Cyclovirobuxine D inhibits hepatocellular carcinoma growth by inducing ferroptosis of hepatocellular carcinoma cells.

OBJECTIVE: Hepatocellular carcinoma (HCC) is one cancer with high death rates. Nowadays, there are no effective drugs to treat it. Cyclovirobuxine D (CVB-D) is the primary ingredient of the traditional Chinese medicine (TCM) Buxus microphylla. Here, we try to explore the impacts of CVB-D on human HCC cells and explain the potential mechanisms. METHODS: HepG2 and Huh-7 cells were used for our experiments. The cell viability and half inhibitory concentration (IC50) were detected by MTT assays. The apoptosis ratio was examined by Annexin V-FITC/7AAD staining and flow cytometry (FCM). The Fe2+ content was examined by ferrous ion content assays. The malondialdehyde (MDA) content was evaluated by lipid peroxidation MDA assays. The reactive oxygen species (ROS) level was examined by the DCFH-DA probe. The expression of apoptotic markers (Bax and Bcl-2) and ferroptosis-related proteins (GPX4 and FSP1) was detected by western blotting. The in vivo curative effect of CVB was explored using xenograft models established in C-NKG mice. RESULTS: The cell viability could be inhibited by CVB-D in HepG2 and Huh-7 cells. The IC50 value of CVB-D on HepG2 and Huh-7 cells are 91.19 and 96.29 µM at 48 h, and 65.60 and 72.80 µM at 72 h. FCM showed that the apoptosis rate was increased by CVB-D in HepG2 and Huh-7 cells. Next, ferrous ion content assays showed that the level of Fe2+ was increased by CVB-D in HepG2 and Huh-7 cells. Then, we found the level of MDA and ROS was increased by CVB-D. And the Fe2+ promotion by CVB-D could be reversed by Fer-1. Additionally, western blotting assays showed that the expression of GPX4 and FSP1 was inhibited by CVB-D in HepG2 and Huh-7 cells. Moreover, in vivo, CVB-D displayed excellent anticancer effects in HCC tumor-bearing C-NKG mice. CONCLUSION: CVB-D suppresses the growth in HCC cells through ferroptosis.

Enhancement of cryopreserved rooster semen and fertility potential after oral administration of Thai ginger (Kaempferia parviflora) extract in Thai native chickens.

Objective: Semen cryopreservation is an effective method of preserving genetic material, particularly in native chicken breeds facing a substantial decline. In this study, we evaluated the quality of frozen/thawed rooster semen treated with different concentrations of oral administrations of black ginger (Kaempferia parviflora: KP) extract and determined its fertility. Methods: Thirty-two Thai native roosters (Pradu Hang Dum, 42 weeks old) were used in this study. The treatments were classified into four groups according to the concentration of KP extract administered to the roosters: 0, 100, 150, and 200 mg/kg body weight. The quality of fresh semen was analyzed before cryopreservation. Post-thaw sperm quality and fertility potential were determined. Also, lipid peroxidation was determined. Results: The results showed that sperm concentration and movement increased in roosters treated with 200 mg/kg of KP extract (P<0.05). The malondialdehyde (MDA) in the rooster receiving 200 mg/kg KP extract was lower than that in the other but had an insignificant difference within the KP treatment groups (P>0.05). The highest MDA levels were observed in the control group (P<0.05). The percentage of motile sperm (total motility and progressive motility) after semen thawing was higher in roosters that received 150 and 200 mg/kg KP extract than in those that received 100 mg/kg KP extract and the control (P<0.05). MDA levels decreased significantly in roosters that received 150 and 200 mg/kg KP extract than in those that received 100 mg/kg KP extract and the control (P<0.05). Fertility and hatchability were greater in the KP150 and KP200 groups than in the KP100 and control groups (P<0.05). Conclusion: The optimal amount of KP extract influencing initial sperm quality was determined to be 200 mg/kg. However, 150 mg/kg was the optimal low dosage of KP extract administration that maintained sperm quality and fertility following semen cryopreservation.

