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Throughout the world, some foods and feeds commonly consumed by humans and animals are inadvertently contaminated with mycotoxins. Zearalenone (ZEA) is a typical environmental/food contaminant that can cause varying degrees of damage to the body, such as reproductive toxicity, hepatotoxicity, immunotoxicity, etc. It poses a serious threat to the living environment and human and animal health. Increasing evidence shows that mycotoxin-induced organ damage may be closely related to ferroptosis. However, the mechanism of ZEA-induced liver injury is still not fully understood. Therefore, this study aimed to explore whether ZEA can trigger ferroptosis in the liver and cause liver injury. This study was conducted by establishing in vivo and in vitro ZEA exposure models. The results showed that ZEA exposure led to typical liver injury indicators. ZEA inhibited the Nrf2/keap1 antioxidant signaling pathway, aggravated the oxidative stress response, and inhibited the body's antioxidant function. Additionally, it was found that ZEA can aggravate lipid peroxidation by blocking the system Xc - /GSH/GPX4 axis, upregulating the protein expression of ACSL4, and affecting the import, storage, and export of iron ions, thereby inducing iron ion metabolism disorders. A combination of multiple factors induces ferroptosis in mouse liver and AML12 cells. Pretreatment with deferoxamine, an inhibitor of ferroptosis, can alleviate ferroptosis damage induced by ZEA, indicating the crucial role of ferroptosis in cell damage caused by ZEA. This study deeply explores the hepatic ferroptosis pathway induced by ZEA, provides a new theoretical basis for ZEA-induced hepatotoxicity, and offers new insights for exploring potential treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study explores the therapeutic benefits of tannic acid (TnA) in an experimental protocol of chronic hypermethioninemia in rats. Rats were categorized into four groups: Group I - control, Group II - TnA 30 mg/kg, Group III - methionine (Met) 0.2-0.4 g/kg + methionine sulfoxide (MS) 0.05-0.1 g/kg, Group IV - TnA/Met + MS. Saline was administered by subcutaneous pathway into groups I and II twice daily from postnatal day 6 (P6) to P28, whereas those in groups III and IV received Met + MS. From P28 to P35, groups II and IV received TnA orally. Animals from group III presented cognitive and memory impairment assessed through object recognition and Y-maze tests (p < 0.05). Elevated levels of reactive species, lipid peroxidation, and nitrites followed by a decline in sulfhydryl content, catalase activity, and superoxide dismutase activity were observed in animals treated with Met + MS (p < 0.05). However, TnA treatment reversed all these effects (p < 0.05). In group III, there was an increase in acetylcholinesterase activity and IL-6 levels, coupled with a reduction in Na + /K + -ATPase activity (p < 0.05). TnA was able to protect against these effects (p < 0.05). The gene expression of catalase, brain-derived neurotrophic factor, and nuclear factor erythroid 2-related factor 2 was decreased in the hippocampus and striatum from group III (p < 0.05). TnA reversed almost all of these alterations (p < 0.05). These findings suggest that TnA is a therapeutic target for patients with hypermethioninemia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abnormal adipose tissue formation is associated with metabolic disorders such as obesity, diabetes, and liver and cardiovascular diseases. Thus, identifying the novel factors that control adipogenesis is crucial for understanding these conditions and developing targeted treatments. In this study, we identified the melanosome-related factor MLPH as a novel adipogenic factor. MLPH was induced during the adipogenesis of 3T3-L1 cells and human mesenchymal stem cells. Although MLPH did not affect lipid metabolism, such as lipogenesis or lipolysis, adipogenesis was severely impaired by MLPH depletion. We observed that MLPH prevented excess reactive oxygen species (ROS) accumulation and lipid peroxidation during adipogenesis and in mature adipocytes. In addition, increased MLPH expression was observed under cirrhotic conditions in liver cancer cells and its overexpression also reduced ROS and lipid peroxidation. Our findings demonstrate that MLPH is a novel adipogenic factor that maintains redox homeostasis by preventing lipid peroxidation and ROS accumulation, which could lead to metabolic diseases., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The aim was to determine whether indirect exposure to pesticides, specifically a copper-based fungicide, induces alterations in oxidative stress and subclinical and early kidney biomarkers in male farmers tasked with olives harvesting. Furthermore, we tested whether sex influences the susceptibility to pesticide-induced renal damage by comparing the results of this study with those obtained previously. The study focused on olive farmers (n = 41) indirectly exposed to copper-based fungicides in Estepa (Sevilla, Spain), comparing them with a control group (n = 32). Blood samples were analyzed for metal concentrations (Cu, Mn, Se, and Zn), lipid peroxidation (MDA), protein oxidation (carbonyl groups), and antioxidant enzyme activities (SOD and CAT) while urine samples were assessed for biomarkers of early kidney damage (NGAL, KIM-1, transferrin, IGFBP7, TIMP-2). Although no significant, a tendency to increase lipid and protein oxidation was observed, together with the activity of antioxidant enzymes SOD and CAT, and a decrease in total antioxidants. Moreover, an increase in urinary NGAL and IGFBP7 among pesticide-exposed farmers suggests potential underdiagnosis of kidney damage. Farmers exhibit a subtle tendency to oxidative stress compared to control, while metal levels are significantly lower in farmers, suggesting potential compensatory responses. Furthermore, biomarkers for early kidney damage are elevated, emphasizing their vulnerability in both sexes. These findings highlight the need for investigations of renal health in pesticide-exposed farmers for preventative measures and regular health monitoring., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Hepatic ischemia-reperfusion injury (IRI) is a major cause of liver damage during hepatic resection, transplantation, and other surgical procedures, often leading to graft failure and liver dysfunction. Recent studies have identified ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, as a key contributor to IRI. In this study, we investigated the protective effects of Ticlopidine, a thienopyridine compound and platelet aggregation inhibitor, on hepatic IRI. Using a C57BL/6J mouse model, we demonstrated that prophylactic Ticlopidine treatment significantly reduced necrotic and fibrotic areas in liver tissues, as well as serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST). Prussian Blue staining revealed that Ticlopidine pretreatment decreased iron accumulation in hepatic tissues, whereas markers of lipid peroxidation (malondialdehyde and 4-hydroxynonenal) and ferroptosis (PTGS2) were significantly downregulated. Additionally, Ticlopidine ameliorated inflammatory infiltration as indicated by reduced Gr-1 staining. In vitro, Ticlopidine dose-dependently inhibited ferroptosis induced by various inducers in liver cancer cell lines HUH7 and fibrosarcoma cells HT1080. The protective effects involved partial rescue of lipid peroxidation, significant reduction of ferrous iron levels, and strong protection against mitochondrial damage. These findings suggested that Ticlopidine acts as a broad-spectrum ferroptosis inhibitor, offering a promising therapeutic approach for protecting the liver against IRI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Thiacloprid (TCL), commonly known as Biscaya, is among the most widely used pesticides in agriculture, designed to eliminate insects by targeting their nicotinic receptors. This study explores the effects of orally administering TCL (at a dose of 50 mg/kg) on the hormone secretion crucial for pregnancy and the factors influencing abortion throughout the early, middle, and late stages of pregnancy in female rats. Following TCL exposure, there were significant increases in levels of 17β-Estradiol, prostaglandins F 2α and E 2 , and serum oxytocin hormone in different stages of pregnancy. In contrast, progesterone and endothelin-1 serum levels notably decreased during the initial and final stages of pregnancy. Additionally, TCL led to a substantial rise in lipid peroxidation levels and a decrease in total thiol molecules and total antioxidant capacity, especially in uterine tissue. Although TCL did not significantly affect the morphological characteristics of the delivered fetuses, it notably increased the number of abortions, especially during the second and third stages of pregnancy. In summary, our findings suggest that TCL elevates the risk of abortion in pregnant rats by disrupting the secretion of hormones crucial for fertility (such as 17β-Estradiol/progesterone) and by increasing the secretion of abortion-inducing hormones like prostaglandins and oxytocin. Furthermore, these effects may be associated with disruptions in the oxidant/antioxidant balance within the ovaries and uterus., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Fenpropathrin (FPT) is a synthetic pyrethroid insecticide, the persistence and accumulation in water of which could cause harmful effects on vulnerable groups like aquatic creatures, particularly posing significant risks to fish immune systems. This study aimed to investigate how environmentally relevant FPT concentrations (10-1000 μ/M) affect lipid peroxidation and Fe 2+ metabolism in Cyprinus carpio head kidney lymphocytes, and its relationship with oxidative stress and immunotoxicity. Firstly, CCK-8 results demonstrated that FPT caused a significant increase in lymphocyte death. Secondly, lymphocytes exposed to FPT could lead ferroptosis in lymphocytes, accompanied by evidence of the Fe 2+ transporter imbalance, lipid peroxidation, Fe 2+ accumulation and ferroptosis related protein increment. Thirdly, we found that FPT esposure leads to a decrease in ATP, mitochondrial DNA and NADPH/NADP + levels, and the mRNA associated with mitochondrial function-related genes (Fis1, Drp1, and OPA1) in lymphocytes. Additionally, FPT induced the increased the levels of inflammatory genes (TNF-α, IFN-γ, and IL-6) in head kidney lymphocytes. Importantly, exposure to FPT induced oxidative stress to produce intracellular ROS, disrupting the function of the CncC signaling pathway and expression disorder of xenobiotics detoxification (CYP 450 family) genes. Notably, Treatment with NAC (a ROS inhibitor, 5 μM) demonstrated that inhibiting ROS alleviated FPT-induced lymphocyte ferroptosis and inflammatory response via the ROS/CncC-xenobiotics signaling pathway. These findings not only introduces a novel approach to investigating the immunotoxicity of FPT but also offers critical insights into mitigating the adverse effects of FPT on aquatic animal health., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ferroptosis induction has emerged as a promising therapeutic approach for prostate cancer (PCa), either as a monotherapy or in combination with hormone therapy. Therefore, identifying the mechanisms regulating ferroptosis in PCa cells is essential. Our previous study demonstrated that HJURP, an oncogene upregulated in PCa cells, plays a role in tumor proliferation. Here, we expand these findings by elucidating a novel mechanism by which HJURP inhibits sensitivity to ferroptosis inducers in PCa cells via the PRDX1/reactive oxygen species (ROS) pathway in vitro and in vivo. Mechanistically, HJURP forms disulfide-linked intermediates with PRDX1 through Cys 327 and Cys 457 residues. This disulfide binding promotes PRDX1 redox cycling and inhibits its hyperoxidation. As a result, HJURP enhances the peroxidase activity of PRDX1, leading to a decrease in ROS levels and subsequently suppressing lipid peroxidation induced by ferroptosis inducers. These findings reveal the potential of HJURP/PRDX1 as novel therapeutic targets and biomarkers of ferroptosis in PCa patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Erythrosine, a synthetic food dye, has been controversial due to its potential health risks. This study examines the effect of erythrosine on activity of antioxidative enzymes, oxidative stress indices, DNA damage through comet assay, and histopathological changes on stomach, intestine, and colon over a period of 28 days in rats. Twenty-four rats were randomly divided into four groups (n = 6). The first is the control group and then one each for three doses of erythrosine based on acceptable daily intake (¼ ADI, ½ ADI, and ADI, 0.1 mg/kg body weight). The results revealed that with increasing dosages the activity of catalase decreased in stomach and intestine but in colon, the catalase activity increased. Superoxide dismutase and glutathione-S-transferase activity decreased in dose-dependent manner in all three tissues. While, in stomach and intestine, the acetylcholinesterase activity showed increment in ¼ ADI dose group and then declined in ½ ADI and ADI dose-administered rats. The oxidative stress indicators showed elevated levels of lipid peroxidation, hydrogen peroxide concentration, and lactate dehydrogenase activity suggesting heightened free radical activity and potential oxidative damage. The comet test was used to evaluate DNA damage, revealing substantial damage in the erythrosine administered groups. Histopathological examination showed inflammatory infiltration and other degenerative changes in gastrointestinal tract, highlighting the dye's adverse effects. The research underscores the need for a comprehensive reevaluation of the safety and toxicity of food dyes like erythrosine, especially considering the inconsistencies in existing studies regarding the dye's safety., (© 2024 Wiley Periodicals LLC.)

