It is now understood that iron crosses the blood-brain barrier via a complex metabolic regulatory network and participates in diverse critical biological processes within the central nervous system, including oxygen transport, energy metabolism, and the synthesis and catabolism of myelin and neurotransmitters. During brain development, iron is distributed throughout the brain, playing a pivotal role in key processes such as neuronal development, myelination, and neurotransmitter synthesis. In physiological aging, iron can selectively accumulate in specific brain regions, impacting cognitive function and leading to intracellular redox imbalance, mitochondrial dysfunction, and lipid peroxidation, thereby accelerating aging and associated pathologies. Furthermore, brain iron accumulation may be a primary contributor to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Comprehending the role of iron in brain development, aging, and neurodegenerative diseases, utilizing iron-sensitive Magnetic Resonance Imaging (MRI) technology for timely detection or prediction of abnormal neurological states, and implementing appropriate interventions may be instrumental in preserving normal central nervous system function.

Chronic stress can lead to nervous system dysfunction and depression-like behaviors in animals. Gypenosides can improve chronic stress-induced neuronal damage, but the protective mechanism remains poorly understood. This study aims to investigate the effect and mechanism of gypenosides on chronic stress-induced neuronal ferroptosis. Therefore, we established a chronic stress-induced neuronal damage model in vitro using corticosterone to induce PC12 cell injury. We demonstrated that ferroptosis inhibitors DFO and Ferrostatin-1 alleviated corticosterone-induced cell death in PC12 cells by reducing iron accumulation, lipid peroxidation, and increasing cell viability. Meanwhile, gypenosides attenuated ferroptosis agonist Erastin-induced ferroptosis in PC12 cells. Then, gypenosides ameliorated corticosterone-induced ferroptosis in PC12 cells. In terms of molecular mechanisms, gypenosides decreased the expression of Hepcidin and DMT1, and increased the expression of Ferritin and FPN1, thereby improving corticosterone-induced iron homeostasis disorders and iron accumulation. Moreover, gypenosides improved corticosterone-induced lipid peroxidation by inhibiting GLS2 expression, upregulating the expression of SLC7A11 and glutathione peroxidase 4, and reducing glutamate accumulation and GSH depletion. Gypenosides also reduced corticosterone-induced release of inflammatory cytokines, the expression of TNFR1, and the phosphorylation of NF-κB and p53 in PC12 cells. These findings indicate that gypenosides attenuate corticosterone-induced ferroptosis by inhibiting TNF-α/NF-κB signaling pathway in PC12 cells.

Along with the hallmark of α-synuclein deposition, neuroinflammation and iron accumulation have emerged as essential pathological features for dopaminergic neuron degeneration in PD patients and animal models. Preclinical studies have highlighted gentiopicroside's anti-inflammatory activities in treating arthritis, colitis and pancreatitis, and its neuroprotective effects on neurological diseases such as AD, chronic neuropathic pain and ischemia. However, the effects and mechanisms of gentiopicroside on PD-related conditions remain uncertain. Here, we evaluated the potential benefits of gentiopicroside using a unilateral 6-OHDA rat model and a MPP+-induced cell model. Our findings indicated that gentiopicroside improved motor deficits and restored nigral TH-positive neurons in vivo. Mechanistically, gentiopicroside ameliorated inflammatory responses of 6-OHDA-induced rats, decreased NF-κB and pro-inflammatory cytokines levels and reduced Iba-1-positive microglia in the substantia nigra. Furthermore, gentiopicroside regulated the levels of DMT1 and FPN1, thereby inhibiting iron accumulation in PD rats. In vitro, gentiopicroside preserved the viability of MPP+-treated SH-SY5Y cells and suppressed NF-κB activity and its downstream factors' levels. Meanwhile, gentiopicroside inhibited lipid peroxidation and ROS production, while it upregulated the expression of GPX4 in MPP+-treated cells. And these antiferroptosis effects were also linked to iron transporters regulation. Conclusively, gentiopicroside exhibits neuroprotective effects via alleviating neuroinflammation and iron-dependent ferroptosis, offering promise for PD treatment.

Iron plays a pivotal role in numerous fundamental biological processes in the brain. Among the various cell types in the central nervous system, microglia are recognized as the most proficient cells in accumulating and storing iron. Nonetheless, iron overload can induce inflammatory phenotype of microglia, leading to the production of proinflammatory cytokines and contributing to neurodegeneration. A growing body of evidence shows that disturbances in iron homeostasis in microglia is associated with a range of neurodegenerative disorders. Recent research has revealed that microglia are highly sensitive to ferroptosis, a form of iron-dependent cell death. How iron overload influences microglial function? Whether disbiosis in iron metabolism and ferroptosis in microglia are involved in neurodegenerative disorders and the underlying mechanisms remain to be elucidated. In this review we focus on the recent advances in research on microglial iron metabolism as well as ferroptosis in microglia. Meanwhile, we provide a comprehensive overview of the involvement of microglial ferroptosis in neurodegenerative disorders from the perspective of crosstalk between microglia and neuron, with a focus on Alzheimer's disease and Parkinson's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the formation of amyloid plaques, neurofibrillary tangles and progressive cognitive decline. Amyloid-beta peptide (Aβ) monoclonal antibody therapeutic clinical trials have nearly failed, raising significant concerns about other etiological hypotheses about AD. Recent evidence suggests that AD patients also exhibit persistent neuronal loss and neuronal death accompanied by brain iron deposition or overload-related oxidative stress. Ferroptosis is a type of cell death that depends on iron, unlike autophagy and apoptosis. Inhibiting neuronal ferroptosis function is effective in improving cognitive impairment in AD. Notably, new research shows that ferroptosis in AD is crucially dependent on glial cell activation. This review examines the relationship between the imbalance of iron metabolism, the regulation of iron homeostasis in glial cells and neuronal death in AD pathology. Finally, the review summarizes some current drug research in AD targeting iron homeostasis, many novel iron-chelating compounds and natural compounds showing potential AD-modifying properties that may provide therapeutic targets for treating AD.