NAD(P)H-quinone oxidoreductase 1 induces complicated effects on mitochondrial dysfunction and ferroptosis in an expression level-dependent manner.

NAD(P)H-quinone oxidoreductase 1 (NQO1) is an essential redox enzyme responsible for redox balance and energy metabolism. Despite of its importance, the brain contains high capacity of polyunsaturated fatty acids and maintains low levels of NQO1 expression. In this study, we examined how levels of NQO1 expression affects cell survival in response to toxic insults causing mitochondrial dysfunction and ferroptosis, and whether NQO1 has a potential as a biomarker in different stressed conditions. Following treatment with rotenone, overexpressed NQO1 in SH-SY5Y cells improved cell survival by reducing mitochondrial reductive stress via increased NAD+ supply without mitochondrial biogenesis. However, NQO1 overexpression boosted lipid peroxidation following treatment with RSL3 and erastin. A lipid droplet staining assay showed increased lipid droplets in cells overexpressing NQO1. In contrast, NQO1 knockdown protected cells against ferroptosis by increasing GPX4, xCT, and the GSH/GSSG system. Also, NQO1 knockdown showed lower iron contents and lipid droplets than non-transfectants and cells overexpressing NQO1, even though it could not attenuate cell death when exposed to rotenone. In summary, our study suggests that different NQO1 levels may have advantages and disadvantages depending on the surrounding environments. Thus, regulating NQO1 expression could be a potential supplementary tool when treating neuronal diseases.

Mapping the Research of Ferroptosis in Parkinson's Disease from 2013 to 2023: A Scientometric Review.

Methods: Related studies on PD and ferroptosis were searched in Web of Science Core Collection (WOSCC) from inception to 2023. VOSviewer, CiteSpace, RStudio, and Scimago Graphica were employed as bibliometric analysis tools to generate network maps about the collaborations between authors, countries, and institutions and to visualize the co-occurrence and trends of co-cited references and keywords. Results: A total of 160 original articles and reviews related to PD and ferroptosis were retrieved, produced by from 958 authors from 162 institutions. Devos David was the most prolific author, with 9 articles. China and the University of Melbourne had leading positions in publication volume with 84 and 12 publications, respectively. Current hot topics focus on excavating potential new targets for treating PD based on ferroptosis by gaining insight into specific molecular mechanisms, including iron metabolism disorders, lipid peroxidation, and imbalanced antioxidant regulation. Clinical studies aimed at treating PD by targeting ferroptosis remain in their preliminary stages. Conclusion: A continued increase was shown in the literature within the related field over the past decade. The current study suggested active collaborations among authors, countries, and institutions. Research into the pathogenesis and treatment of PD based on ferroptosis has remained a prominent topic in the field in recent years, indicating that ferroptosis-targeted therapy is a potential approach to halting the progression of PD.

ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2.

Macrophage cholesterol homeostasis is crucial for health and disease and has been linked to the lipid-peroxidizing enzyme arachidonate 15-lipoxygenase type B (ALOX15B), albeit molecular mechanisms remain obscure. We performed global transcriptome and immunofluorescence analysis in ALOX15B-silenced primary human macrophages and observed a reduction of nuclear sterol regulatory element-binding protein (SREBP) 2, the master transcription factor of cellular cholesterol biosynthesis. Consequently, SREBP2-target gene expression was reduced as were the sterol biosynthetic intermediates desmosterol and lathosterol as well as 25- and 27-hydroxycholesterol. Mechanistically, suppression of ALOX15B reduced lipid peroxidation in primary human macrophages and thereby attenuated activation of mitogen-activated protein kinase ERK1/2, which lowered SREBP2 abundance and activity. Low nuclear SREBP2 rendered both, ALOX15B-silenced and ERK1/2-inhibited macrophages refractory to SREBP2 activation upon blocking the NPC intracellular cholesterol transporter 1. These studies suggest a regulatory mechanism controlling macrophage cholesterol homeostasis based on ALOX15B-mediated lipid peroxidation and concomitant ERK1/2 activation.

