic model of macrophage Hb-clearance. These results identify CD163 as a scavenger receptor for native Hb and small-molecular-weight Hb-based blood substitutes after Hp depletion.     

Influence of the hormonal changes during the normal menstrual cycle in healthy young women on soluble adhesion molecules, plasma homocysteine, free radical markers and lipoprotein fractions.

AIM: Female sex hormones are known to exert a protective role on the vascular endothelial function, but the exact mechanisms of such protection is not known. We aimed to study the possible regulatory role of the female sex hormones changes during the normal menstrual cycle on soluble adhesion molecules E-selectin and ICAM-1, plasma homocyteine, free radical markers and lipoproteins in healthy young women. METHODS: Experimental design: a cross sectional study of healthy female volunteers studied during a single normal menstrual cycle at 3 specific time points. Setting: North Staffordshire Hospitals NHS Trust. Subjects: 20 healthy young menstruating women, aged (mean +/- SEM) 34 +/- 1 years, with normal menstruation, defined as a menstrual cycle of 21-35 days were studied at 3 time points of the same menstrual cycle. First in the early follicular phase (M-phase), at mid-follicular phase (F-phase), and during the luteal phase (L-phase). Intervention: none. Measurement: serum levels of soluble E-selectin, ICAM-1, plasma homocysteine, vitamin E and malondialdehyde (MDA), as well as lipoprotein fractions were measured at each time points. RESULTS: The mean percentage change for E-selectin between the M-phase and L-phase, F-phase and L-phase were 6% and 4%, respectively, p<0.005, p<0.066. Levels of ICAM-1, vitamin E and malondialdehyde did not vary through the cycle. Homocysteine was not different between M-phase and F-phase (10.39 +/- 0.68 micromol/l vs 10.33 +/- 0.65), nor between M-phase and L-phase (10.39+/-0.68 vs 9.77 +/- 0.75 micromol/l). Although the mean percentage decrease in homocysteine between F- and L-phases was significant (5.36 +/- 0.53%, p=0.029), the absolute decrease in concentrations was not (p=0.07). There were no cyclical changes in total, LDL, HDL cholesterol, triglycerides, apo A-I, apo B or Lp(a). Using a linear regression model, after correction for age, smoking, body mass index (BMI) and waist/hip ratio (WHR), oestrogen levels were the only predictor of E-selectin during the L-phase p<0.005. There were no significant correlations between oestrogen with lipids, apolipoproteins or homocysteine. There was an interesting significant univariate correlation between homocysteine with low-density-lipoprotein (LDL) cholesterol and apo B throughout all phases of the cycle, which persisted after correction for the effects of age, BMI, WHR and smoking history. Multiple regression analysis with all these factors showed homocysteine to be a significant predictor of apo B concentration during M (p=0.030) and L-phases (p=0.023) of the cycle and of LDL cholesterol in the M-phase (p=0.033). CONCLUSION: Female sex hormones may have small, though significant modulating role on E-selectin and homocysteine metabolism in healthy premenopausal women. Furthermore, the correlation between homocysteine, LDL and apo B levels suggests that induction of cholesterol synthesis by homocysteine, shown previously in vitro, may be of relevance in vivo.     

Effects of cell-free hemoglobin on hypoxia-inducible factor (HIF-1alpha) and heme oxygenase (HO-1) expressions in endothelial cells subjected to hypoxia

We have investigated the impact of diaspirin cross-linked hemoglobin (DBBF-Hb), a blood substitute, on cell signaling pathways that are modulated in part by biological peroxides (i.e., hydrogen peroxide, lipid peroxide, and peroxynitrite). Bovine aortic endothelial cells (BAECs) subjected to hypoxia expressed hypoxia-inducible factor (HIF-1alpha) in a time course that paralleled the expressions of heme oxygenase (HO-1). Co-incubation of the oxy form (HbFe(2+)) with hypoxic BAECs resulted in an increase in the expression of HIF-1alpha in a manner that corresponded linearly with the decay of HbFe(2+) and accumulation of the ferric form (HbFe(3+)). Inclusion of HbFe(3+) with hypoxic BAECs produced twice as much expression in the HIF-1alpha and HO-1 proteins as opposed to HbFe(2+) alone, or HbFe(2+) plus hypoxia. In addition, higher and more persistent levels of the ferryl form (HbFe(4+)), due to the consumption of endogenous peroxides, were found in the hypoxic media containing hemoglobin. Nitric oxide (NO) released from an NO donor reduced the levels of HIF-1alpha in the hypoxic cells treated with either HbFe(2+) or HbFe(3+), but had little or no effect on the levels of HO-1. DBBF-Hb modulates key cell-signaling pathways by competing with peroxides required for the deactivation of HIF-1alpha, which may modulate important physiological mediators.     