Chronic kidney disease induces alterations in the heterogeneity of iron deposition within the basal ganglia. Quantitative analysis of the heterogeneity of iron deposition within the basal ganglia may be valuable for diagnosing chronic kidney disease-related cognitive impairment.

In this prospective observational cohort study, quantitative susceptibility mapping (QSM) was performed in chronic kidney disease patients. Susceptibility values of each nucleus within the basal ganglia were measured. Radiomic features were extracted from habitats of the basal ganglia on QSM images. Habitat-based models for diagnosing cognitive impairment were constructed using the random forest algorithm. Logistic regression was employed to build the clinical model and the combined model. The performance of each model was evaluated by the receiver operating characteristic (ROC) analysis.

A total of 146 patients (mean age, 51 ± 13 years; 92 male) were included, of which 79 had cognitive impairment. The two habitats-based model achieved an area under the curve of 0.926 (95% CI 0.842-1.000) on the test set, the highest among all prediction models. The two-habitat maps indicated that chronic kidney disease had two distinct patterns of impact on iron deposition in the basal ganglia region. The capability of the two habitats-based model to identify chronic kidney disease-related cognitive impairment was significantly superior to that of the susceptibility values measured in various nuclei (all p < 0.05).

This study innovatively applied a habitat-based quantitative analysis technique to QSM, successfully constructing a model that accurately diagnoses chronic kidney disease-related cognitive impairment.

This study was approved by the Beijing Friendship Hospital Ethics Board (ClinicalTrials.gov Identifier: NCTO5137470) and conducted in accordance with the Declaration of Helsinki ethical standards.

Regional brain iron dyshomeostasis is observed in cerebral small vessel disease (cSVD) and other neurodegeneration processes. However, its spatial patterns, cognitive impact, and underlying pathological mechanisms remain unclear.

Voxel-based analysis of quantitative susceptibility mapping (QSM) was used to detect regional susceptibility changes, and their correlations with cognitive function were assessed using linear regression. We combined the microarray dataset from the Allen Human Brain Atlas (AHBA) to explore the pathological mechanisms of iron deposition patterns.

A total of 87 cSVD patients and 80 controls were included in the study. Increased QSM values in the bilateral putamen and caudate were associated with cognitive decline in cSVD. Gene set enrichment analysis revealed the enrichment of gene sets related to central nervous system integrity.

Iron deposition in deep gray matter may indicate cognitive changes in cSVD and could be linked to the disruption of brain structural and functional integrity.

Increased susceptibility values, indicating focal iron deposition, were observed in the deep gray matter of patients with cerebral small vessel disease (cSVD). Regional iron concentration in the deep gray nuclei was associated with cognitive impairment in cSVD patients. Imaging transcriptomics suggests that cSVD-related iron deposition is linked to the structural and functional integrity of the brain. An open-source script for imaging transcriptomics focusing on regional gene expression was developed and proposed.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons and the aggregation of α-synuclein. Neuroinflammation is triggered by the activation of microglia and astrocytes, which release pro-inflammatory factors that exacerbate neuronal damage. This inflammatory state also disrupts iron homeostasis, leading to the occurrence of ferroptosis. Ferroptosis is characterized by lipid peroxidation of cell membranes and iron overload. Abnormal accumulation of iron in the brain increases oxidative stress and lipid peroxidation, further aggravating neuroinflammation and damage to dopaminergic neurons. Natural products have garnered attention for their antioxidant, anti-inflammatory, and neuroprotective properties, with many plant extracts showing promising therapeutic potential in PD research. This study further investigates the potential therapeutic roles of various natural products in regulating neuroinflammation and ferroptosis. The results suggest that natural products have significant therapeutic potential in modulating the interaction between neuroinflammation and ferroptosis, making them potential treatments for PD. Future research should further validate the safety and efficacy of these natural compounds in clinical applications to develop novel therapeutic strategies for PD.

Inflammatory bowel disease (IBD) is an inflammatory disease that occurs to the intestinal tract. Many patients with IBD often develop anemia and often receive oral iron supplementation. Many of them develop non-compliance with oral iron therapy, but the mechanisms are not well understood. We interrogated whether colonic epithelial iron overload impacts cell viability and disease severity. We observed increased expression of iron importers and iron accumulation in mature colonocytes in dextran sulfate sodium (DSS)-induced acute colitis and in humans with active colitis. Administration of hepcidin increased epithelial iron overload and aggravated colonic inflammation in DSS-treated mice and IL10-/- mice. Hepcidin-induced iron accumulation increased colonic epithelial death, which was prevented by treatment with Trolox, a vitamin E analog and a scavenger of lipid peroxides. By using cultured Caco-2 cells, we showed that iron and inflammatory cytokines (TNF-α and IL-1β) induced a synergistic increase in the number of necrotic cells. We then showed that the combined treatment by hepcidin and cytokines increased labile iron content and lipid peroxidation in Caco-2 cells. Moreover, liproxstatin-1, a ferroptosis inhibitor, and deferoxamine, an iron chelator, both abolished the hepcidin/cytokines induced death of Caco-2 cells, suggesting ferroptosis. We further elucidated that inflammatory cytokines promote lipid peroxidation and ferroptosis by inducing NOX1-dependent exhaustion of reduced glutathione (GSH). Collectively, our findings demonstrate that the inflammatory context predisposes colonic epithelial cells to iron overload mediated ferroptosis, exacerbating colonic inflammation.

