Erythropoietin induces miRNA-210 by JAK2/STAT5 signaling in PBMCs of End-stage Renal Disease patients.

Anemia of chronic kidney disease is associated with blunted response/resistance to erythropoietin-stimulating agents (ESAs) in hemodialysis (HD) patients. Several molecules have been successfully associated with ESA responsiveness; however, none of them is now considered a valid therapeutic biomarker of erythropoietin resistance in these patients. We performed an evaluation of the level of specific plasma circulating miRNAs in blood samples of HD patients, in relation to ESA treatment, with a follow-up of 1 year (T0-T3). We found significantly lower circulating levels of all miRNAs analyzed at baseline (T0) in HD patients vs. healthy control (HC). The plasmatic levels of miRNA-210 resulted significantly and negatively associated with Erythropoietin Resistance Index (ERI), and the variance of ΔmiRNA-210 (miRNA-210T3 minus miRNA-210T0 ) explained significant percentage of ΔERI (ERIT3 minus ERIT0 ) variance. The receiver operating characteristic analysis at T0 showed that the plasmatic level of miRNA-210 could distinguish HD patients with positive or negative trend in ERI at T3. In vitro, recombinant human erythropoietin (EPO) induced significant release of miRNA-210 from cultured peripheral blood mononuclear cells, through the activation of Janus kinase 2 (JAK2)/ signal transducer and activator of transcription 5 (STAT5) signaling, but not by the activation of the MAPK protein 38α and extracellular signal-regulated kinase ½. Accordingly, HD patients with negative ΔERI showed higher level of phosphor-Janus kinase 2 and nuclear translocation of phosphor-signal transducer and activator of transcription 5. vs. patients with positive ΔERI or HC. Our data highlighted that chronic HD significantly reduces the circulating level of the miRNAs evaluated; within the targets analyzed, the miRNA-210 could be considered as a prognostic indicator of ESA responsiveness and index for anemia management.

Memory Training Program Decreases the Circulating Level of Cortisol and Pro-inflammatory Cytokines in Healthy Older Adults.

Aging cognitive decline has been associated to impairment of the Hypothalamus Pituitary Adrenals (HPA) axis activity and a higher level of the systemic inflammation. However, little is known about the molecules driving this process at peripheral level. In addition, the cognitive function is to some extent modifiable with Memory Training (MT) programs, even among older adults and beyond. The study aims to evaluate whether MT could contribute to ameliorate cognitive performance and modulate the HPA axis activity as well the low level inflammation in the aging phenotype. Whether the phosphatase WIP-1, a negative regulator for inflammation, is involved in this process was also investigated. We recruited 31 young adults (19-28, years of age) and 62 older adults aged over 60. Thirty-two older adults were submitted to 6-months of MT program (EG), and 28 older adults were no treated and used as Control Group (CG). Global cognitive functioning (MMSE score), verbal and visual memory, and attention were assessed at baseline (T0) and after 6-months (T1). At the same time, plasmatic level of Cortisol (C), IL-1ß, IL-18, IL-6, and the expression of WIP-1 mRNA and protein in ex vivo Peripheral Blood Mononuclear Cells were analyzed in young adults at T0, as well in older adults at T0 and T1. Together, the results suggest that MT improves the global cognitive functionality, verbal and visual memory, as well as the level of attention. At the same time we observed a decrease of the plasmatic level of C, of the cytokines, and an increase of the expression of mRNA and protein of WIP-1. The analysis of correlations highlighted that the level of the mRNA of WIP-1 was positively associated to the MMSE score, and negatively to the C and cytokine levels. In conclusion, we purpose the MT as tool that could help support successful aging through the improving of memory, attention and global cognitive function performance. Furthermore, this approach could participate to maintain lower the peripheral levels of the C and pro-inflammatory cytokines. The WIP-1 as a potential new target of the pathophysiology of aging is theorized.

Dysregulation of chemo-cytokine production in schizophrenic patients versus healthy controls.

BACKGROUND: The exact cause of schizophrenia is not known, although several aetiological theories have been proposed for the disease, including developmental or neurodegenerative processes, neurotransmitter abnormalities, viral infection and immune dysfunction or autoimmune mechanisms. Growing evidence suggests that specific cytokines and chemokines play a role in signalling the brain to produce neurochemical, neuroendocrine, neuroimmune and behavioural changes. A relationship between inflammation and schizophrenia was supported by abnormal cytokines production, abnormal concentrations of cytokines and cytokine receptors in the blood and cerebrospinal fluid in schizophrenia. Since the neuropathology of schizophrenia has recently been reported to be closely associated with microglial activation we aimed to determined whether spontaneous or LPS-induced peripheral blood mononuclear cell chemokines and cytokines production is dysregulated in schizophrenic patients compared to healthy subjects. We enrolled 51 untreated first-episode schizophrenics (SC) and 40 healthy subjects (HC) and the levels of MCP-1, MIP-1α, IL-8, IL-18, IFN-γ and RANTES were determined by Elisa method in cell-free supernatants of PBMC cultures. RESULTS: In the simultaneous quantification we found significantly higher levels of constitutively and LPS-induced MCP-1, MIP-1α, IL-8 and IL-18, and lower RANTES and IFNγ levels released by PBMC of SC patients compared with HC. In ten SC patients receiving therapy with risperidone, olanzapine or clozapine basal and LPS-induced production of RANTES and IL-18 was increased, while both basal and LPS-induced MCP-1 production was decreased. No statistically significant differences were detected in serum levels after therapy. CONCLUSION: The observation that in schizophrenic patients the PBMC production of selected chemo-cytokines is dysregulated reinforces the hypothesis that the peripheral cyto-chemokine network is involved in the pathophysiology of schizophrenia. These preliminary, but promising data are supportive of the application of wider profiling approaches to the identification of biomarker as diagnostic tools for the analysis of psychiatric diseases.

Expression and secretion of CXCL8 (IL-8), release of tryptase and transcription of histidine decarboxylase mRNA by anti-IgE-activated human umbilical cord blood-derived cultured mast cells.

Activation of cytokine receptors and alterations in cytokines are thought to play important roles in neuronal dysfunction and in the pathogenesis of the nervous system diseases. CXCL8 (IL-8) is a CXC chemokine with chemotactic and inflammatory properties. Chemokines control mast cell infiltration in several inflammatory diseases, including stress and neurological dysfunctions. Using isolated human umbilical cord blood-derived cultured mast cells (HUCMC) from hematopoietic stem cells CD34+, mast cells were immunologically activated with anti-IgE at concentrations of 1, 5, 10 and 20 microg/ml leading to the dose-dependent production of IL-8 (p < 0.05). The increase in IL-8 mRNA expression was also noted when the cells were treated with anti-IgE at 10 microg/ml for 6 h. Immunologically activated HUCMC provoked the generation of tryptase in a dose- and time-dependent manner. We also found increased histidine decarboxylase (HDC) expression in activated HUCMC after 6 h of incubation, a rate-limiting enzyme responsible for the generation of histamine from histidine. Taken together, these results confirm that anti-IgE-activated mast cells release inflammatory mediators including CXCL8, a CXC chemokine which regulates several biological effects of mast cells, e.g. chemoattraction, and possibly causes cell arrest.