Pesticide exposure is a risk factor for the development of several diseases, including breast cancer (BC). The enzyme UGT2B7 participate in detoxification of pesticides and the presence rs7438135 (G > A) variant in your gene increases its glucuronidation potential, contributing to oxidative stress metabolites neutralization. Here we investigated the impact of occupational pesticide exposure on the systemic oxidative stress generation from 228 women with BC depending on their UGT2B7 rs7438135 (G > A) status. q-PCR investigated the presence of the rs7438135 variant, and oxidative stress markers (lipid peroxidation levels, total antioxidant capacity-TRAP, and nitric oxide metabolites-NOx) were measured in plasma. Pesticide exposure induced significant augment in the systemic lipid peroxidation in the presence of the variant for several clinicopathological conditions, including tumors with high proliferation index (ki67) and with high aggressiveness. NOx was augmented in high ki67, positive progesterone receptors, high-grade and triple-negative/Luminal B tumors, and low-risk stratified patients. TRAP was depleted in young patients at menopause and those with triple-negative/Luminal B tumors, as well as those stratified as at low risk for death and recurrence. These findings showed that the presence of the variant was not able to protect from pesticide-induced oxidative stress generation in BC patients., (© 2024 Wiley Periodicals LLC.)

Background: Butin is a naturally occurring compound with a wide range of medicinal properties, including anti-inflammatory, anti-arthritic, and antioxidant properties. Particulate matter 2.5 (PM 2.5 ) and ultraviolet B (UVB) radiation contribute to skin cell damage via the induction of oxidative stress., Methods: This study sought to assess the protective effects of butin against damage triggered by PM 2.5 and UVB in human HaCaT keratinocytes. Assessments were performed to evaluate cell viability, apoptosis, and cellular component damage., Results: Butin exhibited its protective ability via the inhibition of PM 2.5 -induced reactive oxygen species generation, lipid peroxidation, DNA damage, protein carbonylation, and mitochondrial damage. Butin reduced the PM 2.5 -induced c-Fos and phospho-c-Jun protein levels as well as mitogen-activated protein kinase. Furthermore, butin mitigated PM 2.5 - and UVB-induced apoptosis., Conclusion: Butin had the potential as a pharmaceutical candidate for treating skin damage caused by PM 2.5 and UVB exposure., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Curcumin (CUR) is a hydrophobic polyphenol with considerable antitumor efficiency, but its clinical application is limited because of its poor solubility and low stability in aqueous solution and lack of targeting in vivo. Herein, we fabricated a tumor-targeting drug delivery system by loading CUR and cloaking homologous cancer cell membrane (CM) onto mesoporous silica NPs (MSN-CUR@CM). Characterization analysis showed that MSN-CUR@CM with a size of approximately 70 nm showed high water solubility and biocompatibility. Besides, MSN-CUR@CM exhibited tumor-targeting and excellent anti-gastric cancer efficiency both in vitro and in vivo owing to the cellular self-recognition of CM. In the established xenograft tumor nude mouse model, it was still significantly drug accumulated at the tumor site 72 h post administration. In addition, the mean tumor volume and weight of the MSN-CUR@CM group were was 3.97 and 7.47 times smaller than those of the CUR group. Ferroptosis, a type of non-apoptotic regulated cell death accompanied by iron-dependent lipid peroxidation, was triggered by MSN-CUR@CM. Further analysis demonstrated that MSN-CUR@CUR upregulated heme oxygenase (HO-1) levels whereas it downregulated the expression of glutathione peroxidase 4 (GPX4) in SGC7901 cells in vitro, indicating that the canonical and noncanonical ferroptosis pathways were regulated by MSN-CUR@CM. In conclusion, our study demonstrated that MSN-CUR@CM with high water solubility, biocompatibility, and tumor-targeting properties inhibited gastric cancer both in vitro and in vivo by triggering ferroptosis and provided an admirable cancer therapy efficacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

