Aberrant Expression of SLC7A11 Impairs the Antimicrobial Activities of Macrophages in Staphylococcus Aureus Osteomyelitis in Mice.

Staphylococcus aureus (S. aureus) persistence in macrophages, potentially a reservoir for recurrence of chronic osteomyelitis, contributes to resistance and failure in treatment. As the mechanisms underlying survival of S. aureus in macrophages remain largely unknown, there has been no treatment approved. Here, in a mouse model of S. aureus osteomyelitis, we identified significantly up-regulated expression of SLC7A11 in both transcriptomes and translatomes of CD11b+F4/80+ macrophages, and validated a predominant distribution of SLC7A11 in F4/80+ cells around the S. aureus abscess. Importantly, pharmacological inhibition or genetic knockout of SLC7A11 promoted the bactericidal function of macrophages, reduced bacterial burden in the bone and improved bone structure in mice with S. aureus osteomyelitis. Mechanistically, aberrantly expressed SLC7A11 down-regulated the level of intracellular ROS and reduced lipid peroxidation, contributing to the impaired bactericidal function of macrophages. Interestingly, blocking SLC7A11 further activated expression of PD-L1 via the ROS-NF-κB axis, and a combination therapy of targeting both SLC7A11 and PD-L1 significantly enhanced the efficacy of clearing S. aureus in vitro and in vivo. Our findings suggest that targeting both SLC7A11 and PD-L1 is a promising therapeutic approach to reprogram the bactericidal function of macrophages and promote bacterial clearance in S. aureus osteomyelitis.

Ferroptosis in ulcerative colitis: Potential mechanisms and promising therapeutic targets.

Ulcerative colitis (UC) is a complex immune-mediated chronic inflammatory bowel disease. It is mainly characterized by diffuse inflammation of the colonic and rectal mucosa with barrier function impairment. Identifying new biomarkers for the development of more effective UC therapies remains a pressing task for current research. Ferroptosis is a newly identified form of regulated cell death characterized by iron-dependent lipid peroxidation. As research deepens, ferroptosis has been demonstrated to be involved in the pathological processes of numerous diseases. A growing body of evidence suggests that the pathogenesis of UC is associated with ferroptosis, and the regulation of ferroptosis provides new opportunities for UC treatment. However, the specific mechanisms by which ferroptosis participates in the development of UC remain to be more fully and thoroughly investigated. Therefore, in this review, we focus on the research advances in the mechanism of ferroptosis in recent years and describe the potential role of ferroptosis in the pathogenesis of UC. In addition, we explore the underlying role of the crosslinked pathway between ferroptosis and other mechanisms such as macrophages, neutrophils, autophagy, endoplasmic reticulum stress, and gut microbiota in UC. Finally, we also summarize the potential compounds that may act as ferroptosis inhibitors in UC in the future.

Baicalein alleviates cisplatin-induced acute kidney injury by inhibiting ALOX12-dependent ferroptosis.

