Increased Levels Of Lipid Peroxidation Research Articles

Distinctive toxic repercussions of polystyrene nano plastic towards aquatic non target species Nitrobacter vulgaris, Scenedesmus sp and Daphnia magna.

The widespread application of plastics and its eventual degradation to micro-sized or nano-sized plastics has led to several environmental concerns. Moreover, nanoplastics can easily cascade through the food chain accumulating in the aquatic organisms. Thus, our study focussed on investigating the hazardous impact of nano-sized plastics on aquatic species including Nitrobacter vulgaris, Scenedesmus sp, and Daphnia magna. Various concentrations of polystyrene nanoplastics ranging from 0.01 mg/L to 100 mg/L were tested against Nitrobacter vulgaris, Scenedesmus sp, and Daphnia magna. The minimum inhibitory concentration of polystyrene nanoplastics in Nitrobacter vulgaris was found to be 25 mg/L, and in Daphnia magna, the median lethal concentration 50 was observed to be 64.02 mg/L. Exposure of Scenedesmus sp with increasing nanoplastic concentrations showed a significant decrease in total protein (p < 0.001), and chlorophyll content (p < 0.01), whereas the lipid peroxidation increased (p < 0.001) significantly. Similarly, Nitrobacter vulgaris and Daphnia magna showed a significant decrease in catalase activity (p < 0.001) and an increase in lipid peroxidation levels (p < 0.01). Concomitant with lipid peroxidation results, decreased superoxide dismutase levels (p < 0.01) and protein concentrations (p < 0.01) were observed in Daphnia magna. Besides, the increasing concentration of polystyrene nanoplastics displayed an elevated mortality rate in Scenedesmus sp (p < 0.001) and Nitrobacter vulgaris (p < 0.01). Further, scanning electron microscopy analysis substantiated the morphological alterations in Nitrobacter vulgaris and Scenedesmus sp on exposure to polystyrene nanoplastics.

Abstract C018: Targeting KRAS inhibitor resistance by ferroptosis induction in PDAC

Abstract KRAS inhibitors (KRASi) have shown promising antitumor activity in PDAC patients; however, intrinsic and acquired resistance will likely preclude durable monotherapy responses in the clinic. Genetic and pharmacologic targeting of the KRAS pathway is associated with transcriptional and metabolic adaptations, including epithelial-to-mesenchymal transition (EMT) and dysregulated iron homeostasis that contribute to resistance. Therapy resistant mesenchymal cancer cells have a high reliance on iron that increases their susceptibility to ferroptosis, an iron-dependent form of cell death characterized by generation of lipid reactive oxygen species (ROS). We hypothesize that KRASi resistance characterized by EMT can be overcome by ferroptosis induction in PDAC. Here, we use in vitro and ex vivo PDAC models and transcriptomic and proteomic profiling to define critical ferroptotic liabilities in KRASi-treated PDAC. First, we evaluated the effect of inhibiting different ferroptosis defense mechanisms (e.g. SLC7A11, GPX4, FSP1) using newly developed ferroptosis inducers (FINs) in a panel of epithelial and mesenchymal PDAC cells. Mesenchymal cells were more sensitive to ferroptosis induction compared to epithelial cells. Since ferroptotic death is regulated by multiple ferroptosis defense pathways, and in general PDAC are relatively resistant to ferroptosis induction, it is unlikely that a single ferroptosis inducer will be successful. Therefore, targeting multiple nodes with FINs in a combinatorial approach may lead to a more pronounced effect. Combination GPX4 and SLC7A11 inhibition and GPX4 and FSP1 inhibition were the most effective combinations compared to respective monotherapies. Next, we evaluated if combination of KRASi and ferroptosis induction is synergistic. Transcriptomic analysis of KRAS-mutant PDAC cell lines sensitive or with a priori resistance to KRASi revealed that EMT-related gene sets were upregulated in KRASi resistant cell lines. Quantitative proteomics revealed that PDAC cells treated long-term with KRASi undergo EMT and likewise long-term KRASi in in vivo PDAC models induces EMT. A KRASi-anchored CRISPR/Cas9 screen showed that sgRNAs targeting GPX4 dropped out in multiple cell lines indicating that ferroptosis induction may be synergistic upon KRAS inhibition. Remarkably, KRASi induced an increase of lipid peroxidation levels in PDAC cells which was rescued with antioxidant ferrostatin-1. We also observed that previously generated KRASi resistant cells were more sensitive to GPX4 inhibition. Combination of GPX4 inhibitor with KRASi led to a synergistic effect on cell viability and a significantly higher level of lipid peroxidation compared to monotherapy. These findings highlight the importance of investigating ferroptosis induction as a novel strategy to overcome therapeutic resistance in KRAS-mutant PDAC. We aim to further evaluate these combinations in vivo to determine the best combinatorial strategies in PDAC to prevent or circumvent KRASi resistance. Citation Format: Aparna Padhye, Qijia Yu, Nicole Sindoni, Huan Zhang, Julien Dilly, Hanrong Feng, Andrew Aguirre, Joseph Mancias. Targeting KRAS inhibitor resistance by ferroptosis induction in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C018.

