Iron induces two distinct Ca²⁺ signalling cascades in astrocytes.

From Europe PMC via Jisc Publications RouterHistory: ppub 2021-05-01, epub 2021-05-05Publication status: PublishedFunder: National Natural Science Foundation of China (National Science Foundation of China); Grant(s): 81871852Iron is the fundamental element for numerous physiological functions. Plasmalemmal divalent metal ion transporter 1 (DMT1) is responsible for cellular uptake of ferrous (Fe2+), whereas transferrin receptors (TFR) carry transferrin (TF)-bound ferric (Fe3+). In this study we performed detailed analysis of the action of Fe ions on cytoplasmic free calcium ion concentration ([Ca2+]i) in astrocytes. Administration of Fe2+ or Fe3+ in μM concentrations evoked [Ca2+]i in astrocytes in vitro and in vivo. Iron ions trigger increase in [Ca2+]i through two distinct molecular cascades. Uptake of Fe2+ by DMT1 inhibits astroglial Na+-K+-ATPase, which leads to elevation in cytoplasmic Na+ concentration, thus reversing Na+/Ca2+ exchanger and thereby generating Ca2+ influx. Uptake of Fe3+ by TF-TFR stimulates phospholipase C to produce inositol 1,4,5-trisphosphate (InsP3), thus triggering InsP3 receptor-mediated Ca2+ release from endoplasmic reticulum. In summary, these findings reveal the mechanisms of iron-induced astrocytic signalling operational in conditions of iron overload

Sleep Deprivation Selectively Down-Regulates Astrocytic 5-HT_2B Receptors and Triggers Depressive-Like Behaviors via Stimulating P2X₇ Receptors in Mice

Chronic loss of sleep damages health and disturbs the quality of life. Long-lasting sleep deprivation (SD) as well as sleep abnormalities are substantial risk factors for major depressive disorder, although the underlying mechanisms are not clear. Here, we showed that chronic SD in mice promotes a gradual elevation of extracellular ATP, which activates astroglial P2X7 receptors (P2X7Rs). Activated P2X7Rs, in turn, selectively down-regulated the expression of 5-HT2B receptors (5-HT2BRs) in astrocytes. Stimulation of P2X7Rs induced by SD selectively suppressed the phosphorylation of AKT and FoxO3a in astrocytes, but not in neurons. The over-expression of FoxO3a in astrocytes inhibited the expression of 5-HT2BRs. Down-regulation of 5-HT2BsRs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2. This latter cascade promoted the release of arachidonic acid and prostaglandin E2. The depression-like behaviors induced by SD were alleviated in P2X7R-KO mice. Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.</p

Efficacy and safety analysis of hypofractionated and conventional fractionated radiotherapy in postoperative breast cancer patients

Abstract Objectives In this meta-analysis, we conducted a comparative analysis of the safety and efficacy of hypofractionated and conventional fractionated radiotherapy in individuals who had undergone surgery for breast cancer. Methods This study involved a systematic and independent review of relevant research articles published in reputable databases such as PubMed, Embase, Cochrane Library, and Web of Science. Two investigators conducted the review, which included studies published up to January 3, 2023. The quality of the eligible studies was evaluated and data were extracted using Review Manager software 5.4 (RevMan 5.4) to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results The analysis comprised 35 studies and encompassed a collective sample of 18,246 individuals diagnosed with breast cancer. We did not find a statistically significant disparity in efficacy between conventional fractionated (CF) radiotherapy and hypofractionated (HF) radiotherapy regarding local recurrence (LR; OR = 0.91, 95% CI: 0.76–1.09, P = 0.30), disease-free survival (DFS; OR = 1.20, 95% CI: 1.01–1.42, P = 0.03), and overall survival (OS; OR = 1.08, 95% CI: 0.93–1.26, P = 0.28). Concerning safety, there was no significant difference between the HF and CF regimens in terms of breast pain, breast atrophy, lymphedema, pneumonia, pulmonary fibrosis, telangiectasia, and cardiotoxicity. However, the HF regimen resulted in lower skin toxicity (OR = 0.43, 95% CI: 0.33—0.55, P < 0.01) and improved patient fatigue outcomes (OR = 0.73, 95% CI: 0.60 – 0.88, P < 0.01). Conclusions Although there is no substantial difference in LR, DFS, OS, or many other side effects between the HF and CF regimens, the HF regimen reduces skin toxicity and relieves patient fatigue. If these two issues need to be addressed in clinical situations, the HF regimen may be a superior alternative to conventional radiotherapy in postoperative breast cancer patients

