Accumulation Of Lipid Peroxidation Products Research Articles

MCL1 inhibition: a promising approach to augment the efficacy of sorafenib in NSCLC through ferroptosis induction

Ferroptosis, an iron-dependent form of regulated cell death, plays a crucial role in modulating the therapeutic response in non-small cell lung cancer (NSCLC) patients. Studies have identified the signal transducer and activator of transcription 3 (STAT3) and myeloid cell leukemia-1 (MCL1) as potential targets for sorafenib, which exhibits activities in inducing ferroptosis. However, the role of STAT3-MCL1 axis in sorafenib-induced ferroptosis in NSCLC is still unclear. This study provided evidence that ferroptosis is a critical driver of sorafenib-induced cell death in NSCLC, supported by the accumulation of lipid peroxidation products, indicative of oxidative stress-induced cell death. Additionally, both in vitro and in vivo experiments showed that ferroptosis contributed to a significant portion of the anti-cancer effects elicited by sorafenib in NSCLC. The noticeable accumulation of lipid peroxidation products in sorafenib-treated mice underscored the significance of ferroptosis as a contributing factor to the therapeutic response of sorafenib in NSCLC. Furthermore, we identified the involvement of the STAT3/MCL1 axis in sorafenib-induced antitumor activity in NSCLC. Mechanistically, sorafenib inhibited endogenous STAT3 activation and downregulated MCL1 protein expression, consequently unleashing the ferroptosis driver BECN1 from the BECN1-MCL1 complex. Conversely, there is an augmented association of BECN1 with the catalytic subunit of system Xc−, SLC7A11, whose activity to import cystine and alleviate lipid peroxidation is hindered upon its binding with BECN1. Notably, we found that MCL1 upregulation correlated with ferroptosis resistance in NSCLC upon sorafenib treatment. Our findings highlight the importance of sorafenib-triggered ferroptosis in NSCLC and offer a novel strategy to treat advanced NSCLC patients: by downregulating MCL1 and, in turn, predispose NSCLC cells to ferroptosis.

Targeted RNAseq Revealed the Gene Expression Signature of Ferroptosis-Related Processes Associated with Disease Severity in Patients with Multiple Sclerosis.

Detrimental molecular processes in multiple sclerosis (MS) lead to the cellular accumulation of lipid peroxidation products and iron in the CNS, which represents the main driving force for ferroptosis. Ferroptosis is an iron-dependent form of regulated cell death, with proposed roles in neurodegeneration, oligodendrocyte loss and neuroinflammation in the pathogenesis of MS. Ferroptosis-related gene expression signature and molecular markers, which could reflect MS severity and progression, are currently understudied in humans. To tackle these challenges, we have applied a curated approach to create and experimentally analyze a comprehensive panel of ferroptosis-related genes covering a wide range of biological processes associated with ferroptosis. We performed the first ferroptosis-related targeted RNAseq on PBMCs from highly distinctive MS phenotype groups: mild relapsing-remitting (RR) (n = 24) and severe secondary progressive (SP) (n = 24), along with protein detection of GPX4 and products of lipid peroxidation (MDA and 4-HNE). Out of 138 genes, 26 were differentially expressed genes (DEGs), indicating changes in both pro- and anti-ferroptotic genes, representing a molecular signature associated with MS severity. The top three DEGs, as non-core ferroptosis genes, CDKN1A, MAP1B and EGLN2, were replicated by qPCR to validate findings in independent patient groups (16 RR and 16 SP MS). Co-expression and interactions of DEGs were presented as additional valuable assets for deeper understanding of molecular mechanisms and key targets related to MS severity. Our study integrates a wide genetic signature and biochemical markers related to ferroptosis in easily obtainable PBMCs of MS patients with clinical data and disease severity, thus providing novel molecular markers which can complement disease-related changes in the brain and undergo further research as potential therapeutic targets.

Molecular mechanisms of ferroptosis in cardiovascular disease.

