Lipid Peroxidation Accumulation Research Articles

Biochanin A inhibits excitotoxicity-triggered ferroptosis in hippocampal neurons

Excitatory neurotransmitter-induced neuronal ferroptosis has been implicated in multiple neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Although there are several reports pertaining to the pharmacological activities of biochanin A, the effects of this isoflavone on excitotoxicity-triggered neuronal ferroptosis remain unclear. In this study, we demonstrate that biochanin A inhibits ferroptosis of mouse hippocampal neurons induced by glutamate or the glutamate analog, kainic acid. Biochanin A significantly inhibited accumulation of intracellular iron and lipid peroxidation in glutamate- or kainic acid-treated mouse hippocampal neurons. Furthermore, biochanin A regulated the level of glutathione peroxidase 4, a master regulator of ferroptosis, by modulating its autophagy-dependent degradation. We observed that biochanin A reduced the glutamate-induced accumulation of intracellular iron by regulating expression of iron metabolism-related proteins including ferroportin-1, divalent metal transferase 1, and transferrin receptor 1. Taken together, these results indicate that biochanin A effectively inhibits hippocampal neuronal death triggered by glutamate or kainic acid. Our study is the first to report that biochanin A has therapeutic potential for the treatment of diseases associated with hippocampal neuronal death, particularly ferroptosis induced by excitatory neurotransmitter.

GSTA1/CTNNB1 axis facilitates sorafenib resistance via suppressing ferroptosis in hepatocellular carcinoma

The emergence of sorafenib resistance has become a predominant impediment and formidable dilemma in the therapeutic approach for hepatocellular carcinoma (HCC). Although the approval of next-generation drugs as alternatives to sorafenib is a significant development, the concurrent use of inhibitors that target additional key molecular pathways remains an effective strategy to mitigate the acquisition of resistance. Here, we identified Glutathione S-Transferase Alpha 1 (GSTA1) as a critical modulator of sorafenib resistance (SR) in hepatocellular carcinoma (HCC) based on our findings from experiments conducted on recurrent liver cancer tissues, xenograft mouse models, organoids, and sorafenib-resistant cells. Elevated GSTA1 levels are strongly associated with adverse clinical prognoses. The knockout of GSTA1 reinstates sorafenib sensitivity, whereas its overexpression attenuates drug efficacy. Mechanistically, GSTA1 enhances the accumulation of lipid peroxides and suppresses ferroptosis by exerting its peroxidase function to regulate the SR. Notably, the upregulation of GSTA1 expression is mediated by the transcription factor CTNNB1 (β-catenin), resulting in the formation of a cytoplasmic complex between GSTA1 and CTNNB1. This complex facilitates the nuclear translocation of CTNNB1, establishing a positive feedback loop. The combined use of GSTA1 and CTNNB1 inhibitors demonstrated synergistic anti-tumour effects through the induction of ferroptosis both in vitro and in vivo. Our findings reveal a novel regulatory role of the GSTA1/CTNNB1 axis in ferroptosis, suggesting that targeting GSTA1 and CTNNB1 could be a promising strategy to circumvent sorafenib resistance in HCC.

A Supramolecular Self-Assembled Nanoprodrug for Enhanced Ferroptosis Therapy.

Ferroptosis can induce cell death that leverages Fe2+-triggered Fenton reactions within living organisms, leading to an excessive accumulation of lipid peroxides (LPOs) and inducing cell death. Ferroptosis can effectively circumvent the inevitable drug resistance encountered with traditional apoptotic therapies. However, several issues remain in the clinical application of ferroptosis anticancer therapy, primarily due to the poor efficiency of intracellular Fenton reaction. To address this issue, we developed a supramolecular self-assembled codelivery nanoprodrug (DOX@C18Fc-Q[7] NPs) composed of ferrocene (Fc)-based supramolecular amphiphiles (C18Fc-Q[7]) and a nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) activator (doxorubicin, DOX). The C18Fc-Q[7] is based on Fc linked to a hydrophobic long-chain alkane via a disulfide linkage, which interacts with hydrophilic Q[7] to form self-assembled amphiphiles. Importantly, the host-guest interaction between Q[7] and Fc effectively enhances the solubility of Fc while maintaining the stability of the Fe2+ source. Moreover, C18Fc-Q[7] also acts as a good carrier for loading DOX due to its good self-assembly. In cancer cells, elevated glutathione (GSH) triggers the disassembly of nanoprodrug, leading to the release of DOX, which upregulates NOX4 expression and increases H2O2 level, thereby promoting an efficient Fenton reaction for Fc-induced ferroptosis. Moreover, DOX induces cell death through apoptosis, providing a synergistic effect to further enhance the ferroptosis therapy. In vivo studies have demonstrated that this enhanced ferroptosis therapy effectively inhibits tumor growth and metastasis while maintaining good biosafety.