Abstract Mo003: Concomitant administration of dantrolene is sufficient to protect against doxorubicin-induced cardiomyopathy

Background: Doxorubicin (DOX), a commonly used anticancer agent, causes irreversible cardiac dysfunction, which remains a clinical challenge. It has been reported that DOX induces the release of Ca 2+ through ryanodine receptor 2 (RYR2) of the sarcoplasmic reticulum (SR) and increases the Ca 2+ level in the cytoplasm. Objectives: we aimed to investigate whether RYR2 stabilization could suppress DOX-induced cardiomyopathy (DIC) and, if so, the optimal duration of dantrolene treatment (a pharmacological method). Methods: We investigated the relationship between DOX cardiotoxicity and RYR2 stabilization in vivo and in vitro experiments. Results: DOX caused calmodulin dissociation, marked Ca 2+ leakage from RYR2, and increased oxidative stress in isolated cardiomyocytes, which were suppressed by enhancing calmodulin binding affinity of RYR2 and stabilizing its tetramer structure pharmacologically (by dantrolene) or genetically (by RYR2 V3599K mutation). In DIC model mice, cardiac function was impaired, fibrosis and TUNEL-positive cells increased, accompanied by a decrease in GRP78 and increased lipid peroxide levels, which led to endoplasmic reticulum stress and ferroptosis respectively. These cardiac dysfunctions were ameliorated by continuous dantrolene administration or RYR2 V3599K mutation. Interestingly, dantrolene was sufficiently effective for myocardial protection even when terminated 7 days after DOX administration. Conclusions: The short-term concomitant use of dantrolene may be an innovative and clinically feasible DIC preventive strategy. Furthermore, because dantrolene is already safely used clinically as a specific drug for malignant hyperthermia, the results of this study are expected to lead to drug repositioning in the near future.

The involvement of IRP2-induced ferroptosis through the p53-SLC7A11-ALOX12 pathway in Parkinson's disease

Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in the misregulation of iron metabolism and subsequent neurodegeneration. However, growing evidence showed that the levels of IRP2 were increased in the substantia nigra (SN) in MPTP-induced PD mice. To further clarify the role of increased IRP2 in PD, we developed IRP2-overexpressed mice by microinjecting AAV-Ireb2 in the SN. These mice showed decreased motor ability, abnormal gait and anxiety. Iron deposits induced by increased TFR1 and dopaminergic neuronal loss were observed in the SN. When these mice were treated with MPTP, exacerbated dyskinesia and dopaminergic neuronal loss were observed. In addition, TP53 was post-transcriptionally upregulated by IRP2 binding to the iron regulated element (IRE) in its 3′ untranslated region. This resulted in increased lipid peroxidation levels and induced ferroptosis through the SLC7A11-ALOX12 pathway, which was independent of GPX4. This study revealed that IRP2 homeostasis in the SN was critical for PD progression and clarified the molecular mechanism of ferroptosis caused by IRP2.

Central role of Sigma-1 receptor in ochratoxin A-induced ferroptosis.