Toxicities of hemoglobin solutions: in search of in-vitro and in-vivo model systems

Several hemoglobin‐based oxygen carriers (HBOCs) have been developed with a rationale focused on exploiting one or more physicochemical properties (e.g., oxygen affinity, molecular weight, viscosity, and colloid osmotic pressure) resulting from the chemical or recombinant modification of hemoglobin (Hb). Several chemically modified Hbs have reached late stages of clinical evaluation in the United States and Canada. These Hbs, in general, demonstrated mixed preclinical safety and efficacy, and reasonable safety in Phase I trials. However, as clinical development shifted into later stages, an undesirable safety and efficacy profile became clear in patient populations studied, and as a result some products were withdrawn from further clinical pursuit. Several questions still remain unanswered regarding the safety of Hb products for their proposed clinical indication(s). For example, 1) were preclinical studies predictive of clinical outcome? And, 2) were the most appropriate preclinical studies performed to predict clinical outcome? The primary objectives of this analysis are to explore prelinical safety issues associated with HBOCs and provide an overview of the in‐vitro and in‐vivo models employed. The methods for obtaining data to serve as a basis for discussion are compiled from a literature‐based survey of safety and efficacy derived from biochemical, cellular, and whole animal assessment of HBOCs. Results from this overview of a vast body of published data may provide a means for identifying critical preclinical safety issues, which may ultimately lead to identification of potential limitations in the effective clinical use of certain HBOCs.     

Anti-cytokine autoantibodies in experimental autoimmune neuritis in Lewis rats

Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated, inflammatory demyelinating disease of the peripheral nervous system (PNS) that serves as a model for Guillain-Barre syndrome (GBS) in humans. Cytokine production has been suggested to act a pathogenic role for EAN. To study the potential role of cytokines in context with cytokine autoantibodies (Aabs) in EAN, we used in situ hybridization to detect mRNA expression of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-4, IL-10, and transforming growth factor (TGF)-beta in lymph node mononuclear cell (MNC) and in sciatic nerve sections, as well as ELISA for detection of their autoantibodies in sera and cerebrospinal fluid (CSF) over the course of EAN. Increased mRNA expression for IFN-gamma and TNF-alpha was registered correlating with the peak of clinical signs of EAN, and high levels of mRNA expression for IL-4, IL-10, and TGF-beta were associated with EAN recovery. The levels of cytokine mRNAs were generally inversely correlated to their autoantibodies in serum and CSF, whereby the CSF levels were equal to or lower than the serum levels. Autoantibodies to IFN-gamma dose-dependently inhibited IFN-gamma-induced MHC expression by peritoneal macrophages proving a neutralizing biological effect of these autoantibodies. Our data demonstrate the existence of the anti-cytokine autoantibodies in the sera and CSF of rats with EAN; however, the role of anti-cytokine autoantibodies in the disease process of EAN remains to be resolved.     

Loss of muscarinic M4 receptors in spinal cord of arthritic rats: implications for a role of M4 receptors in pain response

Changes in the levels of muscarinic M4 receptors in spinal cord of acute and chronic arthritic rats (animal models of pain) were studied by receptor autoradiography using muscarinic M4 receptor subtype selective ligand. Arthritis was induced in female Lewis rats by single intradermal injection of heat-killed Mycobacterium butyricum and sacrificed 12 days (acute group) and 30 days (chronic and control groups) after induction of arthritis. Our results demonstrate significant reduction in the level of M4 receptors in the spinal cord (Rexed laminae I-X) of acute and chronic arthritic rats compared to controls. These findings suggest that the muscarinic M4 receptor subtype may be involved in cholinergic mechanisms of analgesia.