Vitrectomy with silicone oil (SO) endotamponade is an effective treatment for vision-threatening retinal diseases. However, unexplained vision impairment has been reportedly critical side effects. Previously, we reported that the eyes with ocular toxoplasmosis showed retinal ferroptosis with the clinical sign of reduced intravitreal iron (Fe). We also found that total iron levels in sub-silicone oil fluid (SOF) in eyes with SO endotamponade were significantly reduced. We hypothesized that the cause of complications related to SO endotamponade is retinal ferroptosis and that low total iron in SOF is a secondary change that occurs similarly to the changes in ocular toxoplasmosis. In this study, we measured total iron levels in ocular fluid from patients, rabbits with SO endotamponade. Retinal iron taken up from the SOF was evaluated using laser ablation inductively coupled plasma mass spectrometry in human and rabbit eyes. Retinal ferroptosis was confirmed by immunohistochemistry of 4-hydrox-2-nonenal-modified proteins, FeRhoNox-1 staining, western blotting and RT-PCR. We found low total iron levels in the SOF, increased oxidative stress and Fe uptake from the SOF into the retinae of human and rabbit eyes, as well as decreased GPx4 expression, increased FeRhoNox-1 signals and altered Fe-related gene expression in SO-filled rabbit eyes. Of note, the target of ferroptosis was Müller cells. We generated an in vitro silicone oil-filled eye model using MIO-M1 cells (a human Müller cell line). The in vitro SO-filled eye model showed decreased GPx4 expression and increased intracellular catalytic Fe(II), an increase in ferroptosis, prevention of cell death by ferrostatin-1, a ferroptosis inhibitor, and altered Fe-related gene expression. These results indicate that the cause of complications related to SO endotamponade was the induction of retinal (Müller cell) ferroptosis, which can be prevented by ferrostatin-1.

As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.

Parkinson's disease (PD) is closely related to iron accumulation and inflammation. Emerging evidence indicates that TMEM106B plays an essential role in PD. But whether TMEM106B could act on neuroinflammation and iron metabolism in PD has not yet been investigated. The aim of this study was to investigate the pathological mechanisms of inflammation and iron metabolism of TMEM106B in PD. 1-methyl-4-phenylpyridinium (MPP+)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SH-SY5Y cells and mice were treated with LV-shTMEM106B and AAV-shTMEM106B to construct PD cellular and mouse models. Pole tests and open-field test (OFT) were performed to evaluate the locomotion of the mice. Immunohistochemistry and iron staining were used to detect TH expression and iron deposition in the SN. Iron staining was used to measure the levels of iron. Western blotting was used to detect the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)), NOD-like receptor protein 3 (NLRP3) inflammasome, divalent metal transporter 1 (DMT1), and Ferroportin1 (FPN1)). Knockdown of TMEM106B improved motor ability and rescued dopaminergic (DA) neuron loss. TMEM106B knockdown attenuated the increases of TNF-α, IL-6, NLRP3 inflammasome, and DMT1 expression in the MPP+ and MPTP-induced PD models. Furthermore, TMEM106B knockdown also increases the expression of FPN1. This study provides the first evidence that knockdown of TMEM106B prevents dopaminergic neurodegeneration by modulating neuroinflammation and iron metabolism.

The link between overload brain iron and transcriptional/cellular signatures in Alzheimer's disease (AD) remains inconclusive.

Iron deposition in 41 cortical and subcortical regions of 30 AD patients and 26 healthy controls (HCs) was measured using quantitative susceptibility mapping (QSM). The expression of 15,633 genes was estimated in the same regions using transcriptomic data from the Allen Human Brain Atlas (AHBA). Partial least square (PLS) regression was used to identify the association between the healthy brain gene transcription and aberrant regional QSM signal in AD. The biological processes and cell types associated with the linked genes were evaluated.

Gene ontological analyses showed that the first PLS component (PLS1) genes were enriched for biological processes relating to the "protein phosphorylation" and "metal ion transport". Additionally, these genes were expressed in microglia (MG) and glutamatergic neurons (GLUs).

Our findings provide mechanistic insights from transcriptional and cellular signatures into regional iron accumulation measured by QSM in AD.

Spatial patterns of iron deposition changes in AD correlate with cortical spatial expression genes in healthy subjects. The identified gene transcription profile underlies aberrant iron accumulation in AD was enriched for biological processes relating to "protein phosphorylation" and "metal ion transport". The related genes were predominantly expressed in MG and GLUs.