Ochratoxin A (OTA), a secondary fungal metabolite known for its nephrotoxic effects, is prevalent in various feeds and food items. Our recent study suggests that OTA-induced nephrotoxicity is linked to the Sigma-1 receptor (Sig-1R)-mediated mitochondrial pathway apoptosis in human proximal tubule epithelial-originated kidney-2 (HK-2) cells. However, the contribution of Sig-1R to OTA-induced nephrotoxicity involving other forms of regulated cell death, such as ferroptosis, remains unexplored. In this investigation, cell viability, malondialdehyde (MDA) levels, glutathione (GSH) levels, and protein expressions in HK-2 cells treated with OTA and/or Ferrostatin-1/blarcamesine hydrochloride/BD1063 dihydrochloride were assessed. The results indicate that a 24h-treatment with 1μM OTA significantly induces ferroptosis by inhibiting Sig-1R, subsequently promoting nuclear receptor coactivator 4 (NCOA4), long-chain fatty acid-CoA ligase 4 (ACSL4), arachidonate 5-lipoxygenase (ALOX5), autophagy protein 5 (ATG5), and ATG7, inhibiting ferritin heavy chain (FTH1), solute carrier family 7 member 11 (SLC7A11/xCT), glutathione peroxidase 4 (GPX4), peroxiredoxin 6 (PRDX6), and ferroptosis suppressor protein 1 (FSP1), reducing GSH levels, and increasing MDA levels (P < 0.05). In conclusion, OTA induces ferroptosis by inhibiting Sig-1R, subsequently promoting ferritinophagy, inhibiting GPX4/FSP1 antioxidant systems, reducing GSH levels, and ultimately increasing lipid peroxidation levels in vitro.

Ferroptosis regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer.

Gastric cancer is one of the most common malignant tumors in the world, and its occurrence and development involve complex biological processes. Iron death, as a new cell death mode, has attracted wide attention in recent years. However, the regulatory mechanism of iron death in gastric cancer and its effect on lipid peroxidation metabolism remain unclear. To explore the role of iron death in the development of gastric cancer, reveal its relationship with lipid peroxidation, and provide a new theoretical basis for revealing the molecular mechanism of the occurrence and development of gastric cancer. The process of iron death in gastric cancer cells was simulated by cell culture model, and the occurrence of iron death was detected by fluorescence microscopy and flow cytometry. The changes of gene expression related to iron death and lipid peroxidation metabolism were analyzed by high-throughput sequencing technology. In addition, a mouse model of gastric cancer was established, and the role of iron death in vivo was studied by histology and immunohistochemistry, and the level of lipid peroxidation was detected. These methods comprehensively and deeply reveal the regulatory mechanism of iron death on lipid peroxidation metabolism in the occurrence and development of gastric cancer. Iron death was significantly activated in gastric cancer cells, and at the same time, associated lipid peroxidation levels increased significantly. Through high-throughput sequencing analysis, it was found that iron death regulated the expression of several genes related to lipid metabolism. In vivo experiments demonstrated that increased iron death in gastric cancer mice was accompanied by a significant increase in lipid peroxidation. This study confirmed the important role of iron death in regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer. The activation of iron death significantly increased lipid peroxidation levels, revealing its regulatory mechanism inside the cell.

Acetylcholinesterase and dopamine inhibition suppress the filtration rate, burrowing behaviours, and immunological responses induced by bisphenol A in the hemocytes and gills of date mussels, Lithophaga lithophaga

