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Iron accumulation associated with aging modulates canonical Wnt/β-catenin signaling leading to the progression of liver injury, neurodegenerative diseases, bone remodeling, cancer, and ocular disorders.
Source publication
Iron accumulates in the vital organs with aging. This is associated with oxidative stress, inflammation, and mitochondrial dysfunction leading to age-related disorders. Abnormal iron levels are linked to neurodegenerative diseases, liver injury, cancer, and ocular diseases. Canonical Wnt signaling is an evolutionarily conserved signaling pathway th...
Citations
... In addition, using the cell line LS174T, wild-type APC but mutant beta-catenin also proved responsive, suggesting that the role of Fe is to regulate beta-catenin. The authors therefore speculated that excess Fe could exacerbate tumorigenesis against the background of APC loss, a situation commonly observed in tumors [139][140][141]. ...
Essential trace elements play an important role in human physiology and are associated with various functions regulating cellular metabolism. Non-essential trace elements, on the other hand, often have well-documented toxicities that are dangerous for the initiation and development of diseases due to their widespread occurrence in the environment and their accumulation in living organisms. Non-essential trace elements are therefore regarded as serious environmental hazards that are harmful to health even in low concentrations. Many representatives of these elements are present as pollutants in our environment, and many people may be exposed to significant amounts of these substances over the course of their lives. Among the most common non-essential trace elements are heavy metals, which are also associated with acute poisoning in humans. When these elements accumulate in the body over years of chronic exposure, they often cause severe health damage in a variety of tissues and organs. In this review article, the role of selected essential and non-essential trace elements and their role in the development of exemplary pathophysiological processes in the cardiovascular system will be examined in more detail.
... Desferrioxamine mesylate (DFO) is a kind of chelator that is clinically used to treat iron poisoning and iron overload [4]. Chelates consist of DFO and ferric ion, which could be excreted completely through urine and feces [5]. Therefore, iron deposited in organs could be reduced. ...
Background
Previous meta-analysis had concluded that desferrioxamine mesylate (DFO) could effectively treat intracerebral hematoma (ICH) in animal models. We hope to confirm that DFO could treat ICH patients effectively through the systemic review and meta-analysis of clinical researches.
Method
Data extraction included hematoma volume (HV), reduction of National Institute of Health Stroke Scale (NIHSS) scores, and relative perihematomal edema (RPHE). The standard mean difference (SMD) and 95% confidence interval (95% CI ) were calculated by fixed effects model. I-square ( I ² ) statistic was used to test the heterogeneity. All p values were two-side with a significant level at 0.05.
Results
Five randomized controlled trials were included in the meta-analysis, which included 239 patients. At 7 days after onset, there was significant difference of RPHE development (− 1.87 (− 2.22, − 1.51) ( I ² = 0, p = 0.639)) and significant difference of HV absorption (− 0.71 (− 1.06, 0.36) ( I ² = 17.5%, p = 0.271)) between DFO and control groups. There was significant difference of reduction of NHISS scores (0.25 (0.05, 0.46) ( I ² = 0, p = 0.992)) between DFO and control groups at 30 days after onset.
Conclusion
DFO reduced HV and perihematomal edema in ICH patients at 7 days after onset and improve neurological function at 30 days after onset efficiently and safely. DFO might be a new route of improving treatment of ICH.
... The accumulation of iron due to its impaired homeostasis can be particularly dangerous. The iron toxicity is caused by its potential to induce oxidative stress thought ROS production and consequently inflammation [49]. ROS can affect DNA, protein and lipid integrity damaging cellular functionality [50]. ...
... Equally, ferritin acts as a local cytokine inducing an increase of pro-inflammatory cytokines such as IL-1β [52]. Moreover, inflammation itself induces iron accumulatio in tissues such as liver upregulating hepcidin [53] and thus reducing FPN1 causing the establishment of a vicious circle, where iron-mediated inflammation generates in turn an increase of intracellular iron levels which consequently induces oxidative stress and iron-mediated inflammation [49]. ...
... Recent studies indicate that iron regulates Wnt signaling, and that the iron chelator DFX can inhibit Wnt signaling [91]. Wnt activation is known to enhance inflammatory processes [92], therefore it is implicated in the pathogenesis of several diseases [49]. The relation between iron excess and the alteration of Wnt signaling has been investigated in neurodegenerative disorders. ...
Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.