Ferroptosis is a newly recognized type of regulated cell death that is characterized by the accumulation of iron and lipid peroxides in cells. Studies have shown that ferroptosis plays a significant role in the pathogenesis of various diseases, including cardiovascular diseases. In cardiovascular disease, ferroptosis is associated with ischemia-reperfusion injury, myocardial infarction, heart failure, and atherosclerosis. The molecular mechanisms underlying ferroptosis include the iron-dependent accumulation of lipid peroxidation products, glutathione depletion, and dysregulation of lipid metabolism, among others. This review aims to summarize the current knowledge of the molecular mechanisms of ferroptosis in cardiovascular disease and discuss the potential therapeutic strategies targeting ferroptosis as a treatment for cardiovascular disease.

P53 Regulation upon Lipid Peroxidation and Ferroptosis for Intervention against Atherogenesis

Abstract: Tumor protein 53 (P53), as an intracellular regulator of antioxidant responses, participates in the expression of antioxidant defense and lipid metabolism as well as the synthesis of genes in cells. The balance of oxidation and reduction can be disrupted by many pathological conditions, and the role of the antioxidant system in protecting the equilibrium state from pathological effects, such as reactive lipids, is crucial. In particular, the excessive accumulation of lipid peroxidation products is a key factor driving the occurrence and development of various diseases. Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death cascade reaction, which has become a key research area in cardiovascular diseases. Atherosclerosis (AS) is a pathological change caused by lipid metabolic disorder, inflammatory response, and endothelial cell injury, and is the most common cause of cardiovascular disease. This review briefly outlines lipid peroxidation and key components involving ferroptosis cascade reactions, summarizes and emphasizes the role of P53-related signaling pathways in mediating lipid peroxidation and ferroptosis, and focuses on the known P53 target genes that regulate these pathways, as well as explores the possibility of P53 intervention in the treatment of AS by regulating lipid peroxidation and ferroptosis processes.

Mechanism of cytotoxicity induced by the cigarette smoke extract (CSE) of heated tobacco products in vascular smooth muscle cells: A comparative study of the cytotoxic effects of CSE and the ferroptosis inducer, erastin

Heated tobacco products (HTPs) are marketed worldwide as less harmful alternatives to combustible cigarettes; however, their cytotoxic mechanisms in vascular smooth muscle cells are poorly understood. Ferroptosis is defined as iron-dependent cell death caused by the accumulation of lipid peroxidation products. In this study, the cytotoxic effects of nicotine- and tar-free cigarette smoke extracts (CSE) derived from three types of HTPs and the ferroptosis inducer, erastin, on vascular smooth muscle A7r5 cells were compared. Cigarette smoke from all HTPs was generated according to the following puffing regime: 55 mL, puff volume; 30 s, puff interval; 2 s, puff duration; bell-shaped, puff profile; and no blocking of the ventilation holes. Erastin and CSE decreased mitochondrial metabolic activity and increased lactate dehydrogenase leakage. The cytotoxic effects of erastin were almost completely inhibited by the radical-trapping antioxidant, UAMC-3203; iron chelator, deferoxamine mesylate (DFO); 12/15-lipoxygenase (12/15-LOX) inhibitor, baicalein; and selective 15-LOX inhibitor, ML351. In contrast, CSE-induced cell damage was partially attenuated by UAMC-3203, baicalein, and ML351 but not by DFO. These results suggest that erastin induces ferroptosis via 15-LOX-mediated iron-dependent lipid peroxidation, whereas CSE causes iron-independent cell damage via 15-LOX-mediated lipid peroxidation-dependent and -independent mechanisms.

Сondition of pro-oxidant and antioxidant systems in guinea pigs’ lungs under the condition of immobilization stress.