Bisphenol A (BPA), a common industrial chemical with estrogenic activity, has recently gained attention due to its well-documented negative effects on humans and other organisms in the environment. The potential immunotoxicity and neurotoxicity of BPA remain poorly understood in marine invertebrate species. Therefore, the impacts of exposure to BPA on a series of behaviours, immune responses, oxidative stress, neural biomarkers, histology, and the ultrastructure of gills were investigated in the date mussel, Lithophaga lithophaga. After 28 days of exposure to 0.25, 1, 2, and 5 µg/L BPA, hemolymphs from controls and exposed date mussels were collected, and the effects of BPA on immunological parameters were evaluated. Moreover, oxidative stress and neurochemical levels were measured in the gills of L. lithophaga. BPA reduced filtration rates and burrowing behaviour, whereas a 2 µg/L BPA resulted in an insignificant increase after 24 h. The exposure of date mussels to BPA significantly increased total hemocyte counts, a significant reduction in the diameter and phagocytosis of hemocytes, as well as gill lysozyme level. BPA increased lipid peroxidation levels and SOD activity in gills exposed to 2 and 5 µg/L BPA, but decreased GSH levels and SOD activity in 0.25 and 1 µg/L BPA-treated date mussels. Dose-dependent dynamics were observed in the inhibition of acetylcholinesterase activity and dopamine levels. Histological and scanning electron microscope examination revealed cilia erosion, necrosis, inflammation, and hyperplasia formation in the gills. Overall, our findings suggest a relationship between BPA exposure and changes in the measured immune parameters, oxidative stress, and neurochemical disturbances, which may be factored into the mechanisms underlying BPA toxicity in marine molluscs, providing a scientific foundation for marine BPA risk assessment and indicating immunosuppression in BPA-exposed date mussels.

ARID3A enhances chemoresistance of pancreatic cancer via inhibiting PTEN-induced ferroptosis

Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in recent years has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine (GEM). Through bioinformatics analysis, AT-rich Interactive Domain-containing Protein 3A (ARID3A), one of transcription factors, is discovered to possibly participate in this progress. This study thoroughly investigates the potential role of ARID3A in the malignant progression and GEM chemoresistance of PDAC and explores the underlying mechanisms. The results indicate that ARID3A knockdown suppresses tumor development and enhances the sensitivity of PDAC cells to GEM in vitro and vivo. Mechanically, CUT&Tag profiling sequencing, RNA‐sequencing and functional studies demonstrates that decreased ARID3A expression alleviates the transcriptional inhibition of phosphatase and tensin homolog (PTEN), consequently leading to glutathione peroxidase 4 (GPX4) depletion and increased lipid peroxidation levels. Activated ferroptosis induced by the inhibition of GPX4 subsequently restricts tumor progression and reduces GEM resistance in PDAC. This research identifies the ferroptosis regulatory pathway of ARID3A-PTEN-GPX4 axis and reveals its critical role in driving the progression and chemoresistance of pancreatic cancer. Notably, both inhibition of ARID3A and enhancement of ferroptosis can increase chemosensitivity to GEM, which offers a promising opportunity for developing therapeutic strategies to combat acquired chemotherapy resistance in pancreatic cancer.

Protective effects of 2,4-dinitrophenol in okadaic acid-induced cellular model of Alzheimer's disease

Alzheimer's disease (AD) research started several decades ago and despite the many efforts employed to develop new treatments or approaches to slow and/or revert disease progression, AD treatment remains an unsolved issue. Knowing that mitochondria loss of function is a central hub for many AD-associated pathophysiological processes, there has been renewed interest in exploring mitochondria as targets for intervention. In this perspective, the present study was aimed to investigate the possible beneficial effects of 2,4 dinitrophenol (DNP), a mitochondrial uncoupler agent, in an in vitro model of AD. Retinoic acid-induced differentiated SH-SY5Y cells were incubated with okadaic acid (OA), a neurotoxin often used as an AD experimental model, and/or with DNP. OA caused a decrease in neuronal cells viability, induced multiple mitochondrial anomalies including increased levels of reactive oxygen species, decreased bioenergetics and mitochondria content markers, and an altered mitochondria morphology. OA-treated cells also presented increased lipid peroxidation levels, and overactivation of tau related kinases (GSK3β, ERK1/2 and AMPK) alongside with a significant augment in tau protein phosphorylation levels. Interestingly, DNP co-treatment ameliorated and rescued OA-induced detrimental effects not only on mitochondria but also but also reinstated signaling pathways homeostasis and ameliorated tau pathology. Overall, our results show for the first time that DNP has the potential to preserve mitochondria homeostasis under a toxic insult, like OA exposure, as well as to reestablish cellular signaling homeostasis. These observations foster the idea that DNP, as a mitochondrial modulator, might represent a new avenue for treatment of AD.