The cognitive decline associated with chronic metabolic disease diabetes has garnered extensive scrutiny, yet its pathogenesis remains incompletely understood, and the advancement of targeted therapeutics has posed a persistent challenge. Ferroptosis, a novel form of cell death characterized by intracellular lipid peroxidation and iron overload, has recently emerged as a significant factor. Numerous contemporary studies have corroborated that ferroptosis within the neurovascular unit is intimately associated with the onset of diabetes-induced cognitive impairment. Numerous contemporary studies have corroborated that ferroptosis within the neurovascular unit is intimately associated with the onset of diabetic cognitive impairment (DCI). This article initially conducts a profound analysis of the mechanism of ferroptosis, followed by a detailed elucidation of the specific manifestations of neurovascular unit ferroptosis in the context of diabetic cognitive function impairment. Furthermore, an exhaustive review of pertinent literature from April 2020 to March 2024 has been undertaken, resulting in the selection of 31 documents of significant reference value. These documents encompass studies on 11 distinct drugs, all of which are centered around investigating methods to inhibit the ferroptosis pathway as a potential treatment for DCI. Simultaneously, we conducted a review of 12 supplementary literary sources that presented 10 pharmacological agents with anti-ferroptosis properties in other neurodegenerative disorders. This article critically examines the potential influence of neurovascular unit ferroptosis on the progression of cognitive impairment in diabetes, from the three aforementioned perspectives, and organizes the existing and potential therapeutic drugs. It is our aspiration that this article will serve as a theoretical foundation for scholars in related disciplines when conceptualizing, investigating, and developing novel clinical drugs for DCI.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein in the brain. Ferroptosis, a recently identified form of regulated cell death, is critical in PD pathogenesis due to its association with iron deposition, overproduction of reactive oxygen species, iron-dependent lipid peroxidation and impaired lipid peroxidation clearance. This cell death mechanism is closely linked to several pathogenic processes in PD, including α-synuclein aggregation, oxidative stress, mitochondrial dysfunction, microglia-induced neuroinflammation, and neuromelanin accumulation. Given the significant role of ferroptosis in these mechanisms, there is increasing interest in targeting ferroptosis for PD treatment. Several drugs have shown potential in alleviating PD symptoms by inhibiting ferroptosis. This review aims to consolidate current knowledge on ferroptosis in PD and assess the therapeutic potential of anti-ferroptosis drugs, highlighting promising directions for future research and clinical applications.

Cryptosporidium parvum (C. parvum) is the most prevalent enteric protozoan parasite causing infectious diarrhea in neonatal calves worldwide with a direct negative impact on their health and welfare. This study utilized next-generation sequencing (NGS) to deepen our understanding of intestinal epithelial barriers and transport mechanisms in the pathophysiology of infectious diarrhea in neonatal calves, which could potentially unveil novel solutions for treatment.

At day 1 of life, male Holstein-Friesian calves were either orally infected (n = 5) or not (control group, n = 5) with C. parvum oocysts (in-house strain LE-01-Cp-15). On day 8 after infection, calves were slaughtered and jejunum mucosa samples were taken. The RNA was extracted from collected samples and subjected to sequencing. Differentially expressed genes (DEG) between the infected and CTRL groups were assessed using DESeq2 at a false discovery rate < 0.05 and used for gene ontology (GO) and pathway enrichment analysis in Cytoscape (v3.9.1).

To study the pathophysiology of infectious diarrhea on intestinal permeability, 459 genes related to epithelial cell barrier integrity and paracellular and transmembrane transport systems were selected from 12,908 identified genes in mucus. Among, there were 61 increased and 109 decreased gene transcripts belonged to adhesion molecules (e.g. ADGRD1 and VCAM1), ATP-binding cassette (ABC, e.g. ABCC2 and ABCD1) and solute carrier (SLC, e.g. SLC28A2 and SLC38A3) transporters, and ion channels (e.g. KCNJ15). Our results suggest deregulation of cellular junctions and thus a possibly increased intestinal permeability, whereas deregulation of ABC and SLC transporters and ion channels may influence the absorption/secretion of amino acids, carbohydrates, fats, and organic compounds, as well as acid-based balance and osmotic hemostasis. Besides pathogen-induced gene expression alterations, part of the DEG may have been triggered or consequently affected by inflammatory mechanisms. The study provided a deeper understanding of the pathophysiology of infectious diarrhea in neonatal calves and the host-pathogen interactions at the transcript level. For further studies with a particular focus on the transport system, these results could lead to a new approach to elucidating pathophysiological regulatory mechanisms.

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, where degeneration and death of nucleus pulposus cells within the intervertebral disc (IVD) can be obviously revealed. This degeneration can result in an imbalance in the extracellular matrix due to the loss of proteoglycans and water content, which can further lead to catabolic and anabolic dysfunction of the IVD. Recently, the dysfunction of cartilage endplate (CEP) during aging has drawn large attention due to its essential functions in contributing nutrient exchange and maintaining IVD homeostasis. Furthermore, the inflammation and disturbed homeostasis of CEP not only accelerate the degradation of nucleus pulposus extracellular matrix, but also exacerbate IVDD by causing nucleus pulposus cell death through other pathological factors. Here in this review, we summarized the possible pathological factors and the underlying mechanisms of the CEP inflammation-induced IVDD, including exosomes degeneration, CEP calcification, ferroptosis, mechanical changes, and cell senescence. Besides, changes of miRNAs, pain-related neural reflex arc and pathways associated with CEP inflammation-induced IVDD are also reviewed. In addition, new strategies specifically designed for CEP inflammation-induced IVDD are also discussed in the last section. We hope this paper can not only offer some new insights for advancing novel strategies for treating IVDD, but also serve as a valuable reference for researchers in this field.

Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). In most patients, the disease starts with an acute onset followed by a remission phase, subsequent relapses and a later transition to steady chronic progression. In a minority of patients, this progressive phase develops from the beginning. MS relapses are characterized predominantly by the de novo formation of an inflammatory CNS lesion and the infiltration of immune cells, whereas the pathological features of MS progression include slowly expanding lesions, global brain atrophy and an inflammatory response predominantly mediated by macrophages/microglia. Importantly, this CNS-intrinsic pathophysiology appears to initiate early during the relapsing-remitting disease phase, while it turns into the key clinical MS feature in later stages. Currently approved disease-modifying treatments for MS are effective in modulating peripheral immunity by dampening immune cell activity or preventing the migration of immune cells into the CNS, resulting in the prevention of relapses; however, they show limited success in halting MS progression. In this manuscript, we first describe the pathological mechanisms of MS and summarize the approved therapeutics for MS progression. We also review the treatment options for progressive MS (PMS) that are currently under investigation. Finally, we discuss potential targets for novel treatment strategies in PMS.

The mechanisms of secondary injury following spinal cord injury are complicated. The role of ferroptosis, which is a newly discovered form of regulated cell death in the neurovascular unit(NVU), is increasingly important. Ferroptosis inhibitors have been shown to improve neurovascular homeostasis and attenuate secondary spinal cord injury(SCI). This review focuses on the mechanisms of ferroptosis in NVU cells and NVU-targeted therapeutic strategies according to the stages of SCI, and analyzes possible future research directions.

The activation of complement receptor 3 (CR3) in microglia contributes to neurodegeneration in neurological disorders, including Parkinson's disease (PD). However, it remains unclear for mechanistic knowledge on how CR3 mediates neuronal damage. In this study, the expression of CR3 and its ligands iC3b and ICAM-1 was found to be up-regulated in the midbrain of rotenone PD mice, which was associated with elevation of iron content and disruption of balance of iron metabolism proteins. Interestingly, genetic deletion of CR3 blunted iron accumulation and recovered the expression of iron metabolism markers in response to rotenone. Furthermore, reduced lipid peroxidation, ferroptosis of dopaminergic neurons and neuroinflammation were detected in rotenone-lesioned CR3-/- mice compared with WT mice. The regulatory effect of CR3 on ferroptotic death of dopaminergic neurons was also mirrored in vitro. Mechanistic study revealed that iron accumulation in neuron but not the physiological contact between microglia and neurons was essential for microglial CR3-regulated neuronal ferroptosis. In a cell-culture system, microglial CR3 silence significantly dampened iron deposition in neuron in response to rotenone, which was accompanied by mitigated lipid peroxidation and neurodegeneration. Furthermore, ROS released from activated microglia via NOX2 was identified to couple microglial CR3-mediated iron accumulation and subsequent neuronal ferroptosis. Finally, supplementation with exogenous iron was found to recover the sensitivity of CR3-/- mice to rotenone-induced neuronal ferroptosis. Altogether, our findings suggested that microglial CR3 regulates neuron ferroptosis through NOX2 -mediated iron accumulation in experimental Parkinsonism, providing novel points of the immunopathogenesis of neurological disorders.

We previously reported that high mobility group box 1 (HMGB1), a danger-associated molecular pattern (DAMP), increases intracellular iron levels in the postischemic brain by upregulating hepcidin, a key regulator of iron homeostasis, triggering ferroptosis. Since hepatocytes are the primary cells that produce hepcidin and control systemic iron levels, we investigated whether cerebral ischemia induces hepcidin upregulation in hepatocytes. Following middle cerebral artery occlusion (MCAO) in a rodent model, significant liver injury was observed. This injury was evidenced by significantly elevated Eckhoff's scores and increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, total iron levels were significantly elevated in the liver, with intracellular iron accumulation detected in hepatocytes. Hepcidin expression in the liver, which is primarily localized in hepatocytes, increased significantly starting at 3 h after MCAO and continued to increase rapidly, reaching a peak at 24 h. Interestingly, HMGB1 levels in the liver were also significantly elevated after MCAO, with the disulfide form of HMGB1 being the major subtype. In vitro experiments using AML12 hepatocytes showed that recombinant disulfide HMGB1 significantly upregulated hepcidin expression in a Toll-like receptor 4 (TLR4)- and RAGE-dependent manner. Furthermore, treatment with a ROS scavenger and a peptide HMGB1 antagonist revealed that both ROS generation and HMGB1 induction contributed to hepatocyte activation and liver damage following MCAO-reperfusion. In conclusion, this study revealed that cerebral ischemia triggers hepatocyte activation and liver injury. HMGB1 potently induces hepcidin not only in the brain but also in the liver, thereby influencing systemic iron homeostasis following ischemic stroke.

Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer's disease (AD). In vitro, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of microglial-specific knockdown of Slc11a2 on AD-related cognitive decline and microglial transcriptional phenotype.

In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1Cre-ERT2;Slc11a2flfl;APP/PS1+or - mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b+ microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted.

DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2KD APP/PS1 females displayed significant increases in Enpp2, Ttr, and the iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2KD cells from APP/PS1 females also exhibited decreased expression of markers associated with subsets of disease-associated microglia (DAMs), such as Apoe, Ctsb, Ly9, Csf1, and Hif1α.

This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in Slc11a2KD APP/PS1 female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.

Iron (Fe) is a co-factor for enzymes of the developing brain necessitating sufficient supply. We investigated the effects of administering ferric derisomaltose/Fe isomaltoside (FDI) subcutaneously to Fe-deficient (ID) pregnant rats on cerebral and hepatic concentrations of essential metals and the expression of iron-relevant genes.