High-grade serous ovarian cancer (HGSOC) is a highly aggressive disease often developing resistance to current therapies, necessitating new treatment strategies. Our study identifies SGK1, a key effector in the PI3K pathway, as a promising therapeutic target to exploit ferroptosis, a distinct form of cell death induced by iron overload and lipid peroxidation. Importantly, SGK1 activation, whether through high expression or the constitutively active SGK1-S422D mutation, confers resistance to ferroptosis in HGSOC. Conversely, SGK1 inhibition significantly enhances sensitivity to ferroptosis, as shown by increased PTGS2 expression (a ferroptosis marker), lipid peroxidation, and toxic-free iron levels. Remarkably, this enhanced cytotoxicity is reversed by ferrostatin-1 and the iron chelator deferoxamine, highlighting the pivotal roles of lipid peroxidation and iron dysregulation in the process. Mechanistically, SGK1 protects HGSOC cells from ferroptosis via NRF2-dependent pathways, promoting glutathione synthesis and iron homeostasis, and NRF2-independent pathways via mTOR/SREBP1/SCD1-mediated lipogenesis. Notably, pharmacological SGK1 inhibition sensitizes HGSOC xenograft models to ferroptosis induction, highlighting its therapeutic potential. These findings establish SGK1 as a critical regulator of ferroptosis and suggest targeting SGK1 alongside ferroptosis pathways as a potential therapeutic strategy for HGSOC patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Dysfunction of the extraorbital lacrimal gland (ELG) can lead to loss of vision due to damage to the epithelium of cornea. The broad-spectrum anti-epileptic drug sodium valproate (SV) has numerous side effects. Moringa oleifera (M.oleifera) is widely used as a food and in folk medicine. The effects of orally administered SV and M. oleifera hydroalcoholic leaf extract on rat ELG were investigated in this study by analysing both antioxidant and oxidant parameters. Additionally, boron level and tissue factor (TF) activity were determined. Protein changes were detected by sodium dodecyl sulfate gel electrophoresis (SDS-PAGE). Significantly lower values of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and total antioxidant status (TAS) were observed in the SV group compared to the control group. Treatment with Moringa extract significantly increased SOD, CAT and TAS values in the Moringa given SV group (SVM). While no significant differences were observed between the sialic acid values of the groups, lipid peroxidation (LPO), nitric oxide (NO) and total oxidant status (TOS) values were significantly elevated in the SV group compared to the control group. Due to the effect of Moringa extract, LPO, NO and TOS levels were significantly decreased in the SVM group compared to the SV group. TF activity was not meaningfully altered between groups. Compared to control rats, oxidative stress index (OSI) level significantly increased, whereas the boron level decreased in the SV group. Moringa extract treatment noticeably reduced OSI in the SVM group. According to SDS-PAGE, decreases in the density of protein bands with molecular weights of 51, 83, and 90 kDa were observed in SV given rats compared to the other groups. These decreases were reversed by the administration of Moringa extract. Moringa extract has shown protective properties arising from antioxidant potential, especially with its very low OSI value. Individuals undergoing SV treatment and having ELG complications might consider using Moringa extract to mitigate valproate induced damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Phytocannabinoids inhibit the aggregation and neurotoxicity of the neurotoxic Alzheimer's disease protein β amyloid (Aβ). We characterised the capacity of five proprietary medical cannabis extracts, heated and non-heated, with varying ratios of cannabidiol and Δ 9 -tetrahydrocannabinol and their parent carboxylated compounds to protect against lipid peroxidation and Aβ-evoked neurotoxicity in PC12 cells., Methods: Neuroprotection against lipid peroxidation and Aβ 1-42 -induced cytotoxicity was assessed using the thiazolyl blue tetrazolium bromide (MTT) assay. Transmission electron microscopy was used to visualise phytocannabinoid effects on Aβ 1-42 aggregation and fluorescence microscopy., Results: Tetrahydrocannabinol (THC)/tetrahydrocannabinolic acid (THCA)-predominant cannabis extracts demonstrated the most significant overall neuroprotection against Aβ 1-42 -induced loss of PC12 cell viability. These protective effects were still significant after heating of extracts, while none of the extracts provided significant neuroprotection to lipid peroxidation via tbhp exposure. Modest inhibition of Aβ 1-42 aggregation was demonstrated only with the non-heated BC-401 cannabis extract, but overall, there was no clear correlation between effects on fibrils and conferral of neuroprotection., Conclusions: These findings highlight the variable neuroprotective activity of cannabis extracts containing major phytocannabinoids THC/THCA and cannabidiol (CBD)/cannabidiolic acid (CBDA) on Aβ-evoked neurotoxicity and inhibition of amyloid β aggregation. This may inform the future use of medicinal cannabis formulations in the treatment of Alzheimer's disease and dementia., (© 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Polysaccharides from diverse origins exhibit notable bioactivities, particularly their capacity to exert antitumor and immune-enhancing effects. Concurrently, ferroptosis emerges as a distinctive form of regulated cell death characterized by iron-dependent lipid peroxidation, potentially influencing the demise of specific tumor cells and organismal homeostasis. Recent scholarly attention has increasingly focused on utilizing polysaccharides to modulate tumor cell ferroptosis and manipulate cellular immune responses. This article provides an in-depth analysis of contemporary research concerning using polysaccharides to augment antitumor immunity and combat malignancies. Central to our discourse is examining the pivotal role of polysaccharides in mediating ferroptosis, bolstering immune surveillance, and elucidating the interplay between polysaccharides and antitumor immunity. Furthermore, a comprehensive synthesis of the multifaceted roles of polysaccharides in antitumor and immunomodulatory contexts is provided. Recent advances in understanding how polysaccharides enhance immune function by inducing ferroptosis cell death are explained. Lastly, unresolved inquiries are outlined, and potential avenues for future research are proposed, focusing on the translational applications of polysaccharides in antitumor immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

25-hydroxycholesterol (25HC) is an oxysterol derived from cholesterol and plays a role in various cellular processes, such as lipid metabolism, inflammatory responses, and cell survival. Extravillous trophoblasts (EVTs) are a major cell type found in the placenta, which are highly energetic cells with proliferative and invasive properties. EVT dysfunction can lead to pregnancy complications, including preeclampsia and intrauterine growth restriction. This study investigated the effects and underlying mechanisms of action of 25HC on EVT proliferation. Swan 71 cells, an EVT cell line, were treated with different concentrations of 25HC. Next, cell proliferation was assessed. The mitochondrial reactive oxygen species (mtROS), mitochondrial membrane potentials (MMPs), lipid peroxidation (LPO), and glutathione (GSH) levels were measured. Apoptosis, ferroptosis, and autophagy were evaluated by western blotting and flow cytometry. The results revealed that 25HC significantly inhibited proliferation and decreased the metabolic activity of EVTs. Moreover, 25HC caused oxidative stress by altering mtROS, LPO, MMPs, and GSH levels. Additionally, 25HC induces apoptosis, ferroptosis, and autophagy through the modulation of relevant protein levels. Interestingly, pretreatment with Z-VAD-FMK, an apoptosis inhibitor, and ferrostatin-1, a ferroptosis inhibitor, partially restored the effects of 25HC on cell proliferation, oxidative stress, and cell death. In summary, our findings suggest that 25HC treatment inhibits EVT proliferation and triggers apoptosis, ferroptosis, and autophagy, which are attributable to oxidative stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Silver nanoparticles (AgNPs) and Zinc oxide nanoparticles (ZnONPs) have been widely used and are eventually been discharged into the natural aquatic ecosystem. The current study examined and correlated the toxicity of AgNPs and ZnONPs on the Mozambique tilapia, Oreochromis mossambicus. Lethal concentration (LC 50 ) was determined with four different concentrations (0.05, 0.10, 0.15, and 0.20 mg/L) of AgNPs and ZnONPs; subsequently, the fishes were exposed to sublethal concentrations for a period of 21 days, and the oxidative stress and antioxidant and nonantioxidant parameters were studied. Results revealed oxidative stress evinced by increased lipid peroxidation (LPO) protein carbonyl activity (PCA), glutathione-S-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) activity, metallothionein (MT) activity, and reduced glutathione in chronic exposure compared with acute exposure. Nonspecific immunological characteristics such as lysozyme (LYZ), myeloperoxidase (MPO), and respiratory burst activity (RBA) were also noticed in the serum. Furthermore, severe histological damages including damages in telangiectasia and epithelial cell hyperplasia were found in the combined treated group with Ag and ZnONPs than in individual treatments. When Ag and ZnONPs were combined, a reduction in the accumulation of Ag was observed in the liver, which increased drastically in individual exposure. The current findings highlight the importance of taking into account the combined exposure and correlation of NPs, their bioavailability, and toxicity in the aquatic ecosystem., (© 2024 Wiley Periodicals LLC.)

