Search Results (120)

Redox balance is essential for maintenance of the hematopoietic stem cell (HSC) pool, which ensures the lifelong hematopoiesis. However, oxidative attack induced by various physiopathological stresses always compromises HSC maintenance, while there remains lack of safe and effective antioxidative measures combating these conditions. Here, we show that ferulic acid (FA), a natural antioxidant abundantly present in Angelica sinensis which is a traditional Chinese herb commonly used for promotion of blood production, distinctively and directly promotes HSC maintenance and thereby boosts hematopoiesis at homeostasis, whether supplemented over the long term in vivo or in HSC culture ex vivo. Using a mouse model of acute myelosuppressive injury induced by ionizing radiation, we further reveal that FA supplementation effectively safeguards HSC maintenance and accelerates hematopoietic regeneration after acute myelosuppressive injury. Mechanistically, FA diminishes ferroptosis susceptibility of HSCs through limiting the labile iron pool (LIP), thus favoring HSC maintenance. In addition, the LIP limitation and anti-ferroptosis activity of FA is independent of nuclear-factor erythroid 2-related factor 2 (NRF2), probably relying on its iron-chelating ability. These findings not only uncover a novel pharmacological action and mechanism of FA in promoting HSC maintenance, but also provides a therapeutic rationale for using FA or FA-rich herbs to treat iron overload- and ferroptosis-associated pathologies such as acute myelosuppressive injury. Full article

Iron is essential for cellular respiration, oxidative defense, and host immunity, but its dysregulation is increasingly associated with metabolic disorders, such as obesity and type 2 diabetes. In these diseases, regional iron accumulation occurs in adipose tissue, independent of systemic overload. This process disrupts the mitochondrial redox balance, induces ferroptotic stress, and activates the innate immune pathways. Recent studies have highlighted the NLRP3 (nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing protein 3) inflammasome and its effector cytokine interleukin-1β (IL-1β) as important mediators of the interface between iron and inflammation. In both adipocytes and macrophages, labile iron increased reactive oxygen species (ROS) production and promoted inflammasome formation. Simultaneously, metabolic stress factors upregulate hepcidin expression, suppress ferroportin activity and exacerbate intracellular iron retention. These molecular events converge to maintain low-grade inflammation and impair insulin signaling. Despite these compelling associations, direct mechanistic evidence remains limited, particularly with respect to depot-specific responses and cell type resolution. In this review, I examine the current evidence linking iron handling and inflammasome biology in adipose tissue, focusing on ferroptosis, thioredoxin-interacting protein (TXNIP) signaling, and spatial mapping of iron–cytokine networks. I also discuss novel therapeutic strategies targeting iron overload and inflammasome activation, including chelation, hepcidin modulation, and inflammasome inhibition in the context of metabolic diseases. Full article

Ferroptosis, a form of cell death, is characterized by lipid peroxidation and is dependent on iron and reactive oxygen species (ROS). Here, through bioinformatics analysis, formosanin C was predicted to be a ferroptosis inducer in colorectal cancer (CRC) by suppressing antioxidation capacity. Indeed, formosanin C induced iron accumulation, lipid ROS formation, and ferroptosis in CRC. We found that TP53 and KRAS were the second and third most frequently mutated genes in CRC and were associated with a poor prognosis. Analyses of differentially expressed genes indicated that fatty acid and labile iron levels tended to be higher in CRC than in normal tissues, suggesting the predisposition of CRC cells to ferroptosis. Transcriptomic analyses in CRC patients further identified that wild-type TP53 and mutant KRAS separately favored ferroptosis. Likewise, p53 knockdown rendered HCT 116 cells less sensitive to ferroptosis, and KRAS HT-29 cells were more sensitive to ferroptosis compared with their parental counterparts. Moreover, formosanin C synergistically enhanced chemosensitivity to cisplatin, and this process was mediated by lipid ROS. Overall, our novel gene-expression screening platform allows for the efficient identification of the biological function of novel phytochemicals, and the data suggest that formosanin C is an effective ferroptosis inducer in CRC cells with p53 or oncogenic KRAS. Full article