We have investigated the results of alterations in indices of pro-oxidant (conjugated diene and malondialdehyde ) and antioxidant (superoxide dismutase, ceruloplasmin, catalase) systems in guinea pigs’ lungs under the conditions of immobilization stress. The experiment was conducted on 40 female guinea pigs weighing 0.18-0.20 kg. The animals were divided into 4 groups, each contained 10 guinea pigs: I – intact guinea pigs ( control), II–guinea pigs with model of IS on1st day of experiment;Ш–animals on 2nd day of experiment;IV- group of animals on 34th day of experimental model of IS.
 The results of our experimental work showed a significant accumulation of lipid peroxidation products in the lung`s tissure in different periods ( on 1st, 2nd and 34th days) of immobilization stress. The state of antioxidant defence was characterized by moderate decrease of inzymes activity (superoxide dismutase, catalase and ceruloplasmin). disorders of balance between pro-oxidant and antioxidant systems couse oxidative stress development.

A CRISPR-Cas9 library screening identifies CARM1 as a critical inhibitor of ferroptosis in hepatocellular carcinoma cells

Ferroptosis is an iron-catalyzed form of regulated cell death that results from the accumulation of lipid peroxidation products and reactive oxygen species to a lethal content. However, the transcriptional regulation of ferroptosis is not well understood. Sorafenib, a standard drug for hepatocellular carcinoma (HCC), induces ferroptosis in HCC cells. In this study, we conducted a CRISPR-Cas9 library screening targeting epigenetic factors and identified coactivator-associated arginine methyltransferase 1 (CARM1) as a critical inhibitor of ferroptosis. CARM1 depletion intensified Sorafenib-induced ferroptosis, resulting in decreased cell viability, reduced cellular glutathione level, increased lipid peroxidation, and altered mitochondrial crista structure. Additionally, we investigated a CARM1 inhibitor (CARM1i) as a potential ferroptosis inducer. Combining the CARM1i with Sorafenib enhanced the induction of ferroptosis. Notably, both CARM1 knockdown and CARM1i showed cooperative effects with Sorafenib in inhibiting HCC growth in mice. The underlying mechanism involves CARM1-catalyzed H3R26me2a on the promoter of glutathione peroxidase 4, leading to its transcriptional activation and subsequent ferroptosis inhibition. Furthermore, Sorafenib treatment induced the transcription of CARM1 through the MDM2-p53 axis. In summary, our findings establish CARM1 as a critical ferroptosis inhibitor and highlight the potential of CARM1is as novel ferroptosis inducers, providing promising therapeutic strategies for HCC treatment.

Gemfibrozil Alleviates Cognitive Impairment by Inhibiting Ferroptosis of Astrocytes via Restoring the Iron Metabolism and Promoting Antioxidant Capacity in Type 2 Diabetes.

Diabetes-associated cognitive dysfunction (DACD) is considered a significant complication of diabetes and manifests as cognitive impairment. Astrocytes are vital to the brain energy metabolism and cerebral antioxidant status. Ferroptosis has been implicated in cognitive impairment, but it is unclear whether the ferroptosis of astrocytes is involved in the progression of DACD. PPARA/PPARα (peroxisome proliferator-activated receptor alpha) is a transcription factor that regulates glucose and lipid metabolism in the brain. In this study, we demonstrated that high glucose promoted ferroptosis of astrocytes by disrupting iron metabolism and suppressing the xCT/GPX4-regulated pathway in diabetic mice and astrocytes cultured in high glucose. Administration of gemfibrozil, a known PPARα agonist, inhibited ferroptosis and improved memory impairment in db/db mice. Gemfibrozil also prevented the accumulation of lipid peroxidation products and lethal reactive oxygen species induced by iron deposition in astrocytes and substantially reduced neuronal and synaptic loss. Our findings demonstrated that ferroptosis of astrocytes is a novel mechanism in the development of DACD. Additionally, our study revealed the therapeutic effect of gemfibrozil in preventing and treating DACD by inhibiting ferroptosis.