Revealing mitochondrial microenvironmental changes triggered by ferroptosis regulation.

Ferroptosis is a unique form of iron-dependent cell death characterized by dramatic ultrastructural changes in mitochondria. Since mitochondria are intracellular energy factories and binding sites for producing reactive oxygen species, there is increasing evidence that mitochondria are closely related to ferroptosis and play a crucial role in the regulation and execution of ferroptosis. The pH of the mitochondrial microenvironment is an important parameter for cellular physiological activities. Its abnormal fluctuations are commonly thought to be associated with cancers and other diseases. Herein, a surface-enhanced Raman scattering (SERS)-based pH nanosensor with high sensitivity and targeting function was utilized to quantify and monitor mitochondrial pH value. This nanosensor was constructed by gold nanorods (AuNRs) functionalized with pH-responsive molecules (4-mercaptopyridine, MPy) and mitochondrion-targeting peptides (AMMT) that can precisely deliver AuNRs to mitochondria. Super-resolution fluorescence imaging was employed to evidence the mitochondrial targeting feature of this nanosensor. Ferroptosis regulation induces intracellular accumulation of lipid peroxide (LPO) and reactive oxygen species (ROS), which cause changes in the mitochondrial pH. This method reveals that ferroptosis leads to the gradual acidification of the mitochondrial internal environment. The conclusion deduced by this study will be helpful for the evaluation and diagnosis of diseases according to intracellular abnormal microenvironments.

Pharmacological activation of aldehyde dehydrogenase 2 inhibits ferroptosis via SLC7A11/GPX4 axis to reduce kidney stone formation.

Calcium oxalate (CaOx) kidney stones pose a global health challenge due to their high prevalence and recurrence rates. While cell death mechanisms such as ferroptosis are known to play a crucial role in stone formation, the precise underlying mechanisms remain enigmatic. Aldehyde dehydrogenase 2 (ALDH2) is a metabolic enzyme of the ferroptosis product 4-hydroxy-2-nonenal (4-HNE). However, the function of ALDH2 in kidney stones is poorly understood. In this study, we observed a downregulation of aldehyde dehydrogenase 2 (ALDH2) in the stone group. Significantly, the administration of Alda-1, an ALDH2 agonist, notably reduced crystal deposition in the kidneys and hindered crystal adhesion to cells. Furthermore, Alda-1 induced upregulation of SLC7A11 expression, promoting glutathione synthesis, reducing lipid peroxidation accumulation, and lowering Fe2+ levels. These collective effects attenuated crystal-induced ferroptosis. However, the renoprotective effects of Alda-1 were inhibited by SLC7A11 siRNA. In conclusion, our study explores the applications of Alda-1 and highlights the potential of targeting ALDH2 as a promising therapeutical strategy for urolithiasis.

Iron-Induced Lipid Oxidation Alters Membrane Mechanics Favoring Permeabilization.

Ferroptosis is a form of regulated necrosis characterized by the iron-dependent accumulation of lipid peroxides in cell membranes. However, how lipid oxidation via iron-mediated Fenton reactions affects the biophysical properties of cellular membranes and how these changes contribute to the opening of plasma membrane pores are major questions in the field. Here, we characterized the dynamics of membrane alterations during lipid oxidation induced onsite by Fenton reactions in chemically defined in vitro model membrane systems. We find that lipid vesicle permeabilization kinetically correlates with the appearance of malondialdehyde (MDA), a product of lipid oxidation. Iron-induced lipid oxidation also alters the lateral organization of supported lipid bilayers (SLBs) with lipid phase coexistence in a time-dependent manner, reducing the lipid phase mismatch and the circularity of liquid ordered domains, which indicates a decrease in line tension at the phase boundaries. Further analysis of oxidized SLBs by force spectroscopy reveals a significant decrease in the average membrane breakthrough force upon oxidation, resulting from changes in lipid bilayer organization that make it more susceptible to permeabilization. Our findings suggest that lipid oxidation via iron-mediated Fenton-like reactions induces strong changes in membrane lipid interactions and mechanical properties leading to reduced line tension in the permeabilized state of the bilayer, which promotes membrane pore formation.