Background: Hepatic ischemia/reperfusion (I/R) injury is a major cause of complications in clinical liver surgery. AXL receptor tyrosine kinase (AXL) is a member of the TAM receptor tyrosine kinase family (TYRO3, AXL, and MERTK). Our previous study has shown that AXL expression was markedly upregulated in liver transplantation patients. However, the underlying mechanism of AXL in hepatic I/R injury remains unclear., Methods: A mouse liver warm I/R model and a primary hepatocyte hypoxia/reoxygenation model were established to investigate the role of AXL activation and ferroptosis in hepatic I/R injury by pretreating with recombinant mouse growth arrest-specific protein 6 (AXL activator) or R428 (AXL inhibitor). Moreover, we used LY294002 (phosphatidylinositol 3-kinase [PI3K] inhibitor) to evaluate the relationship between the PI3K/AKT (the Ser and Thr kinase AKT) pathway and ferroptosis in hepatic I/R injury., Results: Hepatic I/R injury decreased phosphorylation AXL expression and enhanced ferroptosis in liver transplantation patients and hepatic I/R-subjected mice. AXL activation attenuated lipid peroxidation and ferroptosis in hepatic I/R injury in vivo and in vitro. Inhibition of AXL activation exacerbated liver pathological damage and liver dysfunction, as well as iron accumulation and lipid peroxidation in hepatic I/R injury. Mechanistically, activated growth arrest-specific protein 6/AXL and its downstream PI3K/AKT signaling pathway inhibited ferroptosis during hepatic I/R injury., Conclusions: AXL activation protects against hepatic I/R injury by preventing ferroptosis through the PI3K/AKT pathway. This study is the first investigation on the AXL receptor and ferroptosis, and activating AXL to mitigate ferroptosis may be an innovative therapeutic strategy to combat hepatic I/R injury., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Purpose: Radiotherapy (RT) is an integral treatment part for patients with head and neck squamous cell carcinoma (HNSCC), but radioresistance remains a major issue. Here, we use MitoTam, a mitochondrially targeted analogue of tamoxifen, which we aim to stimulate ferroptotic cell death with, and sensitize radioresistant cells to RT., Materials and Methods: We assessed viability, reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential, and lipid peroxidation in radiosensitive (UT-SCC-40) and radioresistant (UT-SCC-5) HNSCC cells following MitoTam treatment. To assess ferroptosis specificity, we used the ferroptosis inhibitor ferrostatin-1 (fer-1). Also, total antioxidant capacity and sensitivity to tert-butyl hydroperoxide were evaluated to assess ROS-responses. 53BP1 staining was used to assess radiosensitivity after MitoTam treatment., Results: Our data revealed increased ROS, cell death, disruption of mitochondrial membrane potential, and lipid peroxidation following MitoTam treatment in both cell lines. Adverse effects of MitoTam on cell death, membrane potential and lipid peroxidation were prevented by fer-1, indicating induction of ferroptosis. Radioresistant HNSCC cells were less sensitive to the effects of MitoTam due to intrinsic higher antioxidant capacity. MitoTam treatment prior to RT led to superadditive residual DNA damage expressed by 53BP1 foci compared to RT or MitoTam alone., Conclusion: MitoTam induced ferroptosis in HNSCC cells, which could be used to overcome the elevated antioxidant capacity of radioresistant cells and sensitize such cells to RT. Treatment with MitoTam followed by RT could therefore present a promising effective therapy of radioresistant cancers., Statement of Significance: Radiotherapy is applied in the treatment of a majority of cancer patients. Radioresistance due to elevated antioxidant levels can be overcome by promoting ferroptotic cell death combining ROS-inducing drug MitoTam with radiotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [J.N., J.S. and L.W. own part of MitoTam intellectual property]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aluminium, a ubiquitous environmental toxicant, is distinguished for eliciting a broad range of physiological, biochemical, and behavioural alterations in laboratory animals and humans. The present work was conducted to study the functional and structural changes induced by aluminium in rat liver. Twenty five adult male Wistar rats (150-200 g) were randomly divided into five groups; control group and four Al-treated groups viz: Al 1 (25 mg AlCl 3 /kg b.wt), Al 2 (35 mg AlCl 3 /kg b.wt), Al 3 (45 mg AlCl 3 /kg b.wt), and Al 4 (55 mg AlCl 3 /kg b.wt). Rats in the aluminium-treated groups were administered AlCl 3 for 30 days through oral gavage. Aluminium significantly increased the serum levels of liver function markers (ALT, AST, and ALP), phospholipids, and cholesterol. The activities of hepatocyte membrane (ALP, GGT, and LAP) and carbohydrate metabolic (G6P, F16BP, HK, LDH, MDH, ME, and G6PDH) enzymes were significantly altered by AlCl 3 administration. Prolonged Al exposure induced oxidative stress in the liver, as evident by significant hepatocellular DNA damage, increased lipid peroxidation, and decreased non-enzymatic and enzymatic antioxidants. The toxic effects observed in this study were AlCl 3 dose-dependent. Histopathological examination of liver sections revealed enlargement of sinusoidal spaces, derangement of the hepatic chord, loss of discrete hepatic cell boundaries, congestion of hepatic sinusoids, and degeneration of hepatocytes in Al-intoxicated rats. In conclusion, aluminium causes severe hepatotoxicity by inhibiting the hepatocyte membrane enzymes and disrupting the liver's energy metabolism and antioxidant defence., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: This study aimed to investigate the protective activity of brown seaweed, the ethanolic and water extracts of Sargassum binderi (S. binderi) were examined. Anticancer drug, cisplatin is normally used for the treatment of solid tumors that cause acute kidney damage after assemblage in the renal tubules., Material and Methods: It was an acute nephrotoxicity study, animals were divided into several groups randomly, cisplatin (7mg/kg i.p.) and normal saline were used as positive and negative control respectively. The S. bindari ethanolic and water extract were given orally in a dose of 200mg/kg for 5days. Various biomarkers were assessed to observe the nephroprotective potential, while antioxidant activities were investigated using reduced glutathione, catalase and malondialdehyde as oxidative stress. GCMS was performed to validate the presence of important therapeutic moieties., Results: The current result justified that pretreatment with S. binderi inhibited the elevation of antioxidant parameters and also showed protection against lipid peroxidation, induced by cisplatin challenge. The overall impact was the nephroprotection, which has been revealed from the results. GCMS evaluation of hexanes fraction revealed the presence of therapeutically important compounds including heptasiloxane, 3,7,11,15-tetramethyl-2-hexadecen-1-ol, hexadecamethyl, cyclooctasiloxane, and hexadecamethyl. These compounds have been reported for their antioxidant, antibacterial, anticancer, and antifungal activities., Conclusion: S. binderi showed reno-protective effect by checking their well-known biochemical parameters probably due to the antioxidant activity as confirmed by the presence of compounds., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

The long-term use of antibiotics can cause drug resistance. Natural polysaccharides are a novel means of treating bacterial infections, and the development and utilization of litchi pericarp polysaccharide (LPPs) as a bacteriostatic active substance offer a new research direction for the high-value utilization of litchi by-products. This study revealed that LPPs inhibited Staphylococcus aureus more than Escherichia coli, Listeria monocytogenes, and Salmonella typhimurium, with the minimum inhibitory concentrations of 145, 205, 325, and 445 μg/mL, respectively. The inhibitory activity of LPPs was insignificant for Bacillus subtilis at 505 μg/mL. The assessment of antibacterial mechanisms revealed that LPPs influenced the growth, conductivity, protein, and nucleic acid, reducing sugar, respiratory chain dehydrogenase activity, bacterial lipid peroxidation, intracellular adenosine triphosphate, and extracellular alkaline phosphatase levels of S. aureus. Of note, LPPs could modify the cell wall integrity and cell membrane permeability of S. aureus, resulting in the leakage of intracellular large and small molecules, inhibition of cellular respiratory metabolism, and oxidative losses. These processes exhibited an inhibitory effect and made the bacterium nonfunctional, thereby affecting its growth and metabolism or causing cell death. These findings provide support and insights into the potential application of LPPs as a natural antimicrobial agent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A response surface methodology (RSM) and one-factor method were established to investigate the optimum conditions for the extraction of lychee nuclear polysaccharides (LSP) by ultrasonic-assisted pectinase. The content of basic components in polysaccharides was determined. The antioxidant activity was well determined and compared the differences in the activities of the polysaccharides extracted by water extraction (LSP-HW) and those extracted at ultrasound-assisted enzyme (LSP-UAE). The activity of lychee nuclear polysaccharide increased with the increase of concentration. The anti-hydroxyl radical and anti-lipid peroxidation abilities of lychee nuclear polysaccharide were more excellent, and LSP-HW was slightly better than LSP-UAE in terms of activity, but the difference was not significant. In terms of solubility; LSP-HW without deproteinization was the best, followed by LSP-UAE, and the worst was LSP-UAE after deproteinization. The higher the glycoprotein content, the better the solubility of its polysaccharide. Compared with the existing extraction methods, this experiment greatly improved the extraction rate of lychee nuclear polysaccharides and further enriched the antioxidant activities of polysaccharides., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cigarette smoke (CS) is an important indoor air pollutant associated with an increased risk of ocular surface disease. As the eye's outermost layer, the cornea is highly sensitive to air pollutants like CS. However, the specific mechanisms linking CS exposure to corneal dysfunction have not been fully elucidated. In the present study, we found that CS exposure damages corneal epithelial cells, accompanied by increased iron (Fe 2+ ) levels and lipid peroxidation, both hallmarks of ferroptosis. Ferroptosis inhibitors, including Ferrostatin-1 (Fer-1) and Deferoxamine mesylate (DFO), protect against CS-induced cell damage. To understand the underlying mechanisms, we investigated how CS affects iron and lipid metabolism. Our results showed that CS could upregulate intracellular iron levels by increasing TFRC expression and promote lipid peroxidation by increasing ACSL4 expression. Silencing ACSL4 or TFRC expression prevented CS-induced ferroptosis. Furthermore, we found that the upregulation of TFRC and ACSL4 was driven by increased YAP transcription. Pharmacological or genetic inhibition of YAP effectively prevented corneal epithelial cell ferroptosis under CS stimulation. Additionally, our results suggest that CS exposure could increase O-GlcNAc transferase activity, leading to YAP O-GlcNAcylation. This glycosylation of YAP interfered with its K48-linked ubiquitination, resulting in YAP stabilization. Collectively, we found that CS exposure induces corneal epithelial cell ferroptosis via the YAP O-GlcNAcylation, and provide evidence that CS exposure is a strong risk factor for ocular surface disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