BACKGROUND: In acute kidney injury (AKI), ferroptosis is the main mechanism of cell death in the renal tubular epithelium. Baicalein, a traditional Chinese medicine monomer, plays a protective role in various kidney diseases; however, the effect of baicalein on ferroptosis in AKI still needs further exploration. PURPOSE: In this study, we explored the role of baicalein and its specific mechanism in mediating ferroptosis in cisplatin-induced AKI. METHODS: We used a cisplatin-induced AKI model to study the effects of baicalein on renal tissue and tubular epithelial cell injury. The effects of baicalein on tubular epithelial cell ferroptosis were detected in cisplatin-induced AKI and further verified by folic acid-induced AKI. The Swiss Target Prediction online database was used to predict the possible mechanism by which baicalein regulates ferroptosis, and the specific target proteins were further verified. Molecular docking and SPR were used to further determine the binding potential of baicalein to the target protein. Finally, RNA interference (RNAi) technology and enzymatic inhibition were used to determine whether baicalein regulates ferroptosis through target proteins. RESULTS: Baicalein alleviated cisplatin- and folic acid-induced renal dysfunction and pathological damage and improved cisplatin-induced HK2 cell injury. Mechanistically, baicalein reduced the expression of 12-lipoxygenase (ALOX12), which inhibits phospholipid peroxidation and ferroptosis in AKI. Molecular docking and SPR demonstrated direct binding between baicalein and ALOX12. Finally, we found that silencing ALOX12 had a regulatory effect similar to that of baicalein. Comparable results were also obtained with the ALOX12 inhibitor ML355. CONCLUSION: This was the first study to confirm that baicalein regulates ferroptosis both in vitro and in vivo in cisplatin-induced AKI and to verify the regulatory effect of baicalein in folic acid-induced AKI. Our results reveal the critical role of ALOX12 in kidney damage and ferroptosis caused by cisplatin and emphasize the regulatory effect of baicalein on renal tubular epithelial cell ferroptosis mediated by ALOX12. Baicalein is an effective drug for treating AKI, and ALOX12 is a potential drug target.

Thiourea improves yield and quality traits of Brassica napus L. by upregulating the antioxidant defense system under high temperature stress.

High temperature stress influences plant growth, seed yield, and fatty acid contents by causing oxidative damage. This study investigated the potential of thiourea (TU) to mitigate oxidative stress and restoring seed oil content and quality in canola. The study thoroughly examined three main factors: (i) growth conditions-control and high temperature stress (35 °C); (ii) TU supplementation (1000 mg/L)-including variations like having no TU, water application at the seedling stage, TU application at seedling stage (BBCH Scale-39), water spray at anthesis stage, and TU application at anthesis stage (BBCH Scale-60); (iii) and two canola genotypes, 45S42 and Hiola-401, were studied separately. High temperature stress reduced growth and tissue water content, as plant height and relative water contents were decreased by 26 and 36% in 45S42 and 27 and 42% Hiola-401, respectively, resulting in a substantial decrease in seed yield per plant by 36 and 38% in 45S42 and Hiola-401. Seed oil content and quality parameters were also negatively affected by high temperature stress as seed oil content was reduced by 32 and 35% in 45S42 and Hiola-401. High-temperature stress increased the plant stress indicators like malondialdehyde, H2O2 content, and electrolyte leakage; these indicators were increased in both canola genotypes as compared to control. Interestingly, TU supplementation restored plant performance, enhancing height, relative water content, foliar chlorophyll (SPAD value), and seed yield per plant by 21, 15, 30, and 28% in 45S42; 19, 13, 26, and 21% in Hiola-401, respectively, under high temperature stress as compared to control. In addition, seed quality, seed oil content, linoleic acid, and linolenic acid were improved by 16, 14, and 22% in 45S42, and 16, 11, and 23% in Hiola-401, as compared to control. The most significant improvements in canola seed yield per plant were observed when TU was applied at the anthesis stage. Additionally, the research highlighted that canola genotype 45S42 responded better to TU applications and exhibited greater resilience against high temperature stress compared to genotype Hiola-401. This interesting study revealed that TU supplementation, particularly at the anthesis stage, improved high temperature stress tolerance, seed oil content, and fatty acid profile in two canola genotypes.

Reflections on the complex mechanisms of endometriosis from the perspective of ferroptosis.

Ferroptosis is a novel type of iron-dependent programmed cell death characterised by intracellular iron overload, increased lipid peroxidation and abnormal accumulation of reactive oxygen species.It has been implicated in the progression of several diseases including cancer, ischaemia-reperfusion injury, neurodegenerative diseases and liver disease. The etiology of endometriosis (EMS) is still unclear and is associated with multiple factors, often accompanied by various forms of cell death and a complex microenvironment. In recent decades, the role of non-traditional forms of cell death, represented by ferroptosis, in endometriosis has come to the attention of researchers. This article reviews the transitional role of iron homeostasis in the development of ferroptosis, the characteristics and regulatory mechanisms of ferroptosis, and focuses on summarising the links between iron death and various pathogenic mechanisms of EMS, including oxidative stress, dysregulation of lipid metabolism, inflammation, autophagy and epithelial-mesenchymal transition. The possible applications of ferroptosis in the treatment of EMS, future research directions and current issues are discussed with the aim of providing new ideas for further understanding of EMS.