Perilipin-2 mediates ferroptosis in oligodendrocyte progenitor cells and myelin injury after ischemic stroke.

JOURNAL/nrgr/04.03/01300535-202507000-00024/figure1/v/2024-09-09T124005Z/r/image-tiff Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination. Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage. Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation, and plays an important role in the pathological process of ischemic stroke. However, there are few studies on oligodendrocyte progenitor cell ferroptosis. We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia. Bioinformatics analysis suggested that perilipin-2 (PLIN2) was involved in oligodendrocyte progenitor cell ferroptosis. PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation. For further investigation, we established a mouse model of cerebral ischemia/reperfusion. We found significant myelin damage after cerebral ischemia, as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area. The ferroptosis inhibitor, ferrostatin-1, rescued oligodendrocyte progenitor cell death and subsequent myelin injury. We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells. Plin2 knockdown rescued demyelination and improved neurological deficits. Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.

Txnrd2 Attenuates Early Brain Injury by Inhibition of Oxidative Stress and Endoplasmic Reticulum Stress via Trx2/Prx3 Pathway after Intracerebral Hemorrhage in Rats

Thioredoxin-reductase 2 (Txnrd2) belongs to the thioredoxin-reductase family of selenoproteins and is a key antioxidant enzyme in mammalian cells to regulate redox homeostasis. Here, we reported that Txnrd2 exerted a major influence in brain damage caused by Intracerebral hemorrhage (ICH) by suppressing endoplasmic reticulum (ER) stress oxidative stress and via Trx2/Prx3 pathway. Furthermore, we demonstrated that pharmacological selenium (Se) rescued the brain damage after ICH by enhancing Txnrd2 expression. Primarily, expression and localization of Txnrd2, Trx2 and Prx3 were determined in collagenase IV-induced ICH model. Txnrd2 was then knocked down using siRNA interference in rats which were found to develop more severe encephaledema and neurological deficits. Mechanistically, we observed that loss of Txnrd2 leads to increased lipid peroxidation levels and ER stress protein expression in neurons and astrocytes. Additionally, it was revealed that Se effectively restored the expression of Txnrd2 in brain and inhibited both the activity of ER stress protein activity and the generation of reactive oxygen species (ROS) by promoting Trx2/Prx3 kilter when administrating sodium selenite in lateral ventricle. This study shed light on the effect of Txnrd2 in regulating oxidative stress and ER stress via Trx2/Prx3 pathway upon ICH and its promising potential as an ICH therapeutic target.

Sunset Yellow induced biochemical and histopathological alterations in rat brain sub-regions

Sunset Yellow, a synthetic orange azo food dye was examined in this study for its impact on the Wistar rat brain sub-regions. The dye was administered orally to weanling rats at the Acceptable Daily Intake level (4 mg/kg/bw) for 40 days, and brain sub-regions viz., frontal cortex, cerebellum and hippocampus were examined for biochemical and histopathological changes. The results showed a significant decrease in tissue protein levels, superoxide dismutase, and catalase activity, as well as a significant increase in lipid peroxide levels in all brain sub-regions. Glutathione-S-transferase and Glutathione Reductase activities decreased, while Glutathione peroxidase activity increased. The biogenic amine levels and Acetylcholinesterase activity were also altered, with the frontal cortex and hippocampus being the most affected. Additionally, the dye caused histopathological damage in all brain sub-regions examined. This study indicates that the ADI level of Sunset Yellow may adversely affect brain tissue by causing oxidative damage.

Phycocyanin alleviates alcohol-induced testicular injury in male Wistar rats.