A Novel ⋅OH-Monitor ER-Targeted Probe to Expose the Function of Sorafenib.

The hydroxyl radical (⋅OH), widely recognized as the most potent free radical, plays a crucial role in numerous physiological and pathological pathways due to its strong oxidizability.Ferroptosis, as a novel mode of cell death, is initiated by the accumulation of iron-dependent lipid peroxidation. Among them, ⋅OH as the original reactive oxygen species (ROSs)is mass-produced due to Fenton reaction in vivo and closely related to cancer treatment.Besides, endoplasmic reticulum (ER) as a membrane-rich structure organelle, is a crucial organelle in all eukaryotes where excessive expression of ROSs, including ⋅OH can triggerER stress which was reported thatwasclosely related toferroptosis. So developing a new probe for their interrelationship research is important. In this paper, we constructed a1,8-naphthalimide-based ER-targeted fluorescence probe named M-1 to monitor ⋅OH variation in vitro and vivo. What's more, we achieved the monitor of ⋅OH during ER stress andferroptosis processesin cancer cells, andfurther explored the important role of ER stress and ferroptosis processes in SF (sorafenib) involved cancer cells.

Facile Synthesis of Fe‐Based Metal‐Quinone Networks for Mutually Enhanced Mild Photothermal Therapy and Ferroptosis

AbstractMild photothermal therapy (MPTT) has emerged as a promising therapeutic modality for attenuating thermal damage to the normal tissues surrounding tumors, while the heat‐induced upregulation of heat shock proteins (HSPs) greatly compromises the curative efficacy of MPTT by increasing cellular thermo‐tolerance. Ferroptosis has been identified to suppress the overexpression of HSPs by the accumulation of lipid peroxides and reactive oxygen species (ROS), but is greatly restricted by overexpressed glutathione (GSH) in tumor microenvironment and undesirable ROS generation efficiency. Herein, a synergistic strategy based on the mutual enhancement of MPTT and ferroptosis is proposed for cleaving HSPs to recover tumor cell sensitivity. A facile method for fabricating a series of Fe‐based metal‐quinone networks (MQNs) by coordinated assembly is proposed and the representative FTP MQNs possess high photothermal conversion efficiency (69.3 %). Upon 808 nm laser irradiation, FTP MQNs not only trigger effective MPTT to induce apoptosis but more significantly, potentiate Fenton reaction and marked GSH consumption to boost ferroptosis, and the reinforced ferroptosis effect in turn can alleviate the thermal resistance by declining the HSP70 defense and reducing ATP levels. This study provides a valuable rationale for constructing a large library of MQNs for achieving mutual enhancement of MPTT and ferroptosis.

Facile Synthesis of Fe-Based Metal-Quinone Networks for Mutually Enhanced Mild Photothermal Therapy and Ferroptosis.

Mild photothermal therapy (MPTT) has emerged as a promising therapeutic modality for attenuating thermal damage to the normal tissues surrounding tumors, while the heat-induced upregulation of heat shock proteins (HSPs) greatly compromises the curative efficacy of MPTT by increasing cellular thermo-tolerance. Ferroptosis has been identified to suppress the overexpression of HSPs by the accumulation of lipid peroxides and reactive oxygen species (ROS), but is greatly restricted by overexpressed glutathione (GSH) in tumor microenvironment and undesirable ROS generation efficiency. Herein, a synergistic strategy based on the mutual enhancement of MPTT and ferroptosis is proposed for cleaving HSPs to recover tumor cell sensitivity. A facile method for fabricating a series of Fe-based metal-quinone networks (MQNs) by coordinated assembly is proposed and the representative FTP MQNs possess high photothermal conversion efficiency (69.3 %). Upon 808 nm laser irradiation, FTP MQNs not only trigger effective MPTT to induce apoptosis but more significantly, potentiate Fenton reaction and marked GSH consumption to boost ferroptosis, and the reinforced ferroptosis effect in turn can alleviate the thermal resistance by declining the HSP70 defense and reducing ATP levels. This study provides a valuable rationale for constructing a large library of MQNs for achieving mutual enhancement of MPTT and ferroptosis.