Targeting ferroptosis for treating kidney disease.

Ferroptosis is a type of regulated cell death hallmarked by iron-mediated excessive lipid oxidation. Over the past decade since the coining of the term ferroptosis, advances in research have led to the identification of intracellular processes that regulate ferroptosis such as GSH-GPX4 pathway and FSP1-coenzyme Q10/vitamin K pathway. From a disease perspective, the involvement of ferroptosis in pathological conditions including kidney disease has attracted attention. In terms of renal pathophysiology, ferroptosis has been widely investigated for its involvement in ischemia-reperfusion injury, nephrotoxin-induced kidney damage and other renal diseases. Therefore, therapeutic interventions targeting ferroptosis are expected to become a new therapeutic approach for these diseases. However, when considering cell death as a therapeutic target, careful consideration must be given to (i) in which type of cells, (ii) which type of cell death mode, and (iii) in which stage or temporal window of the disease. In the next decade, elucidation of the true involvement of ferroptosis in kidney disease setting in human, and development of clinically applicable and effective therapeutic drugs that target ferroptosis are warranted.

Free Radical Lipid Peroxidation Induced by Reactive Halogen Species.

The review is devoted to the mechanisms of free radical lipid peroxidation (LPO) initiated by reactive halogen species (RHS) produced in mammals, including humans, by heme peroxidase enzymes, primarily myeloperoxidase (MPO). It has been shown that RHS can participate in LPO both in the initiation and branching steps of the LPO chain reactions. The initiation step of RHS-induced LPO mainly involves formation of free radicals in the reactions of RHS with nitrite and/or with amino groups of phosphatidylethanolamine or Lys. The branching step of the oxidative chain is the reaction of RHS with lipid hydroperoxides, in which peroxyl and alkoxyl radicals are formed. The role of RHS-induced LPO in the development of human inflammatory diseases (cardiovascular and neurodegenerative diseases, cancer, diabetes, rheumatoid arthritis) is discussed in detail.

Jolkinolide B synergistically potentiates the antitumor activity of GPX4 inhibitors via inhibiting TrxR1 in cisplatin-resistant bladder cancer cells.

Glutathione peroxidase 4 (GPX4) is a promising anticancer therapeutic target; however, the application of GPX4 inhibitors (GPX4i) is limited owing to intrinsic or acquired drug resistance. Hence, understanding the mechanisms underlying drug resistance and discovering molecules that can overcome drug resistance are crucial. Herein, we demonstrated that GPX4i killed bladder cancer cells by inducing lipid reactive oxygen species-mediated ferroptosis and apoptosis, and cisplatin-resistant bladder cancer cells were also resistant to GPX4i, representing a higher half-maximal inhibitory concentration value than that of parent bladder cancer cells. In addition, thioredoxin reductase 1 (TrxR1) overexpression was responsible for GPX4i resistance in cisplatin-resistant bladder cancer cells, and inhibiting TrxR1 restored the sensitivity of these cells to GPX4i. In vitro and in vivo studies revealed that Jolkinolide B (JB), a natural diterpenoid and previously identified as a TrxR1 inhibitor, potentiated the antiproliferative efficacy of GPX4i (RSL3 and ML162) against cisplatin-resistant bladder cancer cells. Furthermore, GPX4 knockdown and inhibition could augment JB-induced paraptosis and apoptosis. Our results suggest that inhibiting TrxR1 can effectively improve GPX4 inhibition-based anticancer therapy. A combination of JB and GPX4i, which is well-tolerated and has several anticancer mechanisms, may serve as a promising therapy for treating bladder cancer.

Carrier-Free Self-Assembly Nano-Sonosensitizers for Sonodynamic-Amplified Cuproptosis-Ferroptosis in Glioblastoma Therapy.