Soil co-contamination with antimony (Sb) and arsenic (As) presents significant ecological and human health risks, demanding effective stabilization solutions. This study evaluated iron–manganese-modified hydrochar (FMHC) for synergistic Sb-As stabilization in contaminated smelter soils. Through 60-day natural aging and 30 accelerated aging cycles, we assessed stabilization performance using toxicity leaching tests (acid/water/TCLP), bioavailable fraction analysis, bioaccessibility assessment, and Wenzel sequential extraction. The key findings reveal that FMHC (5 wt%) achieves durable stabilization: (1) leaching concentrations remained stable post-aging (Sb: 0.3–4.5 mg·L⁻¹, >70% stabilization; As: <0.4 mg·L⁻¹, >94% stabilization); (2) bioavailable fractions showed maximum reductions of 64% (Sb) and 53% (As), though with some fluctuation; and (3) bioaccessible As was consistently reduced (55–77%), while Sb exhibited greater variability (maximum 58% reduction). Speciation analysis revealed similar stabilization pathways: Sb stabilization resulted from decreased non-specifically and specifically adsorbed fractions, while As stabilization involved the reduction in non-specifically/specifically adsorbed and amorphous to poorly crystalline Fe/Al hydrous oxide-bound fractions. These transformation mechanisms explain FMHC’s superior performance in converting labile Sb/As into stable forms, offering a sustainable solution for the green remediation of Sb-As co-contaminated soils in mining areas. Full article

Although acetaminophen (APAP) overdose represents the predominant cause of drug-induced acute liver failure (ALF) worldwide and has been extensively studied, the modes of cell death remain debatable and the treatment approach for APAP-induced acute liver failure is still limited. This study investigated the mechanisms of APAP hepatotoxicity in primary mouse hepatocytes (PMHs) by using integrated methods (MTT assay, HPLC analysis for glutathione (GSH), Calcein-AM for labile iron pool detection, confocal microscopy for lipid peroxidation and mitochondrial superoxide measurements, electron microscopy observation, and Western blot analysis for ferritin), focusing on the role of iron dysregulation under oxidative stress. Our results showed that 20 mM APAP treatment induced characteristic features of ferroptosis, including GSH depletion, mitochondrial dysfunction, and iron-dependent lipid peroxidation. Further results showed significant ferritin degradation and subsequent iron releasing. Iron chelator deferoxamine (DFO) and N-acetylcysteine (NAC) could alleviate APAP-induced hepatotoxicity, while autophagy inhibitors did not provide a protective effect. In vitro experiments confirmed that hydrogen peroxide directly damaged ferritin structure, leading to iron releasing, which may aggravate iron-dependent lipid peroxidation. These findings provide evidence that APAP hepatotoxicity involves a self-amplifying cycle of oxidative stress and iron-mediated oxidative damaging, with ferritin destruction playing a key role as a free iron source. This study offers new insights into APAP-induced liver injury beyond conventional cell death classifications, and highlights iron chelation as a potential therapeutic strategy alongside traditional antioxidative treatment with NAC. Full article

Plasma non-transferrin-bound iron (NTBI) comprises multiple subspecies, classified by their composition, chemical reactivity, and susceptibility to chelation. The redox-active and chelatable fraction of NTBI is referred to as labile plasma iron (LPI). The pathophysiological significance of NTBI and LPI lies in their ability to enter cells via alternative transport pathways that are not regulated by the transferrin receptor system or by cellular iron levels. Several mechanisms have been proposed for their cellular entry, including the hijacking of divalent metal transporters and passive diffusion. This unregulated uptake can lead to iron accumulation in vulnerable tissues such as the liver and the heart. NTBI and LPI bypassing normal cellular control mechanisms can rapidly exceed the cell’s capacity to safely store excess iron, leading to toxicity. Both NTBI and LPI contribute to oxidative stress by participating in free-radical-generating reactions. However, LPI concentration in the bloodstream may be differentially affected by the mode and extent of iron overload, the presence of residual serum iron-binding activity, and the antioxidant capacity of individual sera. In summary, both NTBI and LPI contribute to iron-mediated toxicity but differ in terms of reactivity, availability, and pathogenic potential depending on the pathophysiological conditions that influence the degree of toxicity. Full article