Abstract P2033: Western Diet Can Cause Adverse Cardiac Remodeling During Pregnancy By Inducing Foxo1 Expression

Introduction: Pregnancy induces physiological cardiac hypertrophy in healthy women. Our recent findings suggest that obesity can disturb this process and induce pathological cardiac hypertrophy during pregnancy both in human patients and Western Diet (WD) fed mice. Animal studies determined the pathological cardiac hypertrophy is concomitant with increased cardiomyocyte cross-sectional area (CSA), fetal gene activation and fibrosis, however, the underlying mechanisms remain unclear. The present study asks if FoxO1, as a transcriptional factor, may play a role in the adverse cardiac response to pregnancy in WD mice. Methods: The expression levels of FoxO1 and its downstream targeting genes were tested in Ctrl Diet (CD) and WD fed non-pregnant and postpartum animals. To further investigate the role of FoxO1 in pathological cardiac hypertrophy in WD animals during pregnancy, FoxO1 was then silenced by AAV9-shFoxO1 virus in WD mice before breeding. AAV9-scramble RNA served as control. Cardiac phenotype in AAV9 treated WD mice were characterized at post-partum day 1. Results: WD feeding led to increased gene expression levels of FoxO1 and its downstream targeting genes, such as CD36 and PDK4, compared with CD mice. While the gene expression levels of FoxO1 were not different between non-pregnant and pregnant WD mice, FoxO1 protein activation was significantly increased in WD mice after pregnancy determined by a decrease of pFoxO1/tFoxO1 ratio, compared with non-pregnant WD mice. Silencing FoxO1 inhibited the expression levels of FoxO1 and its downstream genes CD36 and PDK4. FoxO1 inhibition in WD fed animals prevented WD induced pathological hypertrophy during pregnancy, with decreased heart weight, cardiomyocyte CSA, attenuated fetal gene activation and fibrosis accumulation. FoxO1 silencing also led to less accumulation of lipid peroxidation product in the myocardium. Conclusions: FoxO1 activation in WD mice with metabolic disturbances during pregnancy can induce pathological cardiac hypertrophy observed during pregnancy.

Evaluation of the toxicity of clozapine on the freshwater diatom Navicula sp. using the FTIR spectroscopy

Clozapine is an often prescribed neuroactive pharmaceutical and frequently detected in the aquatic environments. However, its toxicity on low trophic level species (i.e., diatoms) and associated mechanisms are seldom reported. In this study, the toxicity of clozapine on a widely distributed freshwater diatom Navicula sp. was evaluated using the FTIR spectroscopy along with biochemical analyses. The diatoms were exposed to various concentrations of clozapine (0, 0.01, 0.05, 0.10, 0.50, 1.00, 2.00, 5.00 mg/L) for 96 h. The results revealed that clozapine reached up to 392.8 μg/g in the cell wall and 550.4 μg/g within the cells at 5.00 mg/L, suggesting that clozapine could be adsorbed extracellularly and accumulated intracellularly in diatoms. In addition, hormetic effects were displayed on the growth and photosynthetic pigments (chlorophyll a and carotenoid) of Navicula sp., with a promotive effect at concentrations less than 1.00 mg/L while an inhibited effect at concentrations over 2 mg/L. Clozapine induced oxidative stress in Navicula sp., accompanied by decreased levels of total antioxidant capacity (T-AOC) (>0.05 mg/L), in which, the activity of superoxide dismutase (SOD) (at 5.00 mg/L) was increased whereas the activity of catalase (CAT) (>0.05 mg/L) was decreased. Furthermore, FTIR spectroscopic analysis showed that exposure to clozapine resulted in accumulation of lipid peroxidation products, increased sparse β-sheet structures, and altered DNA structures in Navicula sp. This study can facilitate the ecological risk assessment of clozapine in the aquatic ecosystems.

