The mutation of the homeostatic iron regulatory genes (HFE) impaired the hepatic hepcidin transcription leading to the chronic excess of the iron pool, with the adverse consequences of free radical oxidative damages. We herein reported the findings of Thai family members who had the compound of uncommon HFE rs2794719, together with transferrin (TF) rs1867504, transferrin receptor 2 (TfR2) rs7385804, and hemojuvelin (HJV) rs16827043 genetic variants involved in the hepcidin transcriptional pathway. These compounded genetic variants could produce the spectrum of clinical phenotypes that spanned from mild to moderate symptoms of chronic anemia to an established motor neuron disorder. The feasible pathophysiologies were the impairment of the transferrin receptor functions, which affected the endocytic uptake of halo-transferrin into the erythroblast precursors. Such a defect left the erythropoiesis depleted of their iron supply. These alterations also promoted the TfR-independent uptake of iron into other target tissues and left the TrF2/BMP-dependent-hepcidin activation pathway unattended. We used the predicted molecular interactive proteomes to support our speculated dysregulated iron metabolism. During the early stage of an elevated ferritin level, there was no inhibition of ferroportin activities from hepcidin. These pathophysiological processes went on to the point of an iron overload threshold. After that, the hepcidin transcription started to kick in with the resulting decreased serum iron levels and deterioration of clinical symptoms.

Objectives Caffeine is extensively consumed as a psychostimulant drug, acting on A(1)and A(2A)adenosine receptors blockade. Chronic exposure to caffeine during gestation and breast-feeding may be involved in infant rat's behavioral and biochemical alterations. Our goal was to evaluate the effect of chronic caffeine exposure during gestation and breast-feeding in the functionality of adenosine A(1)receptors in infant rats at P14. NTPDase and 5'-nucleotidase activities were also evaluated. Methods Mating of adult female Wistar rats was confirmed by presence of sperm in vaginal smears. Rats were divided into three groups on the first day of pregnancy: (1) control: tap water, (2) caffeine: 0.3 g/L until P14, and (3) washout caffeine: caffeine was changed to tap water at P7. Evaluation of nociceptive response was performed at P14 using hot plate (HP) and tail-flick latency (TFL) tests. A(1)receptor involvement was assessed using caffeine agonist (CPA) and antagonist (DPCPX). Enzymatic activities assays were conducted in the spinal cord. Results Gestational and breastfeeding exposure to caffeine (caffeine and washout groups) did not induce significant alterations in thermal nociceptive thresholds (HP and TF tests). Both caffeine groups did not show analgesic response induced by CPA when compared to the control group at P14, indicating chronic exposure to caffeine in the aforementioned periods inhibits the antinociceptive effects of the systemic A(1)receptor agonist administration. No effect was observed upon ectonucleotidase activities. Conclusions Our results demonstrate that chronic caffeine exposure in gestational and breastfeeding alters A1-mediated analgesic response in rats.