... The retina is a part of the central nervous system; it contains complex neural circuitry and transduces the converted electrical potentials to the brain [10]. The neuroprotective roles of rapamycin may be a novel therapeutic pathway in ocular neurodegenerative diseases, such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma, which share common pathophysiological mechanisms, especially increased and prolonged oxidative stress, which would ultimately result in retinal neuronal death [11][12][13][14]. Recently, a large number of studies have been conducted to elucidate the neuroprotective role of rapamycin and its underlying mechanism(s) in the treatment of ocular degenerative diseases [15][16][17][18][19][20][21][22][23][24][25][26][27]. ...
Recent advances in the research of the mammalian target of the rapamycin (mTOR) signalling pathway demonstrated that mTOR is a robust therapeutic target for ocular degenerative diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. Although the exact mechanisms of individual ocular degenerative diseases are unclear, they share several common pathological processes, increased and prolonged oxidative stress in particular, which leads to functional and morphological impairment in photoreceptors, retinal ganglion cells (RGCs), or retinal pigment epithelium (RPE). mTOR not only modulates oxidative stress but is also affected by reactive oxygen species (ROS) activation. It is essential to understand the complicated relationship between the mTOR pathway and oxidative stress before its application in the treatment of retinal degeneration. Indeed, the substantial role of mTOR-mediated autophagy in the pathogenies of ocular degenerative diseases should be noted. In reviewing the latest studies, this article summarised the application of rapamycin, an mTOR signalling pathway inhibitor, in different retinal disease models, providing insight into the mechanism of rapamycin in the treatment of retinal neurodegeneration under oxidative stress. Besides basic research, this review also summarised and updated the results of the latest clinical trials of rapamycin in ocular neurodegenerative diseases. In combining the current basic and clinical research results, we provided a more complete picture of mTOR as a potential therapeutic target for ocular neurodegenerative diseases.
This study aimed to investigate the mechanism of iron on intestinal epithelium development of suckling piglets. Compared with newborn piglets, 7-day-old and 21-day-old piglets showed changes in the morphology of the jejunum, increased proliferation, differentiated epithelial cells, and expanded enteroids. Intestinal epithelium maturation markers and iron metabolism genes were significantly changed. These results suggest that lactation is a critical stage in intestinal epithelial development, accompanied by changes in iron metabolism. In addition, deferoxamine (DFO) treatment inhibited the activity of intestinal organoids at passage 4 (P4) of 0-day-old piglets, but no significant difference was observed in epithelial maturation markers at passage 1 (P1) and P4, and only argininosuccinate synthetase 1 (Ass1) and β-galactosidase (Gleb) were up-regulated at passage 7 (P7). These results in vitro show that iron deficiency may not directly affect intestinal epithelium development through intestinal stem cells (ISCs). The iron supplementation significantly down-regulated the mRNA expression of interleukin-22 receptor subunit alpha-2 (IL-22RA2) in the jejunum of piglets. Furthermore, the mRNA expression of IL-22 in 7-day-old piglets was significantly higher than that in 0-day-old piglets. Adult epithelial markers were significantly up-regulated in organoids treated with recombinant murine cytokine IL-22. Thus, IL-22 may play a key role in iron-affecting intestinal epithelium development.
It is a great challenge to develop a safe and effective treatment strategy for age-related osteoporosis and fracture healing. As one of the four FOXO transcription factors, FOXO1 is essential for cell proliferation, survival, senescence, energy metabolism, and oxidative stress in various cells. Our previous study demonstrated that specific Foxo1 gene deletion in osteoblasts in young mice results in bone loss while that in aged mice shows the opposite effect. However, the mechanism underlying the differential regulation of bone metabolism by FOXO1 remains to be elucidated. In this study, we generated osteoblast-specific Foxo1 knockout mice by using Foxo1fl/fl and Bglap-Cre mice. In young mice, Foxo1 gene deletion inhibits osteoblast differentiation, leading to a decreased osteoblast number and decreased bone formation rate because of the weakened ability to resist oxidative stress, eventually resulting in bone loss and delayed healing of bone defects. In aged mice, high levels of reactive oxygen species (ROS) promote the diversion of CTNNB1 (β-catenin) from T cell factor 4 (TCF4)- to FOXO1-mediated transcription, thereby inhibiting Wnt/β-catenin signaling and leading to decreased osteogenic activity. Conversely, FOXO1 deficiency indirectly promotes the binding of β-catenin and TCF4 and activates Wnt/β-catenin signaling, thereby alleviating age-related bone loss and improving bone defect healing. Our study proves that FOXO1 has differential effects on bone metabolism in young and aged mice and elucidates its underlying mechanism. Further, this study provides a new perspective on the treatment of age-related osteoporosis.