Some aspects of antioxidant protection in the body of young cattle

Relevance. Of scientific interest are studies to assess the pro- and antioxidant status of the body of productive animals with age, since they are interconnected with health, the state of the immune and reproductive systems.Methods. In order to study the indicators of antioxidant protection in the body of young cattle of different ages in the conditions of the PZ «Ladozhsky» (Krasnodar district), the following groups of animals were formed in the winter period of 2022: young animals at the age of 1 month (n = 15), 3–4 months (n = 19), young animals 6–7 months old (n = 14), heifers (n = 16). The following indicators were determined in the blood of the studied animals: the concentration of ceruloplasmin (CP), products reacting with thiobarbituric acid (TBA-AP), the total content of water-soluble antioxidants (TAWSA), the total antioxidant status (TAS), peroxidase activity, the ratio of TBA-AP/CP, metabolic processes and hematological indicators were calculated. Correlations between the determined indicators were calculated.Results. The results obtained indicate changes in the LPO and AOD indicators depending on age and physiological state. A significant increase in the concentration of TBA-AP in the blood of young animals 6–7 months old and heifers, compared with analogues of 1 and 3–4 months of age, indicates the accumulation of lipid peroxidation products with age. The decrease in the AOP level in the 6-month-old group of animals is also indicated by the minimum concentration of TAWSA and the trend towards a decrease in the total antioxidant status and peroxidase activity. Due to the high level of ceruloplasmin, the ratio of TBA to CP was at the level of other groups. The age of the animals had a significant effect (p ≤ 0.001) on the content of TBA-AP, ceruloplasmin, TAWSA, and the overall antioxidant status. SLE and TBA-AP are significant markers of the state of LPO and AOP in the body. The results obtained will allow monitoring the health status of animals and will help to provide timely preventive measures that increase the adaptive capabilities of young animals and the most complete realization of the genetic potential of productivity.

Ferroptosis inhibition shields house ear institute-organ of corti 1 cells from free fatty acids-induced inflammatory injuries

Background Free fatty acids (FFAs) could induce inflammatory responses via various pathways. Ferroptosis is characterized by the accumulation of lipid peroxidation products and fatal reactive oxygen species derived from iron accumulation, which may be an upstream event in the inflammatory injuries. Objectives To investigate the involvement of ferroptosis during the FFAs-induced pathological hair cell inflammatory injuries and its underlying mechanisms. Material and Methods We utilized House Ear Institute-Organ of Corti 1 (HEI-OC1) cell line as an in vitro model. The palmitate acid (PA) was utilized as a substitute for FFA, with cotreatment with ferroptosis inducer RSL3 and ferroptosis inhibitor Fer-1. Cell viability, lactase dehydrogenase (LDH) release, the expressions of ferroptosis-related factors such as glutathione peroxidase-4 (GPX4), solute carrier family 7 member 11 (SLC7A11), as well as toll-like receptor 4 (TLR4), ferric ion and reactive oxygen species (ROS), and partial inflammatory cytokines were measured. Results PA treatment might induce ferroptosis in HEI-OC1 cells, manifested as decreased cell viability, upregulated LDH release, iron overload, and ROS accumulation. Several inflammatory cytokines including IL-1β, IL-6, IL-1β, IL-6, TNF-α, MCP-1, IL-13, IL-12 p40, CCL5, G-CSF, and GM-CSF were upregulated compared to the Ctr group, while GPX4 and SLC7A11 were downregulated. The expression of TLR4 in the inflammatory pathway was also upregulated. Besides, these changes were further exacerbated by RSL3 cotreatment and abolished by Fer-1 cotreatment. Conclusions and Significance Ferroptosis inhibition could alleviate the PA-induced inflammatory injuries via inactivation of TLR4 signaling pathway in HEI-OC1 cell line.

Priming Potato Plants with Melatonin Protects Stolon Formation under Delayed Salt Stress by Maintaining the Photochemical Function of Photosystem II, Ionic Homeostasis and Activating the Antioxidant System.