Given the noteworthy implications of alcohol consumption and its association with male infertility, there has been a notable focus on investigating natural alternatives to mitigate its adverse effects. Thus, this study was conducted to assess the potential protective effect of phycocyanin extract derived from the blue algae Arthrospira (Spirulina) platensis against ethanol-induced oxidative stress, disturbances in testicular morphology, and alterations in sperm production. Male rats were divided into four groups (five rats each): the control group received a saline solution, the ethanol exposed group (EtOH) was subjected to intraperitoneal injections of 10 mL/kg of ethanol solution at a concentration of 38% (v/v), the phycocyanin alone treated group (P) received oral administration of phycocyanin at a dosage of 50 mg/kg, and the phycocyanin-cotreated group (PE) was given oral phycocyanin followed by ethanol injections. All treatments were administered over a period of 14 days. Our findings demonstrated that ethanol exposure induced reproductive toxicity, characterized by reduced sperm production and viability, alterations in testicular weight and morphology, increased lipid peroxidation levels, and elevated oxidative enzyme activity. In addition, the ethanol-intoxicated group showed perturbations in serum biochemical parameters. However, the simultaneous exposure to ethanol and phycocyanin exhibited a counteractive effect against ethanol toxicity. The results showed that supplementation of phycocyanin prevented oxidative and testicular morphological damage-induced by ethanol and maintained normal sperm production, and viability.

Formononetin triggers ferroptosis in triple-negative breast cancer cells by regulating the mTORC1/SREBP1/SCD1 pathway.

Triple-negative breast cancer (TNBC) is the most malignant type of breast cancer, and its prognosis is still the worst. It is necessary to constantly explore the pathogenesis and effective therapeutic targets of TNBC. Formononetin is an active ingredient with anti-tumor effects that we screened earlier. The main purpose of this study is to elucidate mechanism of the inhibitory effect of Formononetin on TNBC. We conducted experiments through both in vivo and in vitro methodologies. The in vivo experiments utilized a nude mice xenotransplantation model, while the in vitro investigations employed two breast cancer cell lines, MDA-MB-231 and MDA-MB-468. Concurrently, ferroptosis associated proteins, lipid peroxide levels, and proteins related to the rapamycin complex 1 were analyzed in both experimental settings. In our study, Formononetin exhibits significant inhibitory effects on the proliferation of triple TNBC, both in vivo and in vitro. Moreover, it elicits an increase in lipid peroxide levels, downregulates the expression of ferroptosis-associated proteins GPX4 and xCT, and induces ferroptosis in breast cancer cells. Concurrently, Formononetin impedes the formation of the mammalian target of rapamycin complex 1 (mTORC1) and suppresses the expression of downstream Sterol regulatory element-binding protein 1(SREBP1). The utilization of breast cancer cells with SREBP1 overexpression or knockout demonstrates that Formononetin induces ferroptosis by modulating the mTORC1-SREBP1 signaling axis. In conclusion, this study provides evidence that Formononetin exerts an anti-proliferative effect on triple-negative breast cancer by inducing ferroptosis. Moreover, the mTORC1-SREBP1 signal axis is identified as the primary mechanism through which formononetin exerts its therapeutic effects. These findings suggest that formononetin holds promise as a potential targeted drug for clinical treatment of TNBC.

Endometrial stromal cell autophagy-dependent ferroptosis caused by iron overload in ovarian endometriosis is inhibited by the ATF4-xCT pathway.

Ferroptosis is an iron-dependent programmed cell death process characterized by the accumulation of lethal oxidative damage. Localized iron overload is a unique clinical phenomenon in ovarian endometriosis (EM). However, the role and mechanism of ferroptosis in the course of ovarian EM remain unclear. Traditionally, autophagy promotes cell survival. However, a growing body of research suggests that autophagy promotes ferroptosis under certain conditions. This study aimed to clarify the status of ferroptosis in ovarian EM and explore the mechanism(s) by which iron overload causes ferroptosis and ectopic endometrial resistance to ferroptosis in human. The results showed increased levels of iron and reactive oxygen species in ectopic endometrial stromal cells (ESCs). Some ferroptosis and autophagy proteins in the ectopic tissues differed from those in the eutopic endometrium. In vitro, iron overload caused decreased cellular activity, increased lipid peroxidation levels, and mitochondrial morphological changes, whereas ferroptosis inhibitors alleviated these phenomena, illustrating activated ferroptosis. Iron overload increased autophagy, and ferroptosis caused by iron overload was inhibited by autophagy inhibitors, indicating that ferroptosis caused by iron overload was autophagy-dependent. We also confirmed the effect of iron overload and autophagy on lesion growth in vivo by constructing a mouse EM model; the results were consistent with those of the in vitro experiments of human tissue and endometrial stomal cells. However, ectopic lesions in patients can resist ferroptosis caused by iron overload, which can promote cystine/glutamate transporter hyperexpression by highly expressing activating transcription factor 4 (ATF4). In summary, local iron overload in ovarian EM can activate autophagy-related ferroptosis in ESCs, and ectopic lesions grow in a high-iron environment via ATF4-xCT while resisting ferroptosis. The effects of iron overload on other cells in the EM environment require further study. This study deepens our understanding of the role of ferroptosis in ovarian EM.