Chiisanoside from the Leaves of Acanthopanax sessiliflorus Can Resist Cisplatin-Induced Ototoxicity by Maintaining Cytoskeletal Homeostasis and Inhibiting Ferroptosis.

Ototoxicity is a common side effect of cisplatin cancer treatment, potentially leading to hearing loss. This study demonstrated the significant protective activity of Acanthopanax sessiliflorus (A. sessiliflorus) leaves against cisplatin-induced ototoxicity (CIO), investigated the active compounds, and elucidated their mechanisms in countering CIO. UPLC-Q/TOF-MS analysis identified 79 compounds. Network pharmacology and activity screening determined that chiisanoside (CSS) plays a crucial role in combating CIO. Transcriptomics combined with network pharmacology analysis and experiments revealed that CSS activates the Dock1/PIP5K1A pathway to suppress the actin-severing protein gelsolin, protecting hair cells from cisplatin-induced cytoskeleton damage. CSS also activates the SLC7A11/GPX4 pathway via TGFBR2, reducing lipid peroxidation and intracellular iron accumulation to suppress cisplatin-induced ferroptosis. This study discovers that the major component CSS in A. sessiliflorus leaves reverses CIO by regulating actin homeostasis via Dock1 and inhibiting ferroptosis through TGFBR2, providing a theoretical basis for expanding CIO treatment targets and related drug development.

Fullerenols as efficient ferroptosis inhibitor by targeting lipid peroxidation for preventing drug-induced acute kidney injury

Acute kidney injury (AKI) is characterized by rapid and significant deterioration of renal function over a short duration with high mortality. However, the intricate pathophysiological mechanisms underlying AKI have hindered the development of effective therapeutic strategies. Recent research has highlighted the crucial role of ferroptosis in the pathogenesis of AKI and has identified it as a promising therapeutic target. Herein, we investigated the prophylactic efficacy of fullerenol nanoparticles, renowned for their broad-spectrum free radical scavenging capabilities and favorable biocompatibility, in preventing and mitigating ferroptosis-mediated cisplatin-induced AKI. Our findings demonstrate the remarkable potential of fullerenols in mitigating AKI. Specifically, fullerenols exert their protective effects primarily by suppressing renal lipid peroxidation and ferrous iron accumulation, which are two defining hallmarks of ferroptosis. Notably, fullerenols significantly inhibited the upregulation of key enzymes involved in the intracellular lipid peroxidation induced by cisplatin, including acyl-coA synthetase long chain family member 4 (ACSL4), arachidonate lipoxygenase 3 (ALOXE3), and cytochrome P450 oxidoreductase (POR), and enhanced antioxidant systems xc-/Glutathione (GSH)/Glutathione Peroxidase 4 (GPX4). Fullerenols also significantly suppressed the increase in mRNA expression of iron regulation-related genes and prevented the elevation of low-valent iron levels in the kidney tissue of AKI mice. Collectively, our study presents fullerenol as a promising drug candidate for the prevention of AKI in clinical settings, and provides valuable insights into the management of various ferroptosis-associated diseases.

Copper/iron bimetal phenolic networks boosted apoptosis/ferroptosis/cuproptosis combined tumor therapy through dual glutathione depletion

Cuproptosis, ferroptosis, and reactive oxygen species (ROS)-involved apoptosis are all bound by the overexpressed glutathione (GSH) in tumor microenvironment (TME). Herein, a dual GSH depletor is developed based on copper/iron bimetal gallic acid phenolic networks (CuFeGA MPNs) for combination tumor therapy by GSH depletion boosted apoptosis/ferroptosis/cuproptosis simultaneously. The CuFeGA MPNs are dissociated following exposure to the highly expressed GSH, causing the release of large quantities of GA, Fe2+, and Cu+. The released GA then further consumes the residual GSH. In conjunction with the GSH response-consumption behavior, the GSH depletion is achieved by those dual GSH consumption procedures. Subsequently, the expression of glutathione peroxides 4 (GPX4) is down-regulated by GSH depletion for further accumulation of lipid peroxides (LPO). Moreover, intracellular ROS levels are improved via Fenton reaction with released Cu+ and Fe2+, leading to buildup of LPO concurrently. Eventually, excess ROS can activate mitochondria-associated apoptosis, and the surge of LPO initiates ferroptosis without GSH homeostasis. Meanwhile, the oligomerization of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and decline of iron-sulfur cluster protein are induced by excessive Cu+ in the absence of GSH chelation, activating cuproptosis. This work provides a feasible approach for the realization of multiple mechanisms combined tumor therapy.