Pregnant rats subjected to ID were injected with FDI on the day of mating (E0), 14 days into pregnancy (E14), or the day of birth (postnatal (P0)). The efficacy was evaluated by determination of cerebral and hepatic Fe, copper (Cu), and zinc (Zn) and gene expression of ferroportin, hepcidin, and ferritin H + L in pups on P0 and as adults on P70.

Females fed an ID diet (5.2 mg/kg Fe) had offspring with significantly lower cerebral and hepatic Fe compared to female controls fed a standard diet (158 mg/kg Fe). Cerebral Cu increased irrespective of supplying a standard diet or administering FDI combined with the standard diet. Hepatic hepcidin mRNA was significantly lower following ID. Cerebral hepcidin mRNA was hardly detectable irrespective of iron status.

In conclusion, administering FDI subcutaneously to ID pregnant rats on E0 normalizes fetal cerebral and hepatic Fe. When applied at later gestational ages, supplementation with additional Fe to the offspring is needed to normalize cerebral and hepatic Fe.

Brain iron increases in several neurodegenerative diseases are associated with disease progression. However, the causes of increased brain iron remain unclear. This study investigates relationships between subcortical iron, systemic iron and inflammatory status. Brain magnetic resonance imaging (MRI) scans and blood plasma samples were collected from cognitively healthy females (n = 176, mean age = 61.4 ± 4.5 years, age range = 28-72 years) and males (n = 152, mean age = 62.0 ± 5.1 years, age range = 32-74 years). Regional brain iron was quantified using quantitative susceptibility mapping. To assess systemic iron, haematocrit, ferritin and soluble transferrin receptor were measured, and total body iron index was calculated. To assess systemic inflammation, C-reactive protein (CRP), neutrophil:lymphocyte ratio (NLR), macrophage colony-stimulating factor 1 (MCSF), interleukin 6 (IL6) and interleukin 1β (IL1β) were measured. We demonstrated that iron levels in the right hippocampus were higher in males compared with females, while iron in the right caudate was higher in females compared with males. There were no significant associations observed between subcortical iron levels and blood markers of iron and inflammatory status indicating that such blood measures are not markers of brain iron. These results suggest that brain iron may be regulated independently of blood iron and so directly targeting global iron change in the treatment of neurodegenerative disease may have differential impacts on blood and brain iron.

Apart from dopaminergic neurotoxicity, exposure to rotenone, a commonly used insecticide in agriculture, also adversely affects hippocampal and cortical neurons, resulting in cognitive impairments in mice. We recently established a role of microglia-mediated neuroinflammation in rotenone-elicited deficits of cognition, yet the mechanisms remain elusive. Here, we investigated the involvement of NADPH oxidase 2 (NOX2) catalytic subunit gp91phox in rotenone-induced cognitive deficits and the associated mechanisms. Our study demonstrated that rotenone exposure elevated expression of gp91phox and phosphorylation of the NOX2 cytosolic subunit p47phox, along with NADPH depletion in the hippocampus and cortex of mice, indicating NOX2 activation. Specific knockdown of gp91phox in microglia via adeno-associated virus delivery resulted in reduced microglial activation, proinflammatory gene expression and improved learning and memory capacity in rotenone-intoxicated mice. Genetic deletion of gp91phox also reversed rotenone-elicited cognitive dysfunction in mice. Furthermore, microglial gp91phox knockdown attenuated neuronal damage and synaptic loss in mice. This intervention also suppressed iron accumulation, disruption of iron-metabolism proteins and iron-dependent lipid peroxidation and restored the balance of ferroptosis-related parameters, including GPX4, SLC711, PTGS2, and ACSL4 in rotenone-lesioned mice. Intriguingly, pharmacological inhibition of ferroptosis with liproxstatin-1 conferred protection against rotenone-induced neurodegeneration and cognitive dysfunction in mice. In summary, our findings underscored the contribution of microglial gp91phox-dependent neuroinflammation and ferroptosis to learning and memory dysfunction in rotenone-lesioned mice. These results provided valuable insights into the pathogenesis of cognitive deficits associated with pesticide-induced Parkinsonism, suggesting potential therapeutic avenues for intervention.

Wilson's disease (WD) is inherited in an autosomal recessive manner and is caused by pathogenic variants of the ATP7B gene, which are responsible for impaired copper transport in the cell, inhibition of copper binding to apoceruloplasmin, and biliary excretion. This leads to the accumulation of copper in the tissues. Copper accumulation in the CNS leads to the neurological and psychiatric symptoms of WD. Abnormalities of copper metabolism in WD are associated with impaired iron metabolism. Both of these elements are redox active and may contribute to neuropathology. It has long been assumed that among parenchymal cells, astrocytes have the greatest impact on copper and iron homeostasis in the brain. Capillary endothelial cells are separated from the neuropil by astrocyte terminal legs, putting astrocytes in an ideal position to regulate the transport of iron and copper to other brain cells and protect them if metals breach the blood-brain barrier. Astrocytes are responsible for, among other things, maintaining extracellular ion homeostasis, modulating synaptic transmission and plasticity, obtaining metabolites, and protecting the brain against oxidative stress and toxins. However, excess copper and/or iron causes an increase in the number of astrocytes and their morphological changes observed in neuropathological studies, as well as a loss of the copper/iron storage function leading to macromolecule peroxidation and neuronal loss through apoptosis, autophagy, or cuproptosis/ferroptosis. The molecular mechanisms explaining the possible role of glia in copper- and iron-induced neurodegeneration in WD are largely understood from studies of neuropathology in Parkinson's disease and Alzheimer's disease. Understanding the mechanisms of glial involvement in neuroprotection/neurotoxicity is important for explaining the pathomechanisms of neuronal death in WD and, in the future, perhaps for developing more effective diagnostic/treatment methods.