Radiation therapy is a standard of care treatment for patients with glioblastoma. However, patients’ survival rate is dismal, with nearly all patients experiencing disease progression after treatment. Enriched iron content associated with increased transferrin receptor (TfR) expression is an indicator of poor glioblastoma patient outcomes; however, the underlying contributions to tumor progression remain elusive. The goal of this present study is to understand how iron metabolism in glioma contributes to radiation-induced glioblastoma cell motility. U251 and a doxycycline-inducible ferritin heavy chain overexpressing U251 (U251 FtH⁺) cell line were used. For in vitro studies, cells were irradiated with 2 Gy using a ³⁷Cs source, and after 72 h, atomic force microscopy (AFM) nanoindentation was employed to assess changes in cell stiffness following irradiation. Cell motility was studied using temporal confocal microscopy. For in vivo studies, U251 cells were grown in the rear flanks of female nude athymic mice, and the tumor was irradiated with five fractions of 2 Gy (10 Gy). The tumors were then imaged using a GE 7T small animal MRI to assess changes in T2* MRI, and colorimetric analysis of labile iron was performed using ferrozine. Following irradiation, a biomechanical shift characterized by decreased cell stiffness along with increased cell motility occurred in U251 cells, which corresponded to increased TfR expression. FtH overexpression completely reversed the enhanced cell motility following irradiation. Irradiation of U251 tumors induced the same iron metabolic shift. Interestingly, the change in labile iron in U251 tumors corresponded with an increase in T2* relaxation times, suggesting that T2* mapping may serve as a surrogate marker for assessing radiation-induced changes in iron metabolism. Full article

In older adults with reduced physical performance, an increase in the labile iron pool within skeletal muscle is observed. This accumulation is associated with an altered expression of mitochondrial quality control (MQC) markers and increased mitochondrial DNA damage, supporting the hypothesis that impaired MQC contributes to muscle dysfunction during aging. The autophagy–lysosome system plays a critical role in MQC by tagging and engulfing proteins and organelles for degradation in lysosomes. The endolysosomal system is also instrumental in transferrin recycling, which, in turn, regulates cellular iron uptake. In the neuromuscular system, the autophagy–lysosome system supports the structural integrity of neuromuscular junctions, and its dysfunction contributes to muscle atrophy. While MQC was thought to protect against iron-induced cell death, the discovery of ferroptosis, a form of iron-dependent cell death, has highlighted a complex interplay between MQC and iron-inflicted damage. Ferritinophagy, the autophagic degradation of ferritin, if overactivated, can induce ferroptosis. Alternatively, aging may impair ferritinophagy, leading to ferritin accumulation and the release of toxic labile iron under stress, exacerbating oxidative damage and cellular senescence. Physical activity supports muscle health also by preserving mitochondrial quantity and quality and enhancing bioenergetics. However, therapeutic strategies for preventing or reversing physical function decline in aging are still lacking due to the insufficient understanding of the underlying mechanisms. Unveiling how disruptions in iron homeostasis impact muscle quality in older adults may allow for the development of therapeutic strategies targeting iron handling to alleviate age-associated muscle decline. Full article

Despite centuries of research, metastatic cancer remains incurable due to resistance to all conventional cancer therapeutics. Alternative strategies leveraging non-proliferative vulnerabilities in cancer are required to overcome cancer recurrence. Ferroptosis is an iron dependent cell death pathway that has shown promising pre-clinical activity in several contexts of therapeutic resistant cancer. However, ferroptosis sensitivity is highly variable across tissue types and cell states, posing a challenge for clinical translation. We describe a convergent phenotype induced by chemotherapy where cells surviving chemotherapy have dysregulated iron homeostasis, regardless of initial cell type or chemotherapy used. Elevated labile iron levels are counteracted by NRF2 signaling, yet the resulting antioxidant programs do not alleviate the labile iron burden. Selectively inhibiting GPX4 leads to uniform susceptibility to ferroptosis in surviving cells, highlighting the common reliance on lipid peroxidation defenses. Cellular iron dysregulation is a vulnerability of chemoresistant cancer cells that can be leveraged by triggering ferroptosis. Full article

Background/Objectives: Iron overload is a serious condition that can increase the production of reactive oxygen species (ROS), leading to oxidative tissue damage and organ dysfunction. While current pharmaceutical drugs for iron chelation have limitations, the search for natural herbs with iron-chelating properties is crucial. This study aimed to explore the various biological functions of the Perilla frutescens seed, regarding antioxidant activity and hepatoprotective and iron-chelating properties. Methods:Perilla frutescens seeds were subjected to extraction using a solvent-partitioning technique. Each fraction was evaluated for total phenolic content (TPC), total flavonoid content (TFC), and rosmarinic acid (RA) content by Folin–Ciocalteu assay, aluminum chloride colorimetric assay, and ultra-high-performance liquid chromatography (UHPLC), respectively. Antioxidant activity was assessed using DPPH, ABTS, and FRAP assays. The inhibition of lipid peroxidation was evaluated using the TBARS assay in HepG2 cells and an egg yolk model. The iron-chelating activity was examined using a ferric nitrilotriacetate (Fe³⁺-NTA)-binding assay, labile iron pool (LIP) level assessment, and the transferrin receptor (TfR) expression in HepG2 cells. Results: Phytochemical analysis indicated that the ethyl acetate (EtOAc) fraction had the highest TPC, TFC, and RA. This fraction demonstrated strong antioxidant properties and attenuated lipid peroxidation in HepG2 cells and egg yolk. In addition, this fraction exhibited iron-binding activity, decreased LIP levels, and induced TfR expression in iron-loaded HepG2 cells similar to the rosmarinic acid standard. Conclusions: These findings suggest that the EtOAc fraction of the Perilla frutescens seed possesses promising potential as a therapeutic agent for treating iron overload. Full article