Ferroptosis: Iron-mediated cell death linked to disease pathogenesis.

Ferroptosis is an iron-mediated regulatory cell death pattern characterized by oxidative damage. The molecular regulating mechanisms are related to iron metabolism, lipid peroxidation, and glutathione metabolism. Additionally, some immunological signaling pathways, such as the cyclic GMP-AMP synthase-stimulator ofinterferon genes axis, Janus kinase-signal transducer and activator of transcription 1 axis, and transforming growth factor beta 1-Smad3 axis may also participate in the regulation of ferroptosis. Studies have shown that ferroptosis is closely related to many diseases such as cancer, neurodegenerative diseases, inflammatory diseases, and autoimmune diseases. Considering the pivotal role of ferroptosis-regulating signaling in the pathogenesis of diverse diseases, the development of ferroptosis inducers or inhibitors may have significant clinical potential for the treatment of the aforementioned conditions.

Exosome is a Fancy Mobile Sower of Ferroptosis.

Exosomes, nano-sized small extracellular vesicles, have been shown to serve as mediators between intercellular communications by transferring bioactive molecules, such as non-coding RNA, proteins, and lipids from secretory to recipient cells, modulating a variety of physiological and pathophysiological processes. Recent studies have gradually demonstrated that altered exosome charges may represent a key mechanism driving the pathological process of ferroptosis. This review summarizes the potential mechanisms and signal pathways relevant to ferroptosis and then discusses the roles of exosome in ferroptosis. As well as transporting iron, exosomes may also indirectly convey factors related to ferroptosis. Furthermore, ferroptosis may be transmitted to adjacent cells through exosomes, resulting in cascading effects. It is expected that further research on exosomes will be conducted to explore their potential in ferroptosis and will lead to the creation of new therapeutic avenues for clinical diseases.

Peroxynitrite-Triggered Carbon Monoxide Donor Improves Ischemic Stroke Outcome by Inhibiting Neuronal Apoptosis and Ferroptosis.

Cerebral ischemia-reperfusion injury produces excessive reactive oxygen and nitrogen species, including superoxide, nitric oxide, and peroxynitrite (ONOO-). We recently developed a new ONOO--triggered metal-free carbon monoxide donor (PCOD585), exhibiting a notable neuroprotective outcome on the rat middle cerebral artery occlusion model and rendering an exciting intervention opportunity toward ischemia-induced brain injuries. However, its therapeutic mechanism still needs to be addressed. In the pharmacological study, we found PCOD585 inhibited neuronal Bcl2/Bax/caspase-3 apoptosis pathway in the peri-infarcted area of stroke by scavenging ONOO-. ONOO- scavenging further led to decreased Acyl-CoA synthetase long-chain family member 4 and increased glutathione peroxidase 4, to minimize lipoperoxidation. Additionally, the carbon monoxide release upon the ONOO- reaction with PCOD585 further inhibited the neuronal Iron-dependent ferroptosis associated with ischemia-reperfusion. Such a synergistic neuroprotective mechanism of PCOD585 yields as potent a neuroprotective effect as Edaravone. Additionally, PCOD585 penetrates the blood-brain barrier and reduces the degradation of zonula occludens-1 by inhibiting matrix metalloproteinase-9, thereby protecting the integrity of the blood-brain barrier. Our study provides a new perspective for developing multi-functional compounds to treat ischemic stroke.

A platinum(IV)-artesunate complex triggers ferroptosis by boosting cytoplasmic and mitochondrial lipid peroxidation to enhance tumor immunotherapy.