5α,8α-peroxyergosteryl divaricatinate ( 1 ) is isolated for the first time from acetone extract of the thallus of Cladonia cf. didyma together with condidymic ( 2 ), isodidymic ( 3 ) and barbatic ( 4 ) acids. Their UVB/UVA photoprotective and antioxidant activities were determined along with their cyto- and DNA-protecting actions against OH• damage. Compound 1 showed high UVA, cyto- (%cell viability ca. 82 at 15 µM vs 71 for OH•) and DNA (%DNA-integrity ca. 74 at 100 µM vs 22 for OH•) protecting properties. Compounds 2 and 3 exhibited high UVB (SPF ca. 40) and antioxidant activities (free radical scavenging potency EC 50 = 0.6694 and 1.700 mol compound/mol DPPH•; ferric reducing power 0.392 and 0.546, at 500 ppm and inhibited lipid peroxidation); protecting cells (%cell viability ca. 76 at 15 µM) and DNA (%DNA-integrity ca. 57 at 100 µM). Compounds 1 to 3 fulfilled some physicochemical properties to act topically on the skin.

Nickel phytotoxicity has been attributed, among others, to oxidative stress. However, little is known about Ni-induced phospholipid modifications, including the oxidative ones. Accumulation of reactive oxygen species (ROS), antioxidative enzyme activities, malondialdehyde and the early lipid oxidation products contents, membrane permeability, phospholipid profile as well as phospholipid unsaturation degree were studied in the 1st and the 2nd leaves of hydroponically grown cucumber seedlings subjected to Ni stress. Compared to the 2nd leaf the 1st one showed stronger visual Ni toxicity symptoms, higher Ni, O 2 .- and H 2 O 2 accumulation as well as greater enhancement in membrane permeability. Enzyme activities were differently influenced by Ni stress, however most pronounced changes were generally found in the 1st leaf. Ni treatment resulted in oxidation of leaf lipids, which was evidenced by appearance of increased contents of MDA and the early produced oxylipins. Among the latter 9-hydroxyoctadecatrienoic acid (9-HOTrE) and 13-hydroxyoctadecatrienoic acid (13-HOTrE) contents showed the most pronounced increase in response to Ni treatment. Exposure to the metal led to the changes in the leaf phospholipid profile and increased degree of phospholipid unsaturation. The obtained results have been discussed in relation to the difference in Ni stress severity between the 1st and the 2nd leaves., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Tributyltin (TBT) is an organotin compound that has several adverse health effects, including the development of obesity. Although obesity is strongly associated with adipose redox imbalance, there is a lack of information on whether TBT promotes a pro-oxidative environment in WAT. Thus, adult male Wistar rats were randomly exposed to either vehicle (ethanol 0.4%) or TBT (1000 ng/kg) for 30 days. Body and fat pad masses, visceral fat morphology, lipid peroxidation, protein carbonylation, redox status markers, and catalase activity were evaluated. TBT promoted increased adiposity and visceral fat, with hypertrophic adipocytes, but did not alter body mass and subcutaneous fat. ROS production and lipid peroxidation were elevated in TBT group, as well as catalase protein expression and activity, although protein oxidation and glutathione peroxidase protein expression remained unchanged. In conclusion, this is the first study to demonstrate that subacute TBT administration leads to visceral adipose redox imbalance, with increased oxidative stress. This enlights the understanding of the metabolic toxic outcomes of continuous exposure to TBT in mammals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Transgender is a term for people whose gender identity or expression differs from their natal sex. These individuals often seek cross-hormonal therapy to simulate the individual´s desired gender. However, the use of estrogens and testosterone has side effects such as a higher propensity to cancer, weight changes and cardiovascular diseases. Testosterone has also been linked with hypertension. Still, little is known about the outcomes and prevalence of metabolic perturbations in the trans community. Here we aim to analyze if cross-administering sexual hormones affects heart mitochondrial function. Mitochondria produces the ATP needed for heart function. In fact, different studies show that mitochondrial dysfunction precedes cardiac damage. In this work we used either female rats castrated and injected with testosterone or male rats castrated and injected with estrogens for 4 months. We performed an electrocardiogram, and then we isolated heart mitochondria to measure the rate of oxygen consumption, calcium fluxes, membrane potential, superoxide dismutase activity, lipoperoxidation and cytokines. We detected wide modifications in all parameters associated to cross-hormonal administration., Competing Interests: Declaration of Competing Interest The authors declare that there is not duality of interest associated with this manuscript, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Heterocyclic aromatic amines (HAAs) and advanced glycation end products (AGEs) are hazardous substances produced when food is heated. In this study, the ability of plasma-activated water (PAW) to simultaneously mitigate production of HAAs and AGEs in roasted beef patties was investigated. Assays of free radicals, lipid peroxidation, and active carbonyls were used to analyze the mechanisms. PAW treatment decreased the contents of free HAAs, free AGEs, bound HAAs, and bound AGEs to 12.65 ng/g, 0.10 μg/g, 297.74 ng/g, and 4.32 μg/g, with the inhibition rates of 23.88%, 23.08%, 11.02%, and 8.47%, respectively. PAW treatment decreased HAAs and AGEs and mitigated their increase during storage. The decrease of HAAs and AGEs in PAW-treated samples was correlated with the enhancement of antioxidant capacity. The increase of free radical scavenging ability by PAW treatment led to the decrease of lipid peroxidation and the decrease of active carbonyls, HAAs, and AGEs in meat products., Competing Interests: Declaration of competing interest No conflict of interest exists in the submission of this manuscript. All authors have read and agreed to the published version of the manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Malondialdehyde (MDA) can induce lipoxidation in whey protein isolate (WPI). The physicochemical changes in this reaction with or without the presence of a phenolic compound epicatechin (EC) were characterized in this study. Results suggested the content of MDA was significantly reduced during co-incubation of MDA and EC. The addition of EC dose-dependently alleviated MDA-induced protein carbonylation, Schiff base formation and loss of tryptophan fluorescence. The interruption of MDA-binding to WPI was directly visualized by immunoblotting analysis. Observation of the surface microstructure of WPI showed that MDA-induced protein aggregation was partially restored by EC. Meanwhile, EC was found to promote loss of both protein sulfhydryls and surface hydrophobicity due to possible phenol-protein interactions. These observations suggested the potential of EC in the relief of MDA-mediated protein lipoxidation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background/aims: Lead exposure is known to induce oxidative stress and neurotoxicity. Nitric oxide (NO) plays an important role in modulating oxidative stress, with L-arginine as a precursor of NO and N ω -nitro-L-arginine (L-NNA) as an inhibitor of NO synthase, an enzyme that catalyses the production of nitric oxide (NO) from L-arginine., Methods: This study investigated the differential effects of L-arginine and L-NNA on markers of oxidative stress and biochemical changes in brain tissue from rats with different levels of resistance to hypoxia exposed to lead nitrate. Rats with either low or high resistance to hypoxia were exposed to lead nitrate (oral 3.6 mg lead nitrate/kg b.w. per day for 30 days) and treated with L-arginine (600 mg/kg b.w., i.p., 30 min before and after exposure to lead nitrate) or L-NNA (35 mg/kg b.w., i.p., 30 min before and after exposure to lead nitrate). Brain tissue samples were analysed for lipid peroxidation, oxidative modification of proteins, and activity of antioxidant enzymes, including superoxide dismutase, catalase, glutathione reductase, and peroxidase, and total antioxidant status (TAS). We also examined the biomarkers of biochemical pathways involving the activity of alanine and aspartate aminotransferases, succinate dehydrogenase (SDH), and α-ketoglutarate dehydrogenase (KGDH). In addition, the trend observed was supported by assessments of the acetylcholine levels and acetylcholinesterase activity (ACh-AChE system) in brain tissue., Results: In rats with low resistance to hypoxia, the L-arginine treatment significantly reduced lipid peroxidation and oxidative protein modification but increased antioxidant enzyme activity, suggesting a protective effect against lead-induced oxidative stress. Conversely, in rats with high resistance to hypoxia, L-NNA had a protective effect, reducing lead-induced oxidative damage and decreasing lipid peroxidation, whereas L-arginine exacerbated oxidative stress and impaired antioxidant defences. These findings were supported by corresponding changes in the acetylcholine-acetylcholinesterase system, reflecting the observed patterns of lead-induced oxidative stress and neurotoxicity. The study shows that L-arginine exerts a protective effect by reducing lead-induced oxidative damage via an improvement in TAS. Our study shows that lead nitrate exposure significantly increases ala-nine and aspartate aminotransferase activity in brain tissue, with L-arginine exacerbating and L-NNA reversing this effect. The lead nitrate exposure also affected the activities of SDH and KGDH, which are important for cellular energy production and hypoxia resistance, with L-arginine altering SDH activity depending on the level of resistance and L-NNA enhancing both SDH and KGDH activities. These trends were further validated by alterations in the ACh-AChE system, highlighting the differential role of NO-dependent mechanisms in modulating lead-induced neurotoxicity based on hypoxia resistance., Conclusion: These findings suggest potential targeted therapeutic strategies based on the oxidative stress profile and highlight the potential of nitric oxide system modulators in counteracting lead-induced biochemical alterations and the dynamics of the ACh-AChE system depending on the individual physiological reactivity of organisms., Competing Interests: The authors have no competing interests to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Plastic contamination in agricultural soils has become increasingly evident. Plastic mulching films are widely used in agricultural practices. However, the increased use of biodegradable plastics has, to some extent, replaced their non-degradable counterparts. The fragmentation of plastics generates microplastics (MPs), posing risk to soil functions and organisms. In this study the effects of low-density polyethylene microplastics (PE-MP) and polybutylene adipate terephthalate biodegradable microplastics (PBAT-BD-MP) originating from mulching films on the earthworm Eisenia andrei were studied. The earthworms were exposed to seven concentrations (0, 0.005, 0.05, 0.1, 0.5, 1, and 5 % w/w) based on environmentally relevant levels and worst-case scenarios on soil contamination. Survival, growth, reproduction, and biomarkers for oxidative stress [superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione S-transferase (GST), glutathione (GSH), and lipid peroxidation (LPO)] were analysed. Additionally, the Integrated Biomarker Response Index (IBR) was calculated to assess the overall oxidative stress status of the earthworms. Results showed that PE-MP exposure slightly decreased the biomass of the earthworms towards higher concentrations, whereas PBAT-BD-MPs induced growth at lower concentrations. MPs did not have a significant effect on Eisenia andrei reproduction; however, a slight negative trend was observed in juvenile production with increasing PE-MP concentrations. Both PE-MP and PBAT-BD-MP affected antioxidant system, PE-MPs with changes in CAT and GR levels and PBAT-BD-MPs inducing effects on SOD and LPO levels. Additionally, both MPs exhibited effects on soil parameters, resulting in increased soil pH and water-holding capacity at 5 % concentration. Changes in soil parameters can further affect soil organisms such as earthworms. This study provides understanding of the ecotoxicological effects of conventional and biodegradable microplastics on the earthworm Eisenia andrei. It also shows that MP particles of both conventional and biodegradable mulching films induce oxidative stress, considered as an early-warning indicator for adverse ecological effects, in environmentally relevant concentrations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cinobufagin, the primary active compound in toad venom, is commonly used for anti-tumor, anti-inflammatory, and analgesic purposes. However, its specific bone-protective effects remain uncertain. This research aims to ascertain the bone-protective properties of cinobufagin and investigate underlying mechanisms., Methods: Mice were ovariectomized to establish an osteoporosis model, followed by intraperitoneal injections of cinobufagin and cinobufagin-treated RAW.264.7-derived exosomes for therapy. MicroCT, HE staining, and TRAP staining were employed to evaluate bone mass and therapeutic outcomes, while mRNA sequencing and immunoblotting were utilized to assess markers of bone metabolism, inflammation, and lipid peroxidation. Osteoblast and osteoclast precursor cells were differentiated to observe the impact of cinobufagin-treated exosomes derived from RAW264.7 cells on bone metabolism. Exosomes characteristics were studied using transmission electron microscopy and particle size analysis, and miRNA binding targets in exosomes were determined by luciferase reporting., Results: In ovariectomized mice, cinobufagin and cinobufagin-treated exosomes from RAW264.7 cells increased trabecular bone density and mass in the femur, while also decreasing inflammation and lipid peroxidation. The effect was reversed by an exosomes inhibitor. In vitro experiments revealed that cinobufagin-treated exosomes from RAW264.7 cells enhanced osteogenic and suppressed osteoclast differentiation, possibly linked to Upregulated miR-3102-5p in RAW-derived exosomes. MiR-3102-5p targets the 3'UTR region of alox15, thereby suppressing its expression and reducing the lipid peroxidation process in osteoblasts., Conclusion: Overall, this study clarified cinobufagin's bone-protective effects and revealed that cinobufagin can enhance the delivery of miR-3102-5p targeting alox15 through macrophage-derived exosomes, demonstrating anti-lipid peroxidation and anti-inflammatory effects., Competing Interests: All authors declare no conflict of interest., (© 2024 Geng et al.)