During postherpetic neuralgia (PHN), the cerebral spinal fluid (CSF) possesses the capability to trigger glial activation and inflammation, yet the specific changes in its composition remain unclear. Recent findings from our research indicate elevations of central bone morphogenetic protein 4 (BMP4) during neuropathic pain (NP), serving as an independent modulator of glial cells. Herein, the aim of the present study is to test the CSF-BMP4 expressions and its role in the glial modulation in the process of PHN.

CSF samples were collected from both PHN patients and non-painful individuals (Control) to assess BMP4 and its antagonist Noggin levels. Besides, intrathecal administration of both CSF types was conducted in normal rats to evaluate the impact on pain behavior, glial activity, and inflammation.; Additionally, both Noggin and STAT3 antagonist-Stattic were employed to treat the PHN-CSF or exogenous BMP4 challenged cultured astrocytes to explore downstream signals. Finally, microglial depletion was performed prior to the PHN-CSF intervention so as to elucidate the microglia-astrocyte crosstalk.

BMP4 levels were significantly higher in PHN-CSF compared to Control-CSF (P < 0.001), with a positive correlation with pain duration (P < 0.05, r = 0.502). Comparing with the Control-CSF producing moderate paw withdrawal threshold (PWT) decline and microglial activation, PHN-CSF further exacerbated allodynia and triggered both microglial and astrocytic activation (P < 0.05). Moreover, PHN-CSF rather than Control-CSF evoked microglial proliferation and pro-inflammatory transformation, reinforced iron storage, and activated astrocytes possibly through both SMAD159 and STAT3 signaling, which were all mitigated by the Noggin application (P < 0.05). Next, both Noggin and Stattic effectively attenuated BMP4-induced GFAP and IL-6 upregulation, as well as SMAD159 and STAT3 phosphorylation in the cultured astrocytes (P < 0.05). Finally, microglial depletion diminished PHN-CSF induced astrogliosis, inflammation and endogenous BMP4 expression (P < 0.05).

Our study highlights the role of CSF-BMP4 elevation in glial activation and allodynia during PHN, suggesting a potential therapeutic avenue for future exploration.

Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction secondary to infection, and the severity can range from mild delirium to deep coma. Disorders of iron metabolism have been proven to play an important role in a variety of neurodegenerative diseases by inducing cell damage through iron accumulation in glial cells and neurons. Recent studies have found that iron accumulation is also a potential mechanism of SAE. Systemic inflammation can induce changes in the expression of transporters and receptors on cells, especially high expression of divalent metal transporter1 (DMT1) and low expression of ferroportin (Fpn) 1, which leads to iron accumulation in cells. Excessive free Fe2+ can participate in the Fenton reaction to produce reactive oxygen species (ROS) to directly damage cells or induce ferroptosis. As a result, it may be of great help to improve SAE by treatment of targeting disorders of iron metabolism. Therefore, it is important to review the current research progress on the mechanism of SAE based on iron metabolism disorders. In addition, we also briefly describe the current status of SAE and iron metabolism disorders and emphasize the therapeutic prospect of targeting iron accumulation as a treatment for SAE, especially iron chelator. Moreover, drug delivery and side effects can be improved with the development of nanotechnology. This work suggests that treating SAE based on disorders of iron metabolism will be a thriving field.

Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer's disease (AD). In vitro, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of microglial-specific knockdown of Slc11a2 on AD-related cognitive decline and microglial transcriptional phenotype.

In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1 Cre - ERT2 ;Slc11a2 flfl;APP/PS1 + or - mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b + microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted.

DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2 KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2 KD APP/PS1 females displayed significant increases in Enpp2, Ttr, and the iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2 KD cells from APP/PS1 females also exhibited decreased expression of markers associated with disease-associated microglia (DAMs), such as Apoe, Ctsb, Csf1, and Hif1α.

This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in Slc11a2 KD APP/PS1 female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.

Neuropathic pain, which refers to pain caused by a lesion or disease of the somatosensory system, represents a wide variety of peripheral or central disorders. Treating neuropathic pain is quite demanding, primarily because of its intricate underlying etiological mechanisms. The central nervous system relies on microglia to maintain balance, as they are associated with serving primary immune responses in the brain next to cell communication. Ferroptosis, driven by phospholipid peroxidation and regulated by iron, is a vital mechanism of cell death regulation. Neuroinflammation can be triggered by ferroptosis in microglia, which contributes to the release of inflammatory cytokines. Conversely, neuroinflammation can induce iron accumulation in microglia, resulting in microglial ferroptosis. Accumulating evidence suggests that neuroinflammation, characterized by glial cell activation and the release of inflammatory substances, significantly exacerbates the development of neuropathic pain. By inhibiting microglial ferroptosis, it may be possible to prevent neuroinflammation and subsequently alleviate neuropathic pain. The activation of the homopentameric α7 subtype of the neuronal nicotinic acetylcholine receptor (α7nAChR) has the potential to suppress microglial activation, transitioning M1 microglia to an M2 phenotype, facilitating the release of anti-inflammatory factors, and ultimately reducing neuropathic pain. Recent years have witnessed a growing recognition of the regulatory role of α7nAChR in ferroptosis, which could be a potential target for treating neuropathic pain. This review summarizes the mechanisms related to α7nAChR and the progress of ferroptosis in neuropathic pain according to recent research. Such an exploration will help to elucidate the relationship between α7nAChR, ferroptosis, and neuroinflammation and provide new insights into neuropathic pain management.