Ferroptosis is an iron-dependent cell death form that initiates lipid peroxidation (LPO) in tumors. In recent years, there has been growing interest on ferroptosis, but how to propel it forward translational medicine remains in mist. Although experimental ferroptosis inducers such as RSL3 and erastin have demonstrated bioactivity in vitro, the poor antitumor outcome in animal model limits their development. In this study, we reveal a novel ferroptosis inducer, oxaliplatin-artesunate (OART), which exhibits substantial bioactivity in vitro and vivo, and we verify its feasibility in cancer immunotherapy. For mechanism, OART induces cytoplasmic and mitochondrial LPO to promote tumor ferroptosis, via inhibiting glutathione-mediated ferroptosis defense system, enhancing iron-dependent Fenton reaction, and initiating mitochondrial LPO. The destroyed mitochondrial membrane potential, disturbed mitochondrial fusion and fission, as well as downregulation of dihydroorotate dehydrogenase mutually contribute to mitochondrial LPO. Consequently, OART enhances tumor immunogenicity by releasing damage associated molecular patterns and promoting antigen presenting cells maturation, thereby transforming tumor environment from immunosuppressive to immunosensitive. By establishing in vivo model of tumorigenesis and lung metastasis, we verified that OART improves the systematic immune response. In summary, OART has enormous clinical potential for ferroptosis-based cancer therapy in translational medicine.

Recent Advances in the Inhibition of Membrane Lipid Peroxidation by Food-Borne Plant Polyphenols via the Nrf2/GPx4 Pathway.

Lipid peroxidation (LP) leads to changes in the fluidity and permeability of cell membranes, affecting normal cellular function and potentially triggering apoptosis or necrosis. This process is closely correlated with the onset of many diseases. Evidence suggests that the phenolic hydroxyl groups in food-borne plant polyphenols (FPPs) make them effective antioxidants capable of preventing diseases triggered by cell membrane LP. Proper dietary intake of FPPs can attenuate cellular oxidative stress, especially damage to cell membrane phospholipids, by activating the Nrf2/GPx4 pathway. Nuclear factor E2-related factor 2 (Nrf2) is an oxidative stress antagonist. The signaling pathway regulated by Nrf2 is a defense transduction pathway of the organism against external stimuli such as reactive oxygen species and exogenous chemicals. Glutathione peroxidase 4 (GPx4), under the regulation of Nrf2, is the only enzyme that reduces cell membrane lipid peroxides with specificity, thus playing a pivotal role in regulating cellular ferroptosis and counteracting oxidative stress. This study explored the Nrf2/GPx4 pathway mechanism, antioxidant activity of FPPs, and mechanism of LP. It also highlighted the bioprotective properties of FPPs against LP and its associated mechanisms, including (i) activation of the Nrf2/GPx4 pathway, with GPx4 potentially serving as a central target protein, (ii) regulation of antioxidant enzyme activities, leading to a reduction in the production of ROS and other peroxides, and (iii) antioxidant effects on LP and downstream phospholipid structure. In conclusion, FPPs play a crucial role as natural antioxidants in preventing LP. However, further in-depth analysis of FPPs coregulation of multiple signaling pathways is required, and the combined effects of these mechanisms need further evaluation in experimental models. Human trials could provide valuable insights into new directions for research and application.

Ferrostatin-1 mitigates cellular damage in a ferroptosis-like environment in Caenorhabditis elegans.