Ferroptosis is a cell death modality in which iron-dependent lipid peroxides accumulate on cell membranes. Cysteine, a limiting substrate for the glutathione system that neutralizes lipid peroxidation and prevents ferroptosis, can be converted by cystine reduction or synthesized from methionine. However, accumulating evidence shows methionine-based cysteine synthesis fails to effectively rescue intracellular cysteine levels upon cystine deprivation and is unable to inhibit ferroptosis. Here, we report that methionine-based cysteine synthesis is tissue-specific. Unexpectedly, we find that rather than inhibiting ferroptosis, methionine in fact plays an essential role during cystine deprivation-induced ferroptosis. Methionine-derived S-adenosylmethionine (SAM) contributes to methylation-dependent ubiquinone synthesis, which leads to lipid peroxides accumulation and subsequent ferroptosis. Moreover, SAM supplementation synergizes with Imidazole Ketone Erastin in a tumor growth suppression mouse model. Inhibiting the enzyme that converts methionine to SAM protects heart tissue from Doxorubicin-induced and ferroptosis-driven cardiomyopathy. This study broadens our understanding about the intersection of amino acid metabolism and ferroptosis regulation, providing insight into the underlying mechanisms and suggesting the methionine-SAM axis is a promising therapeutic strategy to treat ferroptosis-related diseases., (© 2024. The Author(s).)

Increased intramitochondrial free iron is a key feature of various liver diseases, leading to oxidative stress, mitochondrial dysfunction, and liver damage. Polydatin is a polyphenol with a hepatoprotective effect, which has been attributed to its ability to enhance mitochondrial oxidative metabolism and antioxidant defenses, thereby inhibiting reactive oxygen species (ROS) dependent cellular damage processes and liver diseases. However, it has not been explored whether polydatin is able to exert its effects by protecting the phospholipid cardiolipin against damage from excess iron. Cardiolipin maintains the integrity and function of electron transport chain (ETC) complexes and keeps cytochrome c bound to mitochondria, avoiding uncontrolled apoptosis. Therefore, the effect of polydatin on oxidative lipid damage, ETC activity, cytochrome levels, and ROS production was explored in iron-exposed rat liver mitochondria. Fe 2+ increased lipid peroxidation, decreased cardiolipin and cytochromes c + c 1 and aa 3 levels, inhibited ETC complex activities, and dramatically increased ROS production. Preincubation with polydatin prevented all these effects to a variable degree. These results suggest that the hepatoprotective mechanism of polydatin involves the attenuation of free radical production by iron, which enhances cardiolipin levels by counteracting membrane lipid peroxidation. This prevents the loss of cytochromes, improves ETC function, and decreases mitochondrial ROS production.