Cuproptosis is a newly discovered form of programmed cell death significantly depending on the transport efficacy of copper (Cu) ionophores. However, existing Cu ionophores, primarily small molecules with a short blood half-life, face challenges in transporting enough amounts of Cu ions into tumor cells. This work describes the construction of carrier-free nanoparticles (Ce6@Cu NPs), which self-assembled by the coordination of Cu2+ with the sonosensitizer chlorin e6 (Ce6), facilitating sonodynamic-triggered combination of cuproptosis and ferroptosis. Ce6@Cu NPs internalized by U87MG cells induce a sonodynamic effect and glutathione (GSH) depletion capability, promoting lipid peroxidation and eventually inducing ferroptosis. Furthermore, Cu+ concentration in tumor cells significantly increases as Cu2+ reacts with reductive GSH, resulting in the downregulation of ferredoxin-1 and lipoyl synthase. This induces the oligomerization of lipoylated dihydrolipoamide S-acetyltransferase, causing proteotoxic stress and irreversible cuproptosis. Ce6@Cu NPs possess a satisfactory ability to penetrate the blood-brain barrier, resulting in significant accumulation in orthotopic U87MG-Luc glioblastoma. The sonodynamic-triggered combination of ferroptosis and cuproptosis in the tumor by Ce6@Cu NPs is evidenced both in vitro and in vivo with minimal side effects. This work represents a promising tumor therapeutic strategy combining ferroptosis and cuproptosis, potentially inspiring further research in developing logical and effective cancer therapies based on cuproptosis.

Elevated ROS Levels Caused by Reductions in GSH and AsA Contents Lead to Grain Yield Reduction in Qingke under Continuous Cropping.

Continuous spring cropping of Qingke (Hordeum viilgare L. var. nudum Hook. f.) results in a reduction in grain yield in the Xizang autonomous region. However, knowledge on the influence of continuous cropping on grain yield caused by reactive oxygen species (ROS)-induced stress remains scarce. A systematic comparison of the antioxidant defensive profile at seedling, tillering, jointing, flowering, and filling stages (T1 to T5) of Qingke was conducted based on a field experiment including 23-year continuous cropping (23y-CC) and control (the first year planted) treatments. The results reveal that the grain yield and superoxide anion (SOA) level under 23y-CC were significantly decreased (by 38.67% and 36.47%), when compared to the control. The hydrogen peroxide content under 23y-CC was 8.69% higher on average than under the control in the early growth stages. The higher ROS level under 23y-CC resulted in membrane lipid peroxidation (LPO) and accumulation of malondialdehyde (MDA) at later stages, with an average increment of 29.67% and 3.77 times higher than that in control plants. Qingke plants accumulated more hydrogen peroxide at early developmental stages due to the partial conversion of SOA by glutathione (GSH) and superoxide dismutase (SOD) and other production pathways, such as the glucose oxidase (GOD) and polyamine oxidase (PAO) pathways. The reduced regeneration ability due to the high oxidized glutathione (GSSG) to GSH ratio resulted in GSH deficiency while the reduction in L-galactono-1,4-lactone dehydrogenase (GalLDH) activity in the AsA biosynthesis pathway, higher enzymatic activities (including ascorbate peroxidase, APX; and ascorbate oxidase, AAO), and lower activities of monodehydroascorbate reductase (MDHAR) all led to a lower AsA content under continuous cropping. The lower antioxidant capacity due to lower contents of antioxidants such as flavonoids and tannins, detected through both physiological measurement and metabolomics analysis, further deteriorated the growth of Qingke through ROS stress under continuous cropping. Our results provide new insights into the manner in which ROS stress regulates grain yield in the context of continuous Qingke cropping.

Investigating the Effects of Diet-Induced Prediabetes on Skeletal Muscle Strength in Male Sprague Dawley Rats.