Repurposing flubendazole for glioblastoma ferroptosis by affecting xCT and TFRC proteins.

New uses of old drugs hold great promise for clinical translation. Flubendazole, an FDA-approved antiparasitic drug, has been shown to target p53 and promote apoptosis in glioblastoma (GBM) cells. However, its damaging mechanism in GBM remains elusive. Herein, we explored the ferroptosis-inducing ability of flubendazole on GBM cells. After treating glioma cell lines U251 and LN229 with the flubendazole (DMSO <1‰), cell viability was inhibited in a concentration-dependent manner (IC50 for LN229 = 0.5331 μM, IC50 for U251 = 0.6809 μM), attributed to the induction of ferroptosis, as evidenced by increased MDA levels, accumulation of ROS and lipid peroxides, change in mitochondrial membrane potential and structure. Protein analysis related to ferroptosis showed upregulation of TFRC, DMT1 and p53, alongside downregulation of xCT, FHC and GPX4 (p < 0.05). All-atom docking studies demonstrated that flubendazole bound closely with xCT, and TFRC, validating its role in inducing glioma ferroptosis via modulation of these proteins. Notably, flubendazole could damage the glioblastoma stem cells (GSC) that are typically resistant to other therapies, thereby possessing advantages in stopping glioma recurrence. This study delved into the mechanisms of flubendazole-induced ferroptosis in glioma, broadening its application and providing new ideas for new uses of other old drugs.

Critical role of non-coding RNA-mediated ferroptosis in urologic malignancies.

Urologic malignancies, characterized by their high aggressiveness and metastatic potential, pose a significant public health challenge globally. Ferroptosis, a novel mode of cell death, typically arises from intracellular iron ion overload and the accumulation of lipid peroxides. This process has been shown to play a crucial regulatory role in various pathological conditions, particularly in cancer, including urologic cancers. However, the comprehensive regulatory mechanisms underlying ferroptosis remain poorly understood, which somewhat limits its broader application in cancer therapy. Non-coding RNAs (ncRNAs), which encompass microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are non-coding transcripts that play pivotal roles in various physiological processes, such as proliferation, differentiation, apoptosis, and cell cycle regulation, by modulating the expression of target genes. The biological functions and potential regulatory mechanisms of ncRNAs in the context of cancer-related ferroptosis have been partially elucidated. Research indicates that ncRNAs can influence the progression of urologic cancers by affecting cell proliferation, migration, and drug resistance through the regulation of ferroptosis. Consequently, this review aims to clarify the functions and mechanisms of the ncRNA-ferroptosis axis in urologic cancers and to evaluate the clinical significance of ferroptosis-related ncRNAs, thereby providing new insights into cancer biology and therapeutic strategies that may ultimately benefit a diverse range of cancer patients.

Inhibiting Ferroptosis Prevents the Progression of Steatotic Liver Disease in Obese Mice