Melatonin is among one of the promising agents able to protect agricultural plants from the adverse action of different stressors, including salinity. We aimed to investigate the effects of melatonin priming (0.1, 1.0 and 10 µM) on salt-stressed potato plants (125 mM NaCl), by studying the growth parameters, photochemical activity of photosystem II, water status, ion content and antioxidant system activity. Melatonin as a pleiotropic signaling molecule was found to decrease the negative effect of salt stress on stolon formation, tissue water content and ion status without a significant effect on the expression of Na+/H+-antiporter genes localized on the vacuolar (NHX1 to NHX3) and plasma membrane (SOS1). Melatonin effectively decreases the accumulation of lipid peroxidation products in potato leaves in the whole range of concentrations studied. A melatonin-induced dose-dependent increase in Fv/Fm together with a decrease in uncontrolled non-photochemical dissipation Y(NO) also indicates decreased oxidative damage. The observed protective ability of melatonin was unlikely due to its influence on antioxidant enzymes, since neither SOD nor peroxidase were activated by melatonin. Melatonin exerted positive effects on the accumulation of water-soluble low-molecular-weight antioxidants, proline and flavonoids, which could aid in decreasing oxidative stress. The most consistent positive effect was observed on the accumulation of carotenoids, which are well-known lipophilic antioxidants playing an important role in the protection of photosynthesis from oxidative damage. Finally, it is possible that melatonin accumulated during pretreatment could exert direct antioxidative effects due to the ROS scavenging activity of melatonin molecules.

Biological control efficacy of Bacillus licheniformis HG03 against soft rot disease of postharvest peach

This study aimed to investigate the biocontrol ability of Bacillus licheniformis HG03 against Rhizopus stolonifer causing agent of peach fruit rot and explore its mechanism. The biocontrol strain B. licheniformis HG03 was applied on inhibition of the pathogen Rhizopus stolonifer, which is expected to improve the preservation of peach fruit. The results revealed that the peach treated with B. licheniformis HG03 were significantly more resistant to postharvest soft rot when stored at 20 °C and high humidity. Comparison to the control, treatment with HG03 improved the activity of related enzymes and balanced the metabolism of reactive oxygen species. Such treatment reduced the accumulation of lipid peroxidation products and enhanced free radical scavenging ability of peaches. Furthermore, the transcriptome analysis revealed that the HG03 treatment activated MAPK signaling pathway, induced the expression of antioxidant activity-related genes and different WRKY transcription factors in plant pathogen interaction metabolic pathway. Hence, the results revealed that HG03 treatment is an effective biological control method to improve peach fruit disease resistance and prolong the storage time of peaches.

Growth responses of wheat seedlings of different varieties to heat-stress and their relation to the antioxidant system state and osmolytes accumulation

Background. In recent decades, Ukraine has been experiencing abnormally high temperatures and droughts in different seasons, including autumn. This creates stressful conditions for winter cereals, especially wheat, at the very beginning of ontogeny. A comprehensive study of the functioning of antioxidant and osmoprotective systems in the early stages of development for wheat varieties of different ecological and geographical origins has not been conducted yet. This study aimed to investigate the effect of heat stress on the growth of etiolated seedlings of seven varieties of winter wheat (Triticum aestivum L.) and the indicators characterizing the functioning of antioxidant and osmoprotective systems. Materials and Methods. Wheat grains of different varieties were germinated at 24 °C for three days in the dark. Subsequently, they were subjected to 4 h of heating at 45 °C in an air thermostat. Immediately after stress, the generation of superoxide anion radical (O2•‒) by seedlings, the content of hydrogen peroxide (H2O2), lipid peroxidation (LPO) products, catalase and guaiacol peroxidase activity, and also proline and soluble carbohydrates were analyzed. One day after heating, the relative inhibition of shoot and root growth was determined. Results and Discussion. The Antonivka and Tobak varieties demonstrated the highest ability to maintain growth after exposure to high temperatures; the Darynka Kyivska and Lira Odeska varieties were medium resistant. In the Doskonala, Bogdana and Avgustina varieties, a strong inhibition of shoot and root growth after heat stress was noted. In Antonivka, after high-temperature exposure, the O2•‒ generation increased slightly, while the content of H2O2 and LPO products did not change. In Tobak, Darynka Kyivska and Lira Odeska, the stress-induced increase in ROS formation and accumulation of LPO products was moderate. The hyperthermia-sensitive Doskonala, Bogdana and Avgustina showed a significant development of oxidative stress. Heat-resistant varieties had high catalase activity and increased total soluble carbohydrate content under heat stress. After exposure to high temperature, the proline content increased in all studied varieties, but no positive correlation was recorded between its amount and their heat resistance. Likewise, no significant correlation was found between the guaiacol peroxidase activity and the ability of varieties to maintain growth after heat stress. Conclusion. The high-level inverse correlation between catalase activity, soluble carbohydrate content, and the manifestation of oxidative stress effect indicates a significant contribution of these stress-protective system components to the adaptation of seedlings to heat stress. Indicators of the oxidative stress intensity and the functioning of individual components of the antioxidant system can be used to assess the heat resistance of wheat varieties at the early stages of development.