Type 2 diabetes mellitus, a condition preceded by prediabetes, is documented to compromise skeletal muscle health, consequently affecting skeletal muscle structure, strength, and glucose homeostasis. A disturbance in skeletal muscle functional capacity has been demonstrated to induce insulin resistance and hyperglycemia. However, the modifications in skeletal muscle function in the prediabetic state are not well elucidated. Hence, this study investigated the effects of diet-induced prediabetes on skeletal muscle strength in a prediabetic model. Male Sprague Dawley rats were randomly assigned to one of the two groups (n = 6 per group; six prediabetic (PD) and six non-pre-diabetic (NPD)). The PD group (n = 6) was induced with prediabetes for 20 weeks. The diet that was used to induce prediabetes consisted of fats (30% Kcal/g), proteins (15% Kcal/g), and carbohydrates (55% Kcal/g). In addition to the diet, the experimental animals (n = 6) were supplied with drinking water that was supplemented with 15% fructose. The control group (n = 6) was allowed access to normal rat chow, consisting of 35% carbohydrates, 30% protein, 15% fats, and 20% other components, as well as ordinary tap water. At the end of week 20, the experimental animals were diagnosed with prediabetes using the American Diabetes Association (ADA) prediabetes impaired fasting blood glucose criteria (5.6-6.9 mmol/L). Upon prediabetes diagnosis, the animals were subjected to a four-limb grip strength test to assess skeletal muscle strength at week 20. After the grip strength test was conducted, the animals were euthanized for blood and tissue collection to analyze glycated hemoglobin (HbA1c), plasma insulin, and insulin resistance using the homeostatic model of insulin resistance (HOMA-IR) index and malondialdehyde (MDA) concentration. Correlation analysis was performed to examine the associations of skeletal muscle strength with HOMA-IR, plasma glucose, HbA1c, and MDA concentration. The results demonstrated increased HbA1c, FBG, insulin, HOMA-IR, and MDA concentrations in the PD group compared to the NPD group. Grip strength was reduced in the PD group compared to the NPD group. Grip strength was negatively correlated with HbA1c, plasma glucose, HOMA-IR, and MDA concentration in the PD group. These observations suggest that diet-induced prediabetes compromises muscle function, which may contribute to increased levels of sedentary behavior during prediabetes progression, and this may contribute to the development of hyperglycemia in T2DM.

Aristolochic acid induces acute kidney injury through ferroptosis.

Aristolochic acid (AA)-induced acute kidney injury (AKI) presents with progressive decline in renal function and rapid progression to end-stage renal disease. Among the multiple mechanisms identified in AKI, ferroptosis has been shown to be involved in various forms of AKI. But few studies have elucidated the role of ferroptosis in AA-induced AKI. In this study, we investigated the role of ferroptosis in AA-induced acute renal tubular injury in vivo and in vitro. Mice with acute aristolochic acid nephropathy showed increased malondialdehyde levels, aggravated lipid peroxidation, decreased superoxide dismutase activity, and glutathione depletion. The expression of glutathione peroxidase 4 was decreased and the expression of acyl-CoA synthetase long-chain family member 4 was increased. Inhibition of ferroptosis by ferrostatin-1 significantly improved the renal function, reduced histopathological lesions, partially alleviated lipid peroxidation, and restored the antioxidant capacity. In vitro studies also revealed that AA significantly reduced cell viability, induced reactive oxygen species production, increased intracellular iron level and decreased ferroptosis-related protein expression. Inhibition of ferroptosis significantly increased cell viability and attenuated AA-induced renal tubular epithelial cell injury. It is suggested that ferroptosis plays an important role in AA-induced acute tubular injury. And inhibition of ferroptosis may exert renoprotective effects possibly by preventing lipid peroxidation, restoring the antioxidant activity or regulating iron metabolism.

Investigation of multidirectional toxicity induced by high-dose molybdenum exposure with Allium test.

