Interleukin-21 receptor might be a novel therapeutic target for the treatment of rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the synovial inflammation of the joints. Various cells and cytokines have been identified that may contribute to RA pathology. Interleukin (IL)-21 is a proinflammatory cytokine mediating pleiotropic functions through the IL-21 receptor (IL-21R). Blockade of IL-21R may represent a hopeful therapeutic approach in RA. The aim of this study was to determine the percentage of IL-21R expressing CD4+ cells and IL-21 mRNA expression in peripheral blood of RA patients. Methods: Surface expression of IL-21R on CD4+ cells in peripheral blood of RA patients (n=32 compared to healthy control participants (n=20) was evaluated by flow cytometry. Simultaneously, mononuclear cells were taken apart from the peripheral blood of individuals on a density gradient. The expression of IL-21 mRNA was assessed by real-time polymerase chain reaction. Results: IL-21R-expressing CD4+ cells from RA patients showed a significantly higher percentage of IL-21R compared with healthy controls (p< 0.05). Moreover, real-time polymerase chain reaction showed that there was no significant difference between patients and healthy controls. Conclusion: Our results indicate higher expression of IL-21R in RA patients and suggest that targeting of the IL-21R may be a novel therapeutic idea for the treatment of RA. © 2014

Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus

Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, including epilepsy and Alzheimer’s disease. Theta rhythm generation involves a specific interplay between cellular (ion channel) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel modulator, and antiepileptic and neuroprotective agent, would affect HPC theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABAA-fast transmission in CA3 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine depressed HPC theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in HPC neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy

The Effect of Fullerenol C₆₀(OH)₃₆ on the Antioxidant Defense System in Erythrocytes

Background: Fullerenols (water-soluble derivatives of fullerenes), such as C60(OH)36, are biocompatible molecules with a high ability to scavenge reactive oxygen species (ROS), but the mechanism of their antioxidant action and cooperation with endogenous redox machinery remains unrecognized. Fullerenols rapidly distribute through blood cells; therefore, we investigated the effect of C60(OH)36 on the antioxidant defense system in erythrocytes during their prolonged incubation. Methods: Human erythrocytes were treated with fullerenol at concentrations of 50–150 µg/mL, incubated for 3 and 48 h at 37 °C, and then hemolyzed. The level of oxidative stress was determined by examining the level of thiol groups, the activity of antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase, and glutathione transferase), and by measuring erythrocyte microviscosity. Results: The level of thiol groups in stored erythrocytes decreased; however, in the presence of higher concentrations of C60(OH)36 (100 and 150 µg/mL), the level of -SH groups increased compared to the control. Extending the incubation to 48 h caused a decrease in antioxidant enzyme activity, but the addition of fullerenol, especially at higher concentrations (100–150 µg/mL), increased its activity. We observed that C60(OH)36 had no effect on the microviscosity of the interior of the erythrocytes. Conclusions: In conclusion, our results indicated that water-soluble C60(OH)36 has antioxidant potential and efficiently supports the enzymatic antioxidant system within the cell. These effects are probably related to the direct interaction of C60(OH)36 with the enzyme that causes its structural changes

Fullerenol C₆₀(OH)₃₆ Protects the Antioxidant Enzymes in Human Erythrocytes against Oxidative Damage Induced by High-Energy Electrons

Ionizing radiation (IR) can pass through the human body easily, potentially causing severe damage to all biocomponents, which is associated with increasing oxidative stress. IR is employed in radiotherapy; however, in order to increase safety, it is necessary to minimize side effects through the use of radioprotectors. Water-soluble derivatives of fullerene exhibit antiradical and antioxidant properties, and these compounds are regarded as potential candidates for radioprotectors. We examined the ability of fullerenol C60(OH)36 to protect human erythrocytes, including the protection of the erythrocytal antioxidant system against high-energy electrons. Human erythrocytes irradiated with high-energy [6 MeV] electrons were treated with C60(OH)36 (150 µg/mL), incubated and haemolyzed. The radioprotective properties of fullerenol were determined by examining the antioxidant enzymes activity in the hemolysate, the concentration of -SH groups, as well as by determining erythrocyte microviscosity. The irradiation of erythrocytes (650 and 1300 Gy) reduces the number of thiol groups; however, an attenuation of this harmful effect is observed (p 60(OH)36. Although no significant effect of fullerenol was recorded on catalase activity, which was preserved in both control and test samples, a more active protection of other enzymes was evident. An irradiation-induced decrease in the activity of glutathione peroxidase and glutathione reductase became an increase in the activity of those two enzymes in samples irradiated in the presence of C60(OH)36 (p p p 60(OH)36, thus, indicating a lower level of ROS in the system. However, the interaction of fullerenol with the active centre of the enzyme cannot be excluded. We also noticed that radiation caused a dose-dependent decrease in the erythrocyte microviscosity, and the presence of C60(OH)36 reduced this effect (p 60(OH)36 manifested as the protection of the antioxidant enzymes of human erythrocytes against IR-induced damage, which has not been the subject of intense research so far

GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylationResearch in context

Background: Glycogen synthase kinase-3β (GSK3β) is a key regulator of cellular homeostasis. In neurons, GSK3β contributes to the control of neuronal transmission and plasticity, but its role in epilepsy remains to be defined. Methods: Biochemical and electrophysiological methods were used to assess the role of GSK3β in regulating neuronal transmission and epileptogenesis. GSK3β activity was increased genetically in GSK3β[S9A] mice. Its effects on neuronal transmission and epileptogenesis induced by kainic acid were assessed by field potential recordings in mice brain slices and video electroencephalography in vivo. The ion channel expression was measured in brain samples from mice and followed by analysis in samples from patients with temporal lobe epilepsy or focal cortical dysplasia in correlation to GSK3β phosphorylation. Findings: Higher GSK3β activity decreased the progression of kainic acid induced epileptogenesis. At the biochemical level, higher GSK3β activity increased the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 4 under basal conditions and in the epileptic mouse brain and decreased phosphorylation of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 at Serine 831 under basal conditions. Moreover, we found a significant correlation between higher inhibitory GSK3β phosphorylation at Serine 9 and higher activating GluA1 phosphorylation at Serine 845 in brain samples from epileptic patients. Interpretation: Our data imply GSK3β activity in the protection of neuronal networks from hyper-activation in response to epileptogenic stimuli and indicate that the anti-epileptogenic function of GSK3β involves modulation of HCN4 level and the synaptic AMPA receptors pool. Keywords: Glycogen synthase kinases-3, GSK3, Epilepsy, AMPA receptors, GluA1 phosphorylatio

Inflammation, immunity, and vaccines for Helicobacter pylori

Helicobacter pylori infects almost half of the population worldwide and represents the major cause of gastroduodenal diseases, such as duodenal and gastric ulcer, gastric adenocarcinoma, autoimmune gastritis, and B-cell lymphoma of mucosa-associated lymphoid tissue. Helicobacter pylori induces the activation of a complex and fascinating cytokine and chemokine network in the gastric mucosa. Different bacterial and environmental factors, other concomitant infections, and host genetics may influence the balance between mucosal tolerance and inflammation in the course of H. pylori infection. An inverse association between H. pylori prevalence and the frequencies of asthma and allergies was demonstrated, and the neutrophil activating protein of H. pylori was shown to inhibit the allergic inflammation of bronchial asthma. During the last year, significant progress was made on the road to the first efficient vaccine for H. pylori that will represent a novel and very important bullet against both infection and gastric cancer