The natural process of lake and reservoir eutrophication through nutrient accumulation within sediments has been accelerated through anthropogenic sources of nitrogen and, especially, phosphorus (P). Stored nutrients can result in significant internal loading (during periods of low sediment redox potential or elevated pH), which may drive poor water quality despite best practices in catchment management. Internal P loading can promote proliferation of cyanobacterial and algal taxa responsible for harmful algal blooms (HABs), as well as taste and odour (T&O) and cyanotoxin events. Here, we investigate the sediment and water column P content of eight reservoirs by analysing iron-bound (Fe-P), calcium-bound (Ca-P), and labile P fractions. We find that all but one reservoir demonstrated high iron (Fe) content (27–52 g Fe/kg sediment), suggesting a high Fe-P binding capacity and hence a potentially high susceptibility to redox-mediated internal loading. However, we found no correlation between Fe-P and Fe content in sediments, suggesting the Fe pool was not saturated with P and thus has capacity for further storage. All sites had low levels of labile P (up to 0.14 mg P-PO₄/g dry sediment), with the highest pool of P being Ca-bound, which would be expected based on catchment geology and the presence of Ca-minerals which bind P. Currently, within industry, emphasis falls on controlling the external loading of nutrients from the surrounding catchment, often ignoring the critical role of internal loading. However, here, we demonstrate the need to continually monitor sediment P content and potential internal loading as part of the standard monitoring regime used by water companies to inform reservoir management strategies. Full article

Background/Objective: Ferroptosis is an iron-dependent form of programmed cell death characterized by lipid peroxidation products (LPOs). A chemotherapeutic drug, 5–fluorouracil (5–FU), can induce epithelial mucositis and favor drug synergism with erastin in ferroptosis. Camellia tea saponin extract (TS) is known to exert antioxidative properties. This study aims to delineate the protective role of TS in mitigating 5–FU-induced ferroptosis and inflammation in human keratinocytes. Methods: HaCaT cells were induced by 5–FU and erastin, treated with different TS doses, and their viability was then determined. Levels of cellular reactive oxygen species (ROS), LPOs, labile iron pool (LIP), glutathione (GSH), glutathione peroxidase 4 (GPX–4) activity, as well as IL–6, IL–1β, and TNF–α levels, and their wound healing properties were assessed. Results: TS per se (at up to 25 µg/mL) was not toxic to HaCaT cells but was unable to restore the viability of 5–FU-induced cells up to the baseline levels. The compound significantly diminished increases in cellular ROS, LPOs, and LIP, while restoring GSH content and GPX–4 activity. Additionally, it suppressed the cytokine production of 5–FU-induced cells in a concentration–dependent manner. Moreover, TS exerted wound-healing effects against skin injuries and 5–FU damage significantly and dose dependently. Conclusions: The insights of this work have identified biochemical mechanisms using tea saponin extract to protect against 5–FU-induced keratinocyte ferroptosis and inflammation. This study highlights the promising adjunctive potential of tea saponin in the mitigation and management of chemotherapy-induced mucositis. Full article