Although iron (Fe) is the most biologically abundant transition metal, it is highly toxic when it accumulates as Fe2+, forming a labile Fe pool and favoring the Fenton reaction. This oxidative scenario leads to a type of caspase-independent programmed cell death, referred to as ferroptosis, where following processes take place: 1) Fe2+ overload; 2) glutathione peroxidase 4 inactivation; 3) lipid peroxidation and 4) glutathione depletion. The present study sought to evaluate the consequences of Fe2+ administration on ferroptosis induction in Caenorhabditis elegans. We demonstrated higher mortality, increased lipid peroxidation, reduced glutathione peroxidase activity, and morphological damage in dopaminergic neurons upon Fe2+ overload. Pharmacological intervention at the level of lipid peroxidation with ferrostatin-1 (250 µM) mitigated the damage and returned the biochemical parameters to basal levels, revealing the potential of this therapeutical approach. Finally, to assess the relationship between ferroptosis and dopamine in a Parkinsonian background, we evaluated the UA44 worm strain which overexpresses the alpha-synuclein protein in cherry-labeled dopaminergic neurons. We demonstrated that Fe2+ administration reduced lethality associated with similar alterations in biochemical and dopaminergic morphological parameters in wild-type animals. These experiments provide mechanistic-based evidence on the efficacy of a pharmacological approach to mitigate the physiological, biochemical, and morphological consequences of Fe2+ overload. At the same time, they encourage further research on the impact of the combined effects resulting from the genetic background and dopamine signaling in a Parkinsonian phenotype.

HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer.

Gastric cancer remains among the deadliest neoplasms worldwide, with limited therapeutic options. Since efficacies of targeted therapies are unsatisfactory, drugs with broader mechanisms of action rather than a single oncogene inhibition are needed. Preclinical studies have identified histone deacetylases (HDAC) as potential therapeutic targets in gastric cancer. However, the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. This is particularly true with regard to ferroptosis as an emerging concept of cell death. In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured and proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA and protein level. Upon HDACi treatment, lipid peroxidation was found increased in all cell lines. Class I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Results were also confirmed in primary human gastric cancer tissue cultures as a relevant ex vivo model. We identify the induction of ferroptosis as new mechanism of action of class I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle.

Au-Based Nanoparticles Enhance Low Temperature Tolerance in Wheat by Regulating Some Physiological Parameters and Gene Expression.

One of the key problems of biology is how plants adapt to unfavorable conditions, such as low temperatures. A special focus is placed on finding ways to increase tolerance in important agricultural crops like wheat. Au-based nanoparticles (Au-NPs) have been employed extensively in this area in recent years. Au-NPs can be produced fast and easily using low-cost chemical reagents. When employed in microdoses, Au-NPs are often non-toxic to plants, animals, and people. In addition, Au-NPs mainly have favorable impacts on plants. In this study, we investigated the effect of Au-NP seed nanopriming (diameter 15.3 nm, Au concentration 5-50 µg mL-1) on cold tolerance, as well as some physiological, biochemical and molecular parameters, of cold-sustainable wheat (Triticum aestivum L.) genotype Zlata. The treatment with Au-NPs improved tolerance to low temperatures in control conditions and after cold hardening. Au-NPs treatment boosted the intensity of growth processes, the quantity of photosynthetic pigments, sucrose in leaves, and the expressions of encoded RuBisCo and Wcor15 genes. The potential mechanisms of Au-NPs' influence on the cold tolerance of wheat varieties were considered.

Plasma Redox Balance in Advanced-Maternal-Age Pregnant Women and Effects of Plasma on Umbilical Cord Mesenchymal Stem Cells.

Pregnancy at advanced maternal age (AMA) is a condition of potential risk for the development of maternal-fetal complications with possible repercussions even in the long term. Here, we analyzed the changes in plasma redox balance and the effects of plasma on human umbilical cord mesenchymal cells (hUMSCs) in AMA pregnant women (patients) at various timings of pregnancy. One hundred patients and twenty pregnant women younger than 40 years (controls) were recruited and evaluated at various timings during pregnancy until after delivery. Plasma samples were used to measure the thiobarbituric acid reactive substances (TBARS), glutathione and nitric oxide (NO). In addition, plasma was used to stimulate the hUMSCs, which were tested for cell viability, reactive oxygen species (ROS) and NO release. The obtained results showed that, throughout pregnancy until after delivery in patients, the levels of plasma glutathione and NO were lower than those of controls, while those of TBARS were higher. Moreover, plasma of patients reduced cell viability and NO release, and increased ROS release in hUMSCs. Our results highlighted alterations in the redox balance and the presence of potentially harmful circulating factors in plasma of patients. They could have clinical relevance for the prevention of complications related to AMA pregnancy.