Disinfection by-products (DBPs) generated from water treatment have serious adverse effects on human health and natural ecosystems. However, research on the mutagenicity of DBPs with different chemical structures is still limited. In the present study, we compared the mutagenicity of 8 typical DBPs in human-hamster hybrid (A L ) cells and clarified the mechanisms involved. Our data displayed that the rank order for mutagenicity was as follows: iodoacetamide (IAcAm) > iodoacetonitrile (IAN) > iodoacetic acid (IAA) > bromoacetamide (BAcAm) ≈ bromoacetonitrile (BAN) > bromoacetic acid (BAA), which was confirmed by DNA double strand breaks and oxidative DNA damage. In contrast, bromoform (TBM) and iodoform (TIM) had minimal mutagenicity. The mutation spectrum analysis further revealed that IAN, IAcAm, and IAA could induce multilocus deletions in mammalian cells. Interestingly, nitrogenous DBPs (N-DBPs) and IAA were found to cause varying degrees of iron overload and lipid peroxidation, which was mediated by the activation of the Nrf2/HO-1 signaling pathway. Moreover, the presence of deferoxamine (DFO), an iron ion inhibitor, effectively reduced γ-H2AX and 8-OHdG induced by N-DBPs and IAA. These results indicated that the variations in genotoxicity among DBPs with different structures were associated with their ability to disrupt iron homeostasis. This study provided new insights into the mechanisms underlying the structure-dependent toxicity of DBPs and established a foundation for a more comprehensive understanding and intervention of the health risks associated with DBPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Maternal anemia has been identified as a contributing factor to adverse reproductive outcomes associated with cadmium (Cd) exposure, a common heavy metal. Our recent findings suggest that inhibited erythroid differentiation and enucleation also play significant roles in the direct embryonic toxicity resulting from maternal Cd exposure. However, the effects of Cd exposure on lipid metabolism remodeling, which is essential for physiological erythropoiesis, remain poorly understood. In the present study, pregnant mice were administered low doses of CdCl 2 via oral exposure from early to late gestation to mitigate Cd-induced maternal anemia. Compared to vehicle-treated controls, embryos from Cd-treated mice exhibited a slight decrease in weight, though without signs of atrophy. Consistent with our previous observations, fetal livers from Cd-exposed embryos demonstrated a dose-dependent inhibition of erythroid differentiation, as confirmed by ex vivo analysis. Notably, an intrinsic decrease in lipid peroxidation during erythroid differentiation was observed in the bone marrow and fetal livers of vehicle-treated mice, attributed to diminished lipid content. In contrast, this decrease in lipid peroxidation was absent in fetal liver erythroblasts from Cd-treated mice, where an increase in lipid peroxidation was instead noted. These findings elucidate a potential mechanism, lipid peroxidation, underlying Cd-induced embryonic toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ferroptosis is a type of cell death that depends on iron and is driven by lipid peroxidation, playing a crucial role in neuronal death during stroke. A central element in this process is the inactivation of glutathione peroxidase 4 (GPx4), an antioxidant enzyme that helps maintain redox balance by reducing lipid hydroperoxides. This review examines the critical function of GPx4 in controlling neuronal ferroptosis following ischemic and hemorrhagic stroke. We explore the mechanisms through which GPx4 becomes inactivated in various stroke subtypes. In strokes, excess glutamate depletes glutathione (GSH) and products of hemoglobin breakdown overwhelm GPx4. Studies using genetic models with GPx4 deficiency underscore its vital role in maintaining neuronal survival and function. We also consider new therapeutic approaches to enhance GPx4 activity, including novel small molecule activators, adjustments in GSH metabolism, and selenium supplementation. Additionally, we outline the potential benefits of combining these GPx4-focused strategies with other anti-ferroptotic methods like iron chelation and lipoxygenase inhibition for enhanced neuroprotection. Furthermore, we highlight the significance of understanding the timing of GPx4 inactivation during stroke progression to design effective therapeutic interventions., Competing Interests: Declaration of Competing Interest The author declares that there are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2024. Published by Elsevier Inc.)

The disease burden of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Emerging evidence has revealed that silica nanoparticles (SiNPs) could disorder the liver lipid metabolism and cause hepatotoxicity, but the underlying mechanism remains unknown. The purpose of this study is to elucidate the molecular mechanism of hepatic lipid metabolism disorder caused by SiNPs, and to reveal the role of ferroptosis in SiNPs-induced hepatotoxicity. To explore the phenotypic changes in liver, the wild-type C57BL/6J mice were exposed to different doses of SiNPs (5, 10, 20 mg/kg·bw) with or without melatonin (20 mg/kg·bw). SiNPs accelerated hepatic oxidative stress and promoted pathological injury and lipid accumulation, resulting in NAFLD development. Melatonin significantly inhibited the oxidative damage caused by SiNPs. Then, the hepatocytes were treated with SiNPs, the ferroptosis inducer and inhibitor, respectively. In vitro, SiNPs (25 μg/mL) generated mitochondrial and intracellular Fe 2+ accumulation and lipid peroxidation repair ability impairment, decreased the activity of GPX4 through ACSL4/p38 MAPK signaling pathway, resulting in ferroptosis of hepatocytes. Notably, Erastin (the ferroptosis activator, 5 μM) increased the sensitivity of hepatocytes to ferroptosis. Ferrostatin-1 (Fer-1, the ferroptosis inhibitor, 5 μM) restored GPX4 activity and protected against deterioration of lipid hydroperoxides (LOOHs) to salvage SiNPs-induced cytotoxicity. Finally, the liver tissue conditional ACSL4 knockout (cKO) mice and ACSL4-KO hepatocytes were adopted to further identify the role of the ACSL4-mediated ferroptosis on SiNPs-induced NAFLD development. The results displayed ACSL4 knockout could down-regulate the lipid peroxidation and ferroptosis, ultimately rescuing the progression of NAFLD. In summary, our data indicated that ACSL4/p38 MAPK/GPX4-mediated ferroptosis was a novel and critical mechanism of SiNPs-induced NAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ferroptosis is a form of regulated cell death, characterized by excessive iron-dependent lipid peroxidation. Biochemically, ferroptosis can be selectively induced by erastin through glutathione depletion or through inhibition of glutathione peroxidase 4 by RSL3, which leads to accumulation of cytotoxic lipid reactive oxygen species (ROS). Protein disulfide isomerase (PDI) was recently shown to mediate erastin/RSL3-induced ferroptosis and thus also become a new target for protection against chemically-induced ferroptosis. The present study aims to identify endogenous compounds that can protect against erastin/RSL3-induced ferroptotic cell death. We find that 2-hydroxyestrone, 2-hydroxyestradiol, 4-hydroxyestrone and 4-hydroxyestradiol, four major endogenous catechol estrogens, are effective inhibitors of PDI, and can strongly protect against chemically-induced ferroptotic cell death in cultured HT22 mouse hippocampal neuronal cells. The CETSA assay showed that these catechol estrogens can bind to PDI in live cells. PDI knockdown attenuates the protective effect of these catechol estrogens against chemically-induced ferroptosis. Mechanistically, inhibition of PDI's catalytic activity by catechol estrogens abrogates erastin/RSL3-induced dimerization of nitric oxide synthase, thereby preventing the subsequent accumulation of cellular nitric oxide, ROS and lipid-ROS, and ultimately ferroptotic cell death. In addition, joint treatment of cells with catechol estrogens also abrogates erastin/RSL3-induced upregulation of nitric oxide synthase protein levels, which also contributes to the cytoprotective effect of the catechol estrogens. In conclusion, the present study demonstrates that the catechol estrogens are protectors of HT22 neuronal cells against chemically-induced ferroptosis, and inhibition of PDI's catalytic activity by these estrogens contributes to a novel, estrogen receptor-independent mechanism of cytoprotection., (© 2024. The Author(s).)

Phenylketonuria (PKU) stems from a rare genetic metabolic imbalance attributed to an insufficiency in the enzyme phenylalanine hydroxylase. Within the context of PKU, brain‑derived neurotrophic factor (BDNF) plays a pivotal role in brain function. 7,8‑dihydroxyflavone (7,8‑DHF) operates as a tropomyosin receptor kinase B (TrkB) agonist, mimicking the effects of BDNF. This study aimed to examine the effects of administering 7,8‑DHF in chemically‑induced rat models specifically induced to simulate PKU chemically. The rats were subcutaneously injected with phenylalanine and p‑chlorophenylalanine, a phenylalanine hydroxylase inhibitor, along with 7,8‑DHF. The injections began on the 2nd day after birth and continued until the 10th day. Levels of interleukin‑1β (IL‑1β), interleukin‑6 (IL‑6), interleukin‑33 (IL‑33), BDNF, malondialdehyde (MDA), monoamine oxidase (MAO), and superoxide dismutase (SOD) in the brain tissues were quantified using the enzyme‑linked immunosorbent assay (ELISA). Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was performed to assess the gene expressions of inducible nitric oxide synthase (iNOS), nuclear factor kappa beta (NF‑κB), caspase‑3, nuclear factor erythroid 2‑related factor 2 (Nrf2), heme oxygenase‑1 (HO‑1), and BDNF. The results showed a decrease in mRNA levels of iNOS, IL‑1β, IL‑6, and lipid peroxidation in the group that received 7,8‑DHF. These results indicate that administering 7,8‑DHF has the potential to reduce brain damage in PKU by lowering proinflammatory cytokine levels and lipid peroxidation in PKU models. Thus, 7,8‑DHF, as a small molecule, might offer a promising adjunct therapeutic approach for PKU.