Oxidative stress, gene expression and histopathology of cultured gilthead sea bream (Sparus aurata) naturally co-infected with Ergasilus sieboldi and Vibrio alginolyticus

BackgroundParasitic and bacterial co-infections have been associated with increasing fish mortalities and severe economic losses in aquaculture through the past three decades. The aim of this study was to evaluate the oxidative stress, histopathology, and immune gene expression profile of gilthead sea bream (Sparus aurata) co-infected with Ergasilus sieboldi and Vibrio alginolyticus.ResultsVibrio alginolyticus and Ergasilus sieboldi were identified using 16 S rRNA and 28 S rRNA sequencing, respectively. The collagenase virulence gene was found in all Vibrio alginolyticus isolates, and the multiple antimicrobial resistance index ranged from 0.286 to 0.857. Oxidant-antioxidant parameters in the gills, skin, and muscles of naturally infected fish revealed increased lipid peroxidation levels and a decrease in catalase and glutathione antioxidant activities. Moreover, naturally co-infected gilthead sea bream exhibited substantial up-regulation of il-1β, tnf-α, and cyp1a1. Ergasilus sieboldi encircled gill lamellae with its second antennae, exhibited severe gill architectural deformation with extensive eosinophilic granular cell infiltration. Vibrio alginolyticus infection caused skin and muscle necrosis in gilthead sea bream.ConclusionThis study described some details about the gill, skin and muscle tissue defense mechanisms of gilthead sea bream against Ergasilus sieboldi and Vibrio alginolyticus co-infections. The prevalence of co-infections was 100%, and no resistant fish were detected. These co-infections imbalance the health status of the fish by hampering the oxidant-antioxidant mechanisms and proinflammatory/inflammatory immune genes to a more detrimental side. Our results suggest that simultaneous screening for bacterial and parasitic pathogens should be considered.

Acute and subacute toxic effects of CUMYL-4CN-BINACA on male albino rats.

There is very little information about the toxicological and pathological effects of synthetic cannabinoids, which have cannabis-like properties. This study was carried out to histopathologically, hematologically, and biochemically determine the toxic effects of acute and subacute exposure to a novel synthetic cannabinoid 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)indazole-3-carboxamide in internal organs of adult male rats. The cannabinoid was injected intraperitoneally at three doses (0.5, 1.0, and 2.0mg/kg, body weight). The cannabinoid was administered to acute groups for 2days and to subacute groups for 14days. Observations were made for 14days and various changes such as mortality, injury, and illness were recorded daily. Hematological and biochemical changes were evaluated and histopathological analyses in lung, liver, and kidney tissues were also performed. No mortality was observed. It was observed that there were fluctuations in hematological and serum biochemical parameters. Among the oxidative stress parameters, significant decreases in superoxide dismutase, catalase levels and significant increases in lipid peroxidation levels were determined. Serious pathological changes such as necrosis, vacuolation, congestion, and fibrosis were observed in the internalorgans in a dose-dependent and time-dependent manner. It was also found that the synthetic cannabinoid triggered apoptosis in the organs. The results demonstrated that the most affected organ by the cannabinoid was the kidney. This study showed for the first time that CUMYL-4CN-BINACA adversely affects healthy male albinorats. It can be estimated that the abuse of the cannabinoid may harm human health in the same way.

Excessive Lipid Peroxidation in Uterine Epithelium Causes Implantation Failure and Pregnancy Loss.