Ferroptosis, a form of regulated cell death characterized by lipid peroxidation and iron accumulation, has been implicated in the progression of metabolic-dysfunction-associated steatohepatitis (MASH) in obesity. This study investigated the role of ferroptosis in the development of hepatic steatosis and MASH in obese mice and assessed the therapeutic potential of ferrostatin-1, a ferroptosis inhibitor. C57BL/6J wild-type (n = 8) and ob/ob mice (n = 16) were maintained on a standard chow diet. Mice were divided into three groups that included C57BL/6 (n = 8), ob/ob (n = 8), and ob/ob + ferrostatin-1 (FER) (n = 8), with the latter group receiving an intraperitoneal injection of 5 μM/kg ferrostatin three times per week for eight weeks. Following treatment, serum and tissue samples were collected for analysis. Significant hepatic steatosis and increased lipogenesis markers were observed in ob/ob mice, which were restored to baseline levels in the ob/ob + FER group treated with ferrostatin-1. Elevated oxidative stress was indicated by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the ob/ob group, while glutathione peroxidase 4 (GPX4) activity was significantly reduced. Ferrostatin-1 treatment decreases MDA levels and restores GPX4 activity. Additionally, ferrostatin mitigates iron overload and promotes macrophage polarization from M1 to M2, thereby reducing liver inflammation and fibrosis. Ferrostatin treatment reversed mitochondrial dysfunction in ob/ob mice. Our findings revealed that ferroptosis plays a significant role in the progression of obesity to hepatic steatosis and MASH. Inhibiting ferroptosis using ferrostatin-1 effectively improves liver histology, reduces oxidative stress, normalizes lipogenesis, and modulates macrophage polarization. This study highlights the potential of targeting ferroptosis as a therapeutic strategy for obesity-related liver diseases, warranting further investigation in clinical settings.

Interactions Between Ferroptosis and Oxidative Stress in Ischemic Stroke

Ischemic stroke is a devastating condition that occurs due to the interruption of blood flow to the brain, resulting in a range of cellular and molecular changes. In recent years, there has been growing interest in the role of ferroptosis, a newly identified form of regulated cell death, in ischemic stroke. Ferroptosis is driven by the accumulation of lipid peroxides and is characterized by the loss of membrane integrity. Additionally, oxidative stress, which refers to an imbalance between prooxidants and antioxidants, is a hallmark of ischemic stroke and significantly contributes to the pathogenesis of the disease. In this review, we explore the interactions between ferroptosis and oxidative stress in ischemic stroke. We examine the underlying mechanisms through which oxidative stress induces ferroptosis and how ferroptosis, in turn, exacerbates oxidative stress. Furthermore, we discuss potential therapeutic strategies that target both ferroptosis and oxidative stress in the treatment of ischemic stroke. Overall, this review highlights the complex interplay between ferroptosis and oxidative stress in ischemic stroke and underscores the need for further research to identify novel therapeutic targets for this condition.

The Role and Interactive Mechanism of Endoplasmic Reticulum Stress and Ferroptosis in Musculoskeletal Disorders

Endoplasmic reticulum (ER) stress is a cellular phenomenon that arises in response to the accumulation of misfolded proteins within the ER. This process triggers the activation of a signalling pathway known as the unfolded protein response (UPR), which aims to restore ER homeostasis by reducing protein synthesis, increasing protein degradation, and promoting proper protein folding. However, excessive ER stress can perturb regular cellular function and contribute to the development of diverse pathological conditions. As is well known, ferroptosis is a kind of programmed cell death characterized by the accumulation of lipid peroxides and iron-dependent reactive oxygen species (ROS), resulting in oxidative harm to cellular structures. In recent years, there has been increasing evidence indicating that ferroptosis occurs in musculoskeletal disorders (MSDs), with emerging recognition of the complex relationship between ER stress and ferroptosis. This review presents a summary of ER stress and the ferroptosis pathway. Most importantly, it delves into the significance of ER stress in the ferroptosis process within diverse skeletal or muscle cell types. Furthermore, we highlight the potential benefits of targeting the correlation between ER stress and ferroptosis in treating degenerative MSDs.

Neurotoxic and developmental effects of scented incense stick smoke: Network toxicology and zebrafish model study