Soil acidification activates most of the cationic heavy metals in soil and thus enhances their accumulation in crops, posing an accentuated threat to human health, while there is limited knowledge regarding the accumulation of metalloid arsenic (As) in crops, which is influenced by acidification due to its opposite behavior in soil. In this study, the acidification processes of neutral purple soil together with the accompanied changes in soil properties and As fractionation were examined through a column-leaching experiment. Subsequently, growth and As accumulation in pakchoi (Brassica campestris L.) were investigated under various combinations of soil pH and As pollution levels in a pot experiment. This allowed us to elucidate the mechanisms of As accumulation in pakchoi under the co-stresses of soil acidification and As pollution. The results indicated that soil acidification followed a two-phase process, initially rapid and later slow, with a turning point at a pH of 4.7–4.8. Below this critical pH, the leaching rates of base ions and As accelerated significantly and the decomposition of primary minerals began, primarily from chlorite to green/mesospheric minerals, resulting in a substantial increase in the content of amorphous iron oxide. Meantime, soil As was transformed from highly labile forms, such as non-specifically and specifically adsorbed forms, to less active ones like amorphous hydrous oxide-bound and residual forms, resulting in decreased As availability. In this context, As pollution remarkably delayed the growth of pakchoi, while the influence of acidification on growth only occurred when the soil was acidified to a pH lower than 6, as demonstrated by a substantial biomass reduction at higher As levels and a 41.8% biomass decrease at pH 4.6. Moreover, soil acidification exacerbated the inhibitory effect of As on pakchoi growth. The As contents in the edible parts of pakchoi dramatically increased with the increase in the soil As level, and soil acidification did not mitigate As accumulation in plants via the suppression of soil As availability but rather greatly increased it due to the bioconcentration effect caused by As toxicity. In conclusion, significant interactions existed between soil acidification and As pollution in terms of soil properties and As transformation, leading to comprehensive effects on growth and As accumulation in crops. Full article

The speciation of heavy metals (Mn, Fe, Co, Ni, Cu, Zn, Cd, and Pb) in the bottom sediments of the Mozhaisk Reservoir and the Moskva River is described. They were characterized using the Tessier sequential selective extraction procedure trace element concentrations determined by inductively coupled plasma–mass spectrometry (ICP-MS). The bottom sediments of the Mozhaisk Reservoir are characterized by higher concentrations of the examined metals compared to the channel alluvium of the Moskva River. In this case, the most widespread metal compounds in the bottom sediments of the Mozhaisk Reservoir are firmly bound (stable form) to the mineral matrix. High concentrations of the firmly bound forms of metals (Co, Ni, Cu, Zn, Cd, Pb, and Fe) in the bottom sediments are due to an increased proportion of the silt fraction (0.1–0.01 mm) entering the reservoir due to abrasion of its shores. The only exceptions are Mn and Cd, which are present in labile compounds with carbonates and hydroxides of iron and manganese. In the bottom sediments of the Moskva River, strongly bound forms prevail for most metals—for Ni, Zn, and Cd, they are complex compounds with Fe and Mn hydroxides; for Co, Cu, Pb, and Fe, they are compounds with stable silicate minerals. The proportion of labile bioavailable forms of metals in the bottom sediments of the Moskva River is higher than in the reservoir due to anthropogenic input. Among the labile forms of the metal compounds, carbonates predominate. The proportion of elements in the most mobile exchange form and in compounds with organic matter is not large and does not exceed 14% for most elements. The only exceptions are Co and Cd, for which the concentration of the exchange form reaches 25%. Full article

Inorganic phosphorus (P) is a key component of soil P pools, influencing their availability and mobility. Although studies on biochar’s effect on inorganic P fractions in various soils are growing, a critical review of these findings is lacking. Herein, we conducted a quantitative meta-analysis of 74 peer-reviewed datasets, drawing general conclusions and confirming the absence of publication bias through funnel plot statistics. The results showed that biochars can influence soil inorganic P fractions, with their effects depending on biochar (i.e., feedstock, pyrolysis temperature and time, C:N ratio, pH, ash and P content) and soil-related properties (i.e., pH, texture, P content). Specifically, the addition of biochar significantly enhanced the diverse soil inorganic P fractions and P availability (as indicated by Olsen-P). Only biochars produced from wood residues and having high C/N ratios (>200) did not significantly increase the labile P fractions (water extracted soil phosphorus (H₂O-P), Olsen-P, and soil calcium compounds bound phosphorus (Ca₂-P)). The application of biochars derived from crop residues significantly increased the soil P associated with iron and aluminum oxides, while there was no significant effect on manure- and wood residue-derived biochars. In addition, applications of low temperature biochars and manure residue-derived biochars could increase the proportions of soil highly stable P. We identified knowledge gaps in biochar production and its potential for soil phosphorus regulation. Due to the complex processes by which biochar affects soils, more systematic evaluations and predictive methods (e.g., modeling, machine learning) are needed to support sustainable agriculture and environmental practices. Full article