Substantiation of the choice of the model for the formation of oxidative stress in preclinical studies

At the preclinical stage, a comparative assessment of various models of the formation of oxidative stress by exposure to high and low temperatures, ultraviolet irradiation, and the influence of a low-frequency alternating magnetic field was carried out. Exposure to laboratory animals was carried out daily for 21 days. It has been established that the modeling of oxidative stress by exposure to ultraviolet rays on rats allows, by the end of the first week of the experiment, to induce an increase in the intensity of lipid peroxidation processes with the accumulation of lipid peroxidation products by 48-61% and a decrease in the activity of antioxidant components by 31-33% in comparison with the control, which exceeds similar parameters on day 7 in models of hypothermia, hyperthermia and magnetic induction. Cold exposure in rats is accompanied by a more pronounced shift in the antioxidant status towards the prooxidant side by the end of the third week, which is confirmed by an increase in the concentration of lipid peroxidation products by 45-67% and a decrease in the level of components of the antioxidant system by 28-37% relative to the control. In general, the prooxidant effect in vivo of all the studied effects was confirmed, which we recommend as experimental models for the formation of oxidative stress at the preclinical stage, substantiating in the work the possibility of using each effect depending on the purpose of the pharmacological study.

КЛИНИКО-ЛАБОРАТОРНЫЕ ПОКАЗАТЕЛИ БЕРЕМЕННЫХ КОРОВ, ПРЕДРАСПОЛОЖЕННЫХ К РАЗВИТИЮ ГЕСТОЗА

The article presents materials on studying clinical and laboratory indicators of pregnant cows at 60 days of gestation, prone to the development of gestosis. In cows with the uterine fetal growth retardation syndrome at 2 months of pregnancy, subsequently complicated by gestosis, the established morphobiochemical changes indicate failures in the protein metabolism, functioning of the liver, kidneys, and the circulatory system. The changes also show an intensive accumulation of lipid peroxidation products, with a decrease in the activity of the enzymatic and non-enzymatic link of the AOD. The development of the fetal intrauterine growth retardation syndrome occurs against the background of a trophism disorders in the developing embryo. This at early stages of pregnancy is clinically manifested by a decrease in the size of the uterine horn cavity by 22.2-34.2%, the length of the fetus – by 41.5-48.9%, the body diameter – by 19.9-28.9%, the size of the corpus luteum of the ovary – by 15.7-24.1%.

Sphingosine 1-phosphate alleviates radiation-induced ferroptosis in ovarian granulosa cells by upregulating glutathione peroxidase 4