In this study, the multifaceted toxicity induced by high doses of the essential trace element molybdenum in Allium cepa L. was investigated. Germination, root elongation, weight gain, mitotic index (MI), micronucleus (MN), chromosomal abnormalities (CAs), Comet assay, malondialdehyde (MDA), proline, superoxide dismutase (SOD), catalase (CAT) and anatomical parameters were used as biomarkers of toxicity. In addition, detailed correlation and PCA analyzes were performed for all parameters discussed. On the other hand, this study focused on the development of a two hidden layer deep neural network (DNN) using Matlab. Four experimental groups were designed: control group bulbs were germinated in tap water and application group bulbs were germinated with 1000, 2000 and 4000 mg/L doses of molybdenum for 72 h. After germination, root tips were collected and prepared for analysis. As a result, molybdenum exposure caused a dose-dependent decrease (p < 0.05) in the investigated physiological parameter values, and an increase (p < 0.05) in the cytogenetic (except MI) and biochemical parameter values. Molybdenum exposure induced different types of CAs and various anatomical damages in root meristem cells. Comet assay results showed that the severity of DNA damage increased depending on the increasing molybdenum dose. Detailed correlation and PCA analysis results determined significant positive and negative interactions between the investigated parameters and confirmed the relationships of these parameters with molybdenum doses. It has been found that the DNN model is in close agreement with the actual data showing the accuracy of the predictions. MAE, MAPE, RMSE and R2 were used to evaluate the effectiveness of the DNN model. Collective analysis of these metrics showed that the DNN model performed well. As a result, it has been determined once again that high doses of molybdenum cause multiple toxicity in A. cepa and the Allium test is a reliable universal test for determining this toxicity. Therefore, periodic measurement of molybdenum levels in agricultural soils should be the first priority in preventing molybdenum toxicity.

Lipid peroxidation and stress-induced signalling molecules in systemic resistance mediated by azelaic acid/AZELAIC ACID INDUCED1: signal initiation and propagation.

Systemic acquired resistance protects plants against a broad spectrum of secondary infections by pathogens. A crucial compound involved in the systemic spread of the threat information after primary pathogen infection is the C9 oxylipin azelaic acid (AZA), a breakdown product of unsaturated C18 fatty acids. AZA is generated during lipid peroxidation in the plastids and accumulates in response to various abiotic and biotic stresses. AZA stimulates the expression of AZELAIC ACID INDUCED1 (AZI1), and a pool of AZI1 accumulates in the plastid envelope in association with AZA. AZA and AZI1 utilize the symplastic pathway to travel through the plasmodesmata to neighbouring cells to induce systemic stress resistance responses in distal tissues. Here, we describe the synthesis, travel and function of AZA and AZI1 and discuss open questions of signal initiation and propagation.

Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination.

Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE) and plasmenyl-PE. Plasmenyl-PE is a key component of myelin and is characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant. In humans, multiple loss-of-function mutations in genes affecting plasmenyl-PE metabolism have been implicated in hereditary spastic paraplegia, including SELENOI. Herein, we developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of hereditary spastic paraplegia. Resulting mice exhibited pronounced alterations in brain lipid composition, which coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly. Further studies revealed increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro. Altogether, these findings detail a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment.

Murine Alox8 versus the human ALOX15B ortholog: differences and similarities.

Human arachidonate 15-lipoxygenase type B is a lipoxygenase that catalyzes the peroxidation of arachidonic acid at carbon-15. The corresponding murine ortholog however has 8-lipoxygenase activity. Both enzymes oxygenate polyunsaturated fatty acids in S-chirality with singular reaction specificity, although they generate a different product pattern. Furthermore, while both enzymes utilize both esterified fatty acids and fatty acid hydro(pero)xides as substrates, they differ with respect to the orientation of the fatty acid in their substrate-binding pocket. While ALOX15B accepts the fatty acid "tail-first," Alox8 oxygenates the free fatty acid with its "head-first." These differences in substrate orientation and thus in regio- and stereospecificity are thought to be determined by distinct amino acid residues. Towards their biological function, both enzymes share a commonality in regulating cholesterol homeostasis in macrophages, and Alox8 knockdown is associated with reduced atherosclerosis in mice. Additional roles have been linked to lung inflammation along with tumor suppressor activity. This review focuses on the current knowledge of the enzymatic activity of human ALOX15B and murine Alox8, along with their association with diseases.

Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 µM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

Identifying ALOX15-initiated lipid peroxidation increases susceptibility to ferroptosis in asthma epithelial cells.

Ferroptosis is a programmed form of cell death regulated by iron and has been linked to the development of asthma. However, the precise mechanisms driving ferroptosis in asthma remain elusive. To gain deeper insights, we conducted an analysis of nasal epithelial and sputum samples from the GEO database using three machine learning methods. Our investigation identified a pivotal gene, Arachidonate 15-lipoxygenase (ALOX15), associated with ferroptosis in asthma. Through both in vitro and in vivo experiments, we further confirmed the significant role of ALOX15 in ferroptosis in asthma. Our results demonstrate that ferroptosis manifests in an HDM/LPS-induced allergic airway inflammation (AAI) mouse model, mimicking human asthma, and in HDM/LPS-stimulated 16HBE cells. Moreover, we observed an up-regulation of ALOX15 expression in HDM/LPS-induced mice and cells. Notably, silencing ALOX15 markedly decreased HDM/LPS-induced ferroptosis in 16HBE cells. These findings indicate that ferroptosis may be implicated in the onset and progression of asthma, with ALOX15-induced lipid peroxidation raising the susceptibility to ferroptosis in asthmatic epithelial cells.

Effect of F-isoprostane class on cow peripheral blood neutrophil microbicidal function in vitro.

Isoprostanes (isoP) are formed during conditions of oxidative stress (OS) through the oxidation of cell membrane fatty acids. Different classes of isoP are formed depending on the fatty acid being oxidized but the biological activity of these molecules in innate immune cells is poorly understood. Thus, the objective of this study was to compare in vitro the effects of F2- and F3-isoP on neutrophil microbicidal functions. We isolated neutrophils from 6 dairy cows and incubated them for 8 h at various concentrations of F2- and F3-isoP. Then, microbicidal function was assessed in terms of phagocytosis, respiratory burst, myeloperoxidase activity, and extracellular trap formation. In vitro supplementation with F3-isoP enhanced microbicidal capabilities whereas supplementation with F2-isoP decreased or did not impact these microbe killing functions. Hence, favoring the production of F3- over F2-isoprostanes may be a strategy to augment neutrophils' functional capacity during OS conditions. This should be tested in vivo.

Exploring the Role of Ferroptosis-Related Circular RNAs in Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular event associated with high mortality and significant morbidity. Recent studies have highlighted the emerging role of ferroptosis, a novel form of regulated cell death, in the pathogenesis of SAH. Circular RNAs (circRNAs), have been found to play essential roles in various cellular processes, including gene regulation and disease pathogenesis. The expression profile of circRNAs in neural tissues, particularly in the brain, suggests their critical role in synaptic function and neurogenesis. Moreover, the interplay between circRNAs and ferroptosis-related pathways, such as iron metabolism and lipid peroxidation, is explored in the context of SAH. Understanding the functional roles of specific circRNAs in the context of SAH may provide potential therapeutic targets to attenuate ferroptosis-associated brain injury. Furthermore, the potential of circRNAs as diagnostic biomarkers for SAH severity, prognosis, and treatment response is discussed. Overall, this review highlights the significance of studying the intricate interplay between circRNAs and ferroptosis in the context of SAH. Unraveling the mechanisms by which circRNAs modulate ferroptotic cell death may pave the way for the development of novel therapeutic strategies and diagnostic approaches for SAH management, ultimately improving patient outcomes and quality of life.