Burning incense sticks is a traditional practice in many cultures, especially in Southeast Asia. While it is often regarded as sacred and beneficial, modern incense sticks contain various chemicals that can pose health risks. A GCMS analysis of the ICS revealed potential compounds. Network toxicology revealed that ICS contains compounds violating Lipinski's rule of five, leading to potential neurotoxic effects. Key pathways affected include neuroactive ligand-receptor interaction and calcium signaling, associated with neurodegenerative diseases like Parkinson's and Alzheimer's. Significant genes involved are STAT3, BCL2, and MTOR, emphasizing the chemical hazards of ICS exposure. We investigated the toxicity of ICS using zebrafish (Danio rerio) embryos as a mode. ICS exposure resulted in a dose-dependent increase in toxicity. High concentrations (7 and 14 µg/ml) led to immediate mortality, while lower concentrations (0.1, 0.3, 0.5, and 1 µg/ml) caused developmental defects such as yolk sac edema, skeletal malformations, and pericardial edema. Mortality rates increased with higher concentrations, confirming dose-dependent ICS exposure caused hypoactive locomotion, with reduced distance traveled and velocity toxicity. Higher concentrations of ICS led to increased ROS levels and cellular damage, as evidenced by enhanced staining levels. A dose-dependent increase in lipid peroxidation (DPPP assay) and lipid accumulation (Nile red assay) was observed. Higher ICS concentrations led to significant oxidative damage to lipids and increased lipid deposition. Enzymatic assays showed that ICS exposure significantly decreased the activities of antioxidant enzymes SOD and CAT, indicating impaired antioxidant defense, while increasing LDH activity, signaling tissue damage and cytotoxicity. Gene expression analysis revealed downregulation of SOD1 and CAT genes, upregulation of inflammatory genes TNF-α and IL-1β, and increased expression of the apoptotic gene p53 with decreased expression of Bcl-2 and BDNF. These findings highlight ICS's potential to cause oxidative stress, inflammation, apoptosis, and neurodevelopmental impairments.

Effects of nickel, lead, and copper stress on the growth and biochemical responses of Aegilops tauschii seedlings

Heavy metal pollution causes severe abiotic stress in cereal crops around the world. This study investigated the effects of different concentrations (0, 100, 200, and 300 mg·kg–1) of nickel, lead, and copper stress on the growth and biochemical responses of Aegilops tauschii seedlings, to provide a reference for research on the mechanism of invasion and screening potential sources of wheat tolerance genes. The results showed that nickel, lead, and copper stress caused a significant decrease in the contents of chlorophyll a, chlorophyll b, and chlorophyll (a + b) in A. tauschii, thereby inhibiting photosynthesis to different degrees and hindering seedling growth, which was reflected in significant reductions in plant height and root length, with the most notable effect observed under stress by 300 mg·kg–1 lead. As the concentration of heavy metals increased, the activities of antioxidant enzymes (SOD, POD, and APX), non-enzymatic antioxidants (GSH and AsA), and the contents of osmotic regulatory substances (proline and soluble proteins) in A. tauschii significantly increased. Additionally, heavy metal stress increased H2O2 and TBARS levels. However, when the nickel, lead, and copper concentrations reached 300 mg·kg–1, no significant differences were found in H2O2 or TBARS levels compared to those in the CK group. To summarize, A. tauschii can mitigate the accumulation of ROS and membrane lipid peroxidation caused by heavy metal stress through self-regulation, thus exhibiting a certain degree of tolerance to stress caused by different concentrations of nickel, lead, and copper. Finally, the evaluation using the membership function method revealed that among the three heavy metals, A. tauschii exhibited the strongest adaptation to Cu, followed by Ni and Pb.

Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis

AbstractFerroptosis is a novel form of cell death driven by oxidative damage, and is implicated in various pathological conditions, including neurodegenerative diseases, retinal damage, and ischemia‐reperfusion injury of organs. Inhibiting ferroptosis has shown great promise as a therapeutic strategy for these diseases, underscoring the urgent need to develop effective ferroptosis inhibitors. Although Ferrostatin‐1 (Fer‐1) is a potent ferroptosis inhibitor, its susceptibility to oxidation and metabolic inactivation limits its clinical utility. In this study, the accumulation of peroxides and the resulting oxidative damage in the cellular microenvironment during ferroptosis were utilized to design Ferrostatin‐1 prodrugs with reactive oxygen species‐responsive features. This approach led to the development of a series of ferroptosis inhibitors that were capable of recognizing oxidative damage in diseased areas, allowing for targeted release and improved stability. The novel compounds demonstrated significant inhibitory effects and selectivity against RSL‐3‐induced ferroptosis in HK‐2 cells, with compound a1 exhibiting an EC50 of 15.4 ± 0.7 μM, outperforming Fer‐1. These compounds effectively identify the oxidative microenvironment associated with ferroptosis, enabling the targeted release of Fer‐1, which prevents lipid peroxide accumulation and inhibits ferroptosis. This strategy holds promise for treating diseases related to ferroptosis, offering a targeted and intelligent therapeutic approach.