Background/objectives: Despite advances in ulcer treatment research, the search for new, safe, and effective strategies for preventing and treating ulcer diseases persists., Methods: In this study, the protective effects of dietary supplementation with krill oil (KO), fish oil (FO), and astaxanthin (ASX) on an ethanol-induced gastric ulcer model were compared during biochemical and histological observations. Sprague-Dawley ( n = 64) rats randomly divided into four groups-normal control (vehicle), KO, FO, and ASX groups-received the supplements via the orogastric route at a rate of 2.5% ( v / w ) of their daily feed consumption for 4 weeks. Then, ulcer induction was performed with ethanol., Results: The ulcer group showed increased levels of malondialdehyde (MDA), chemiluminescence (CL), and myeloperoxidase (MPO) activity and decreased levels of glutathione in the gastric tissues. While KO, FO, and ASX supplementation decreased chemiluminescence levels in the ulcer group, only ASX supplementation decreased MDA levels and MPO activity., Conclusions: In conclusion, supplementation with KO or FO has a similar protective effect against ethanol-induced ulcer damage, as it inhibits ROS formation and reduces lipid peroxidation. However, ASX supplementation has a higher protective effect than KO or FO supplementations against experimental ethanol-induced gastric lesions in rats, as it inhibits ROS formation and reduces neutrophil infiltration and lipid peroxidation.

This study evaluated the effects of ora-pro-nobis (Pereskia aculeate) flour supplementation on the in vivo basal antioxidant system of Drosophila melanogaster, and its action on the neural modulation observed by the enzyme acetylcholinesterase (AChE). The flies will receive a standard diet with flour incorporated at 5, 10 and 20% for 7 days. There was no change in food consumption, body weight, protein thiol levels and negative geotaxis behavior. The flies showed a reduction in the basal production of reactive species at concentrations of 10 and 20%, while there was a reduction in lipid peroxidation and catalase activity at all concentrations, accompanied by an increase in the levels of non-protein thiols. Superoxide dismutase activity was reduced in the 5 and 20% groups, while the reduction of superoxide anion in the 10% group may have contributed to the increase in longevity also in the 10% group. Longevity increased in groups 5 and 10%. The open field test may be related to the reduction in AChE activity in the 5, 10 and 20% groups. In general, the data show that supplementation with ora-pro-nobis flour at the concentrations tested did not cause toxicity and modulated the cholinergic system, demonstrating a therapeutic potential.

Nephrotoxicity is a common complication that limits the clinical utility of cisplatin. Ferroptosis is an iron-dependent necrotic cell death program that is mediated by phospholipid peroxidation. The molecular mechanisms that disrupt iron homeostasis and lead to ferroptosis are yet to be elucidated. In this study, we aimed to investigate the involvement of nuclear receptor coactivator 4 (NCOA4), a selective cargo receptor that mediates ferroptosis and autophagic degradation of ferritin in nephrotoxicity. Adult male Sprague-Dawley rats were randomly-assigned to four groups: control group, cisplatin (Cis)-treated group, deferiprone (DEF)-treated group, and Cis+DEF co-treated group. Serum, urine, and kidneys were isolated to perform biochemical, morphometric, and immunohistochemical analysis. Iron accumulation was found to predispose to ferroptotic damage of the renal tubular cells. Treatment with deferiprone highlights the role of ferroptosis in nephrotoxicity. Upregulation of NCOA4 in parallel with low ferritin level in renal tissue seems to participate in iron-induced ferroptosis. This study indicated that ferroptosis may participate in cisplatin-induced tubular cell death and nephrotoxicity through iron-mediated lipid peroxidation. Iron dyshomeostasis could be attributed to NCOA4-mediated ferritin degradation.

Background/aims: High Monomeric Polyphenols Berries Extract (HMPBE) is a formula highly rich in polyphenols clinically proven to enhance learning and memory. It is currently used to enhances cognitive performance including accuracy, working memory and concentration., Methods: Here, we investigated for the first time the beneficial effects of HMPBE in a mouse model of acute and chronic traumatic brain injury (TBI)., Results: HMPBE, at the dose of 15 mg/kg was able to reduce histological alteration as well as inflammation and lipid peroxidation. HMPBE ameliorate TBI by improving Nrf-2 pathway, reducing Nf-kb nuclear translocation and apoptosis, and ameliorating behavioral alteration such as anxiety and depression. Moreover, in the chronic model of TBI, HMPBE administration restored the decline of Tyrosine Hydroxylase (TH) and dopamine transporter (DAT) and the accumulation of a-synuclein into the midbrain region. This finding correlates the beneficial effect of HMPBE administration with the onset of parkinsonism related to traumatic brain damage., Conclusion: The data may open a window for developing new support strategies to limit the neuroinflammation event of acute and chronic TBI., Competing Interests: The authors have no relevant financial or non-financial interests to disclose., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

The global attention on microplastic pollution and its implications for human health has grown in recent years. Additionally, the co-existence of heavy metals may significantly alter microplastics' physicochemical characteristics, potentially amplifying their overall toxicity-a facet that remains less understood. In this study, we focused the membrane toxicity of modified polystyrene microplastics (PS-MPs) following cadmium (Cd) pretreatment. Our findings revealed that Cd-pretreated PS-MPs exacerbated their toxic effects, including diminished membrane integrity and altered phase fluidity in simulated lipid membrane giant unilamellar vesicles (GUVs), as well as heightened membrane permeability, protein damage, and lipid peroxidation in red blood cells and macrophages. Mechanistically, these augmented membrane toxicities can be partially ascribed to modifications in the surface roughness and hydrophilicity of Cd-pretreated PS-MPs, as well as to interactions between PS-MPs and lipid bilayers. Notably, hydrogen bonds emerged as a crucial mechanism underlying the enhanced interaction of PS-MPs with lipid bilayers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology., (© 2024. The Author(s).)

Sperm cryopreservation in small ruminant is an efficient strategy to distribute spermatozoa for reproductive programmes, but this process reduces the fertility potential of frozen-thawed spermatozoa. The aim of the current research was to evaluate the impact of different concentrations of cysteamine (CYS) in soybean lecithin (SL)-based medium on postthawed buck semen quality and fertility potential. Semen samples were collected from five bucks, twice a week, then diluted in the SL-based extender containing different concentrations of CYS as follows: extender containing 0 mM (control, C0), 1 mM (C1), 2 mM (C2), 4 mM (C4) and 8 mM (C8) CYS. Motility characteristics, membrane integrity, abnormal morphology, mitochondrial activity, acrosome integrity, viability, apoptotic-like changes, lipid peroxidation, DNA fragmentation, ROS concentration, pregnancy rate and kidding rate were evaluated after freeze-thaw process. In results, C1 resulted in greater (p ≤ 0.05) total motility, progressive motility, average path velocity, membrane integrity, mitochondrial activity, acrosome integrity, viability, pregnancy rate and kidding rate compared to the other groups. Furthermore, supplementation of freezing medium with 1 mM of CYS presented lower (p ≤ 0.05) apoptotic-like changes, lipid peroxidation, DNA fragmentation and ROS concentration compared to the other groups. On the other hand, C8 presented the least (p ≤ 0.05) total motility, progressive motility, average path velocity, membrane integrity, mitochondrial activity, acrosome integrity and viability as well as the highest (p ≤ 0.05) apoptotic-like changes, lipid peroxidation, DNA fragmentation and ROS concentration compared to the other groups. Therefore, supplementation of freezing medium with 1 mM CYS could be a helpful strategy to protect buck's spermatozoa quality and fertility potential during cryopreservation process., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Purpose: To explore the application and potential ferroptosis mechanisms of sonodynamic therapy (SDT) using titanium dioxide nanoparticles (TiO2-NPs) as sonosensitizers for the prevention of posterior capsule opacification (PCO)., Methods: We fabricated TiO2-NP-coated intraocular lenses (TiO2-IOLs) using the spin-coating method, followed by ultrasound activation of the photosensitizer TiO2. In vitro experiments were performed with human lens epithelial cells (HLECs) to explore the appropriate concentration of TiO2 and ultrasonic parameters. Investigations included reactive oxygen species (ROS) generation, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) western blot analysis, lipid peroxidation assays, and transcriptomics analysis. Finally, TiO2-IOLs were implanted in rabbit eyes to explore the in vivo performance of SDT., Results: Through both in vitro and in vivo experiments, the study determined that the ultrasound parameters of 5-minute duration, 1-MHz frequency, 50% duty cycle, and 1.2-W/cm2 intensity were reliable and valid for killing HLECs without damaging other ocular structures. In vitro experiments demonstrated that SDT generated excess ROS, which disrupted the mitochondrial membrane potential and significantly reduced the GSH content. Additionally, the downregulation of GPX4, accumulation of lipid peroxides, and alteration of mitochondrial morphology were observed, suggesting that ferroptosis may be the underlying mechanism. The RNA-sequencing analysis results also showed an increase in the expression of multiple pro-ferroptosis genes and the ferroptosis marker gene PTGS2. Animal experiments preliminarily demonstrated the safety and effectiveness of SDT in treating PCO in vivo., Conclusions: TiO2-IOLs combined with SDT effectively prevented PCO by generating ROS and intracellular ferroptosis.