Brain iron content is widely reported to increase during "ageing", across multiple species from nematodes, rodents (mice and rats) and humans. Given the redox-active properties of iron, there has been a large research focus on iron-mediated oxidative stress as a contributor to tissue damage during natural ageing, and also as a risk factor for neurodegenerative disease. Surprisingly, however, the majority of published studies have not investigated brain iron homeostasis during the biological time period of senescence, and thus knowledge of how brain homeostasis changes during this critical stage of life largely remains unknown. This commentary examines the literature published on the topic of brain iron homeostasis during ageing, providing a critique on limitations of currently used experimental designs. The commentary also aims to highlight that although much research attention has been given to iron accumulation or iron overload as a pathological feature of ageing, there is evidence to support functional iron deficiency may exist, and this should not be overlooked in studies of ageing or neurodegenerative disease.

The dentate gyrus of the hippocampus is important for many cognitive functions, including learning, memory, and mood. Here, we investigated age-associated changes in transcriptome-wide spatial gene expression in the human dentate gyrus across the lifespan. Genes associated with neurogenesis and the extracellular matrix were enriched in infants, while gene markers of inhibitory neurons and cell proliferation showed increases and decreases in post-infancy, respectively. While we did not find evidence for neural proliferation post-infancy, we did identify molecular signatures supporting protracted maturation of granule cells. We also identified a wide-spread hippocampal aging signature and an age-associated increase in genes related to neuroinflammation. Our findings suggest major changes to the putative neurogenic niche after infancy and identify molecular foci of brain aging in glial and neuropil enriched tissue.

This study aims to analyse hyperechoic substantia nigra (HSN) characteristics and the correlation of HSN with clinical features and blood biomarkers in patients with Parkinson's disease (PD). Transcranial sonography (TCS) evaluations of the substantia nigra (SN) were performed in 40 healthy controls and 71 patients with PD, including patients with SN hyperechogenicity (SN+) and those with normal SN echogenicity (SN-). Evaluation of motor and non-motor symptoms was assessed by a series of rating scales. The uricase method was used to determine serum uric acid (UA) levels, and enzyme-linked immunosorbent assay (ELISA) was used to measure plasma interleukin (IL)-1β levels. TCS showed 92.50% specificity and 61.97% sensitivity in differentiating PD patients from controls. The area of SN+ contralateral to the side of initial motor symptoms (SNcontra) was larger than that ipsilateral to the side of initial motor symptoms (SNipsi). The PDSN+ group had lower Argentine Hyposmia Rating Scale (AHRS) scores and UA levels than the PDSN- group. Binary logistic regression analysis revealed that AHRS scores and UA levels could be independent predictors for HSN. The larger SN echogenic area (SNL) sizes positively correlated with plasma IL-1β levels in PD patients with SN+. The present study provides further evidence of the potential of SN echogenicity as an imaging biomarker for PD diagnosis. PD patients with HSN have more severe non-motor symptoms of hyposmia. HSN in PD patients is related to the mechanism of abnormal iron metabolism and microglial activation.

Sepsis is recognized as a multiorgan and systemic damage caused by dysregulated host response to infection. Its acute systemic inflammatory response highly resembles that of lipopolysaccharide (LPS)-induced endotoxemia. Propofol and dexmedetomidine are two commonly used sedatives for mechanical ventilation in critically ill patients and have been reported to alleviate cognitive impairment in many diseases. In this study, we aimed to explore and compare the effects of propofol and dexmedetomidine on the encephalopathy induced by endotoxemia and to investigate whether ferroptosis is involved, finally providing experimental evidence for multi-drug combination in septic sedation.

A total of 218 C57BL/6J male mice (20-25 g, 6-8 weeks) were used. Morris water maze (MWM) tests were performed to evaluate whether propofol and dexmedetomidine attenuated LPS-induced cognitive deficits. Brain injury was evaluated using Nissl and Fluoro-Jade C (FJC) staining. Neuroinflammation was assessed by dihydroethidium (DHE) and DCFH-DA staining and by measuring the levels of three cytokines. The number of Iba1+ and GFAP+ cells was used to detect the activation of microglia and astrocytes. To explore the involvement of ferroptosis, the levels of ptgs2 and chac1; the content of iron, malondialdehyde (MDA), and glutathione (GSH); and the expression of ferroptosis-related proteins were investigated.

The single use of propofol and dexmedetomidine mitigated LPS-induced cognitive impairment, while the combination showed poor performance. In alleviating endotoxemic neural loss and degeneration, the united sedative group exhibited the most potent capability. Both propofol and dexmedetomidine inhibited neuroinflammation, while propofol's effect was slightly weaker. All sedative groups reduced the neural apoptosis, inhibited the activation of microglia and astrocytes, and relieved neurologic ferroptosis. The combined group was most prominent in combating genetic and biochemical alterations of ferroptosis. Fpn1 may be at the core of endotoxemia-related ferroptosis activation.