Ferroptosis is a form of cell death caused by the accumulation of lipid peroxidation products due to abnormal iron metabolism. However, it remains unknown whether ferroptosis participates in the process of radiation-induced ovarian injury. Sphingosine-1-phosphate (S1P) is an important bioactive sphingolipid that has a protective effect on ovarian injury. The present study aims to determine whether X-ray radiation induces ferroptosis in the ovarian granulosa KGN cell line, and explore the potential effect of S1P and its mechanism in radiation-induced ferroptosis. The results indicated that irradiation reduced the viability of KGN cells, altered the mitochondrial morphology, induced the intracellular accumulation of iron ions, increased oxidative stress, and induced lipid peroxidation. Furthermore, the radiation exposure triggered the ferroptosis in KGN cells. S1P can alleviate radiation-induced ferroptosis. Furthermore, the protective effect of S1P was reversed after the application of siRNA to interfere with the glutathione peroxidase 4 expression. Ferroptosis might be pervasive in radiation-induced ovarian injury, and S1P may serve as a potential therapeutic approach to protect against the toxic effect of radiation in female gonads by inhibiting ferroptosis.

Copper Induced DNA Damage in the Gills of the Mussel Mytilus trossulus and Reversibility after Depuration

The pollution of coastal water areas by heavy metals is constantly growing; therefore, the study of the mechanisms of impact of these toxicants on the organisms of hydrobionts is a topical direction of toxicology. Particularly pertinent are questions about the state of the reparation system in the aquatic organisms, which make it possible to assess the resistance, survival of hydrobionts, and the probability of remote consequences under the impact of heavy metals. Therefore, in this work, we investigated genome integrity and DNA repair ability in the gill cells of Mytilus trossulus, under conditions of copper (Cu2+) accumulation, and in the process of tissue depuration from this metal. Although the biochemical detoxification system was functioning, it is noted that destructive processes developed, including the accumulation of lipid peroxidation products (MDA) and DNA damage. It was also found that in all of the experimental groups of Mytilus trossulus, in the process of depuration from Cu2+ for 24 h, the levels of DNA damage and MDA content were markedly reduced, and further reduction was less intense.

Identification of a novel gene signature with regard to ferroptosis, prognosis prediction, and immune microenvironment in osteosarcoma.

Ferroptosis is a novel form of non-apoptotic cell death that mainly results from the iron-dependent lethal accumulation of lipid peroxidation products. Here, we defined differentially expressed genes between control and RSL3-treated osteosarcoma cells as ferroptosis-associated genes (FAGs). These FAGs were then subjected to weighted gene correlation network analysis (WGCNA), and we found that the turquoise module, containing 71 FAGs, was markedly related to the patient's vital status. After that, FAGs in the turquoise module were utilized to construct a prognostic multigene (COL5A2, HOXB4, and UNC5B) signature for risk stratification in osteosarcoma. Validation in internal and external cohorts indicated the accuracy and clinical applicability of this signature in predicting the prognosis of patients with osteosarcoma. Univariate and multivariate Cox regression analyses suggested that the signature-derived risk score is an independent indicator of patient prognosis. Immunological analysis indicated that significant variations in stromal and ESTIMATE scores, as well as tumor purity, were found when the high- and low-risk groups were compared. Regarding immune cell infiltration, the proportion of activated CD4 memory T cells was significantly lower in the high-risk group than that in the low-risk group. The ssGSEA results suggested that CD8+ T, Tfh, and Th1 cell scores were consistently lower in the high-risk group than those in the low-risk group. In terms of immune-related activities, the high-risk group had considerably lower scores for promoting inflammation, T-cell co-inhibition, and T-cell co-stimulation than the low-risk group, indicating the differential immunological state of the high- and low-risk groups. Of the three FAGs included in the signature, the expression of COL5A2, HOXB4, and UNC5B was higher in the high-risk groups, and the expression of COL5A2 and UNC5B was negatively associated with patient prognosis. Additionally, the mRNA levels of COL5A2 and HOXB4 were lower and those of UNC5B were higher in RSL3-treated cells than in control cells. In all, we systematically analyzed the transcriptional changes of osteosarcoma cells induced by RSL3 and constructed a novel three-gene signature with regard to ferroptosis, prognosis prediction, and immune microenvironment. We also identified COL5A2, HOXB4, and UNC5B as potential therapeutic targets and important regulators of ferroptosis in osteosarcoma.