Iatrogenic Iron Promotes Neurodegeneration and Activates Self-Protection of Neural Cells against Exogenous Iron Attacks

Metal implants are used worldwide, with millions of nails, plates, and fixtures grafted during orthopedic surgeries. Iron is the most common element of these metal implants. As time passes, implants can be corroded and iron can be released. Ionized iron permeates the surrounding tissues and enters circulation; importantly, iron ions pass through the blood-brain barrier. Can iron from implants represent a risk factor for neurological diseases? This remains an unanswered question. In this study, we discovered that patients with metal implants delivered through orthopedic surgeries have higher incidence of Parkinson's disease or ischemic stroke compared to patients who underwent similar surgeries but did not have implants. Concentration of serum iron and ferritin was increased in subjects with metal implants. In experiments in vivo, we found that injection of iron dextran selectively decreased the presence of divalent metal transporter 1 (DMT1) in neurons through increasing the expression of Ndfip1, which degrades DMT1 and does not exist in glial cells. At the same time, excess of iron increased expression of DMT1 in astrocytes and microglial cells and triggered reactive astrogliosis and microgliosis. Facing the attack of excess iron, glial cells act as neuroprotectors to accumulate more extracellular iron by upregulating DMT1, whereas neurons limit iron uptake through increasing DMT1 degradation. Cerebral accumulation of iron in animals is associated with impaired cognition, locomotion, and mood. Excess iron from surgical implants thus can affect neural cells and may be regarded as a risk factor for neurodegeneration.</p

The neuroprotective mechanism of lithium after ischaemic stroke

Stroke causes degeneration and death of neurones leading to the loss of motor function and frequent occurrence of cognitive impairment and depression. Lithium (Li+), the archetypal mood stabiliser, is neuroprotective in animal models of stroke, albeit underlying mechanisms remain unknown. We discover that Li+ inhibits activation of nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in the middle cerebral artery occlusion (MCAO) stroke model in mice. This action of Li+ is mediated by two signalling pathways of AKT/GSK3β/β-catenin and AKT/FoxO3a/β-catenin which converge in suppressing the production of reactive oxygen species (ROS). Using immunocytochemstry, MRI imaging, and cell sorting with subsequent mRNA and protein quantification, we demonstrate that Li+ decreases the infarct volume, improves motor function, and alleviates associated cognitive and depressive impairments. In conclusion, this study reveals molecular mechanisms of Li+ neuroprotection during brain ischaemia, thus providing the theoretical background to extend clinical applications of Li+ for treatment of ischemic stroke.</p

Iron induces two distinct Ca

From PubMed via Jisc Publications RouterHistory: received 2020-09-18, accepted 2021-03-30Publication status: epublishFunder: National Natural Science Foundation of China (National Science Foundation of China); Grant(s): 81871852Iron is the fundamental element for numerous physiological functions. Plasmalemmal divalent metal ion transporter 1 (DMT1) is responsible for cellular uptake of ferrous (Fe ), whereas transferrin receptors (TFR) carry transferrin (TF)-bound ferric (Fe ). In this study we performed detailed analysis of the action of Fe ions on cytoplasmic free calcium ion concentration ([Ca ] ) in astrocytes. Administration of Fe or Fe in μM concentrations evoked [Ca ] in astrocytes in vitro and in vivo. Iron ions trigger increase in [Ca ] through two distinct molecular cascades. Uptake of Fe by DMT1 inhibits astroglial Na -K -ATPase, which leads to elevation in cytoplasmic Na concentration, thus reversing Na /Ca exchanger and thereby generating Ca influx. Uptake of Fe by TF-TFR stimulates phospholipase C to produce inositol 1,4,5-trisphosphate (InsP ), thus triggering InsP receptor-mediated Ca release from endoplasmic reticulum. In summary, these findings reveal the mechanisms of iron-induced astrocytic signalling operational in conditions of iron overload