Crosstalk between melatonin and nitric oxide restrains Cadmium-induced oxidative stress and enhances vinblastine biosynthesis in Catharanthus roseus (L) G Don.

KEY MESSAGE: Nitric oxide functions downstream of the melatonin in adjusting Cd-induced osmotic and oxidative stresses, upregulating the transcription of D4H and DAT genes, and increasing total alkaloid and vincristine contents. A few studies have investigated the relationship between melatonin (MT) and nitric oxide (NO) in regulating defensive responses. However, it is still unclear how MT and NO interact to regulate the biosynthesis of alkaloids and vincristine in leaves of Catharanthus roseus (L.) G. Don under Cd stress. Therefore, this context was explored in the present study. Results showed that Cd toxicity (200 µM) induced oxidative stress, decreased biomass, Chl a, and Chl b content, and increased the content of total alkaloid and vinblastine in the leaves. Application of both MT (100 µM) and sodium nitroprusside (200 µM SNP, as NO donor) enhanced endogenous NO content and accordingly increased metal tolerance index, the content of total alkaloid and vinblastine. It also upregulated the transcription of two respective genes (D4H and DAT) under non-stress and Cd stress conditions. Moreover, the MT and SNP treatments reduced the content of H2O2 and malondialdehyde, increased the activities of superoxide dismutase and ascorbate peroxidase, enhanced proline accumulation, and improved relative water content in leaves of Cd-exposed plants. The scavenging NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy l-3-oxide (cPTIO) averted the effects of MT on the content of total alkaloid and vinblastine and antioxidative responses. Still, the effects conferred by NO on attributes mentioned above were not significantly impaired by p-chlorophenylalanine (p-CPA as an inhibitor of MT biosynthesis). These findings and multivariate analyses indicate that MT motivated terpenoid indole alkaloid biosynthesis and mitigated Cd-induced oxidative stress in the leaves of periwinkle in a NO-dependent manner.

Mitochondrial GPX4 acetylation is involved in cadmium-induced renal cell ferroptosis.

Increasing evidences demonstrate that environmental stressors are important inducers of acute kidney injury (AKI). This study aimed to investigate the impact of exposure to Cd, an environmental stressor, on renal cell ferroptosis. Transcriptomics analyses showed that arachidonic acid (ARA) metabolic pathway was disrupted in Cd-exposed mouse kidneys. Targeted metabolomics showed that renal oxidized ARA metabolites were increased in Cd-exposed mice. Renal 4-HNE, MDA, and ACSL4, were upregulated in Cd-exposed mouse kidneys. Consistent with animal experiments, the in vitro experiments showed that mitochondrial oxidized lipids were elevated in Cd-exposed HK-2 cells. Ultrastructure showed mitochondrial membrane rupture in Cd-exposed mouse kidneys. Mitochondrial cristae were accordingly reduced in Cd-exposed mouse kidneys. Mitochondrial SIRT3, an NAD+-dependent deacetylase that regulates mitochondrial protein stability, was reduced in Cd-exposed mouse kidneys. Subsequently, mitochondrial GPX4 acetylation was elevated and mitochondrial GPX4 protein was reduced in Cd-exposed mouse kidneys. Interestingly, Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis were exacerbated in Sirt3-/- mice. Conversely, Cd-induced mitochondrial oxidized lipids were attenuated in nicotinamide mononucleotide (NMN)-pretreated HK-2 cells. Moreover, Cd-evoked mitochondrial GPX4 acetylation and renal cell ferroptosis were alleviated in NMN-pretreated mouse kidneys. These results suggest that mitochondrial GPX4 acetylation, probably caused by SIRT3 downregulation, is involved in Cd-evoked renal cell ferroptosis.

Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

The mechanisms of ferroptosis in the pathogenesis of kidney diseases.

The pathological features of acute and chronic kidney diseases are closely associated with cell death in glomeruli and tubules. Ferroptosis is a form of programmed cell death characterized by iron overload-induced oxidative stress. Ferroptosis has recently gained increasing attention as a pathogenic mechanism of kidney damage. Specifically, the ferroptosis signaling pathway has been found to be involved in the pathological process of acute and chronic kidney injury, potentially contributing to the development of both acute and chronic kidney diseases. This paper aims to elucidate the underlying mechanisms of ferroptosis and its role in the pathogenesis of kidney disease, highlighting its significance and proposing novel directions for its treatment.

Protective Effect of Prunetin on Isoproterenol-Induced Myocardial Infarction in Wistar Rats via Biochemical Characterization.

BACKGROUND: The development of MI following ischemia damage is influenced by oxidative stress. Myocardial Infarction (MI) generates myocardial ischemia injury, which damages the cardiomyocytes. Ischemia builds up to a critical level over time in MI, causing permanent myocardial cell damage or death. AIM: The current study sought to determine whether Prunetin (PRU) could protect against Isoproterenol (ISO)-induced cardiac heart failure in rats by examining cardiac diagnostic markers, lipid peroxidation products, enzymatic and non-enzymatic antioxidant levels, and histological changes. METHODS: PRU (20 mg/kg bwt) was orally administered for 19 days to rats, and after the treatment, ISO (85 mg/kg bwt) was subcutaneously administered with an intermission of 24 h for a couple of days to induce myocardial infarction on 20th and 21st days. ISO-treated rats exhibited considerable alterations in cardiac-sensitive markers in the serum. The levels of lipid peroxidation markers augmented drastically in the plasma and myocardium. Enzymatic antioxidant levels in erythrocytes and myocardium and the states of non-enzymatic antioxidants were diminished in the plasma and heart tissue of ISO-treated rats. The histopathological examination of heart tissue exhibited cardiac damage in ISO-induced rats. RESULTS: The oral administration of PRU significantly lowered the levels of lipid peroxidation and biochemical indicators, while significantly improving the antioxidant system function of ISO-interposed rats. In PRU-treated ISO-injected rats, histological examinations revealed suppressed myocardial destruction. CONCLUSION: Our research shows that oral pretreatment of PRU prevented ISO-induced oxidative stress in MI.

Assessment of Phthalate Esters and Physiological Biomarkers in Bottlenose Dolphins (Tursiops truncatus) and Killer Whales (Orcinus orca).

There is growing concern about the potential adverse health effects of phthalates (PAEs) on human health and the environment due to their extensive use as plasticizers and additives in commercial and consumer products. In this study, we assessed PAE concentrations in serum samples from aquarium-based delphinids (Tursiops truncatus, n = 36; Orcinus orca, n = 42) from California, Florida, and Texas, USA. To better understand the physiological effects of phthalates on delphinids, we also explored potential correlations between phthalates and the biomarkers aldosterone, cortisol, corticosterone, hydrogen peroxide, and malondialdehyde while accounting for sex, age, and reproductive stage. All PAEs were detected in at least one of the individuals. ΣPAE ranges were 5.995-2743 ng·mL-1 in bottlenose dolphins and 5.372-88,675 ng·mL-1 in killer whales. Both species displayed higher mean concentrations of DEP and DEHP. PAEs were detected in newborn delphinids, indicating transference via placenta and/or lactation. Linear mixed model results indicated significant correlations between aldosterone, month, location, status, and ΣPAEs in killer whales, suggesting that aldosterone concentrations are likely affected by the cumulative effects of these variables. This study expands on the knowledge of delphinid physiological responses to PAEs and may influence management and conservation decisions on contamination discharge regulations near these species.