The uterine epithelium undergoes a dramatic spatiotemporal transformation to enter a receptive state, involving a complex interaction between ovarian hormones and signals from stromal and epithelial cells. Redox homeostasis is critical for cellular physiological steady state; emerging evidence reveals that excessive lipid peroxides derail redox homeostasis, causing various diseases. However, the role of redox homeostasis in early pregnancy remains largely unknown. It is found that uterine deletion of Glutathione peroxidase 4 (GPX4), a key factor in repairing oxidative damage to lipids, confers defective implantation, leading to infertility. To further pinpoint Gpx4's role in different cell types, uterine epithelial-specific Gpx4 is deleted by a lactotransferrin (Ltf)-Cre driver; the resultant females are infertile, suggesting increased lipid peroxidation levels in uterine epithelium compromises receptivity and implantation. Lipid peroxidation inhibitor administration failed to rescue implantation due to carbonylation of major receptive-related proteins underlying high lipid reactive oxygen species. Intriguingly, superimposition of Acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme that promotes biosynthesis of phospholipid hydroperoxides, along with uterine epithelial GPX4 deletion, preserves reproductive capacity. This study reveals the pernicious impact of unbalanced redox signaling on embryo implantation and suggests the obliteration of lipid peroxides as a possible therapeutic approach to prevent implantation defects.

PRMT3-Mediated Arginine Methylation of METTL14 Promotes Malignant Progression and Treatment Resistance in Endometrial Carcinoma.

Protein arginine methyltransferase (PRMT) plays essential roles in tumor initiation and progression, but its underlying mechanisms in the treatment sensitivity of endometrial cancer (EC) remain unclear and warrant further investigation. Here, a comprehensive analysis of the Cancer Genome Atlas database and Clinical Proteomic Tumor Analysis Consortium database identifies that PRMT3 plays an important role in EC. Specifically, further experiments show that PRMT3 inhibition enhances the susceptibility of EC cells to ferroptosis. Mechanistically, PRMT3 interacts with Methyltransferase 14 (METTL14) and is involved in its arginine methylation. In addition, PRMT3 inhibition-mediated METTL14 overexpression promotes methylation modification via an m6 A-YTHDF2-dependent mechanism, reducing Glutathione peroxidase 4 (GPX4) mRNA stability, increasing lipid peroxidation levels, and accelerating ferroptosis. Notably, combined PRMT3 blockade and anti-PD-1 therapy display more potent antitumor effects by accelerating ferroptosis in cell-derived xenograft models. The specific PRMT3 inhibitor SGC707 exerts the same immunotherapeutic sensitizing effect in a patient-derived xenograft model. Notably, blocking PRMT3 improves tumor suppression in response to cisplatin and radiation therapy. Altogether, this work demonstrates that PRMT3 depletion is a promising target for EC.

Combined impact of elevated temperature and zinc oxide nanoparticles on physiological stress and recovery responses of Scylla serrata

Global climate change is the major cause behind unexpected fluctuations in temperature. In recent years, application of nanotechnology also has become widespread and nanomaterials are constantly being released into aquatic environments, posing a potential risk to various organisms and ecosystems. The lack of detailed understanding of how multiple stressors work, and how they differ from single stressors, impede to assess their combined effect on aquatic organisms and ecosystems. The prime aim of the current investigation is to decipher the toxicity of ZnO-NP after simultaneous exposure to a global environmental stressor, elevated temperature for 14 days, followed by a 7 days recovery period, on the eco-physiological responses of mud crab Scylla serrata collected from Sundarbans. Physiological energetics such as ingestion, assimilation, absorption, respiration, and excretion rates were measured to determine the Scope for growth (SfG). Additionally, we assessed various biomarkers from different levels of biological organisation (antioxidant, detoxification defence mechanisms, and lipid peroxidation levels) of the species. Combined stress attenuated the SfG in crabs which deteriorated further in the recovery phase. Oxidative stress also exacerbated under coalesced stress condition. Recovery was not observed in crabs with increased lipid peroxidation level under combined stress conditions. Elevated temperature disturbed the energy budget of crabs as mirrored by diminished energy left for compensatory actions under added metal stress, ultimately sensitizing the animals to ZnO NP pollutants. The current results advocate future ocean temperature to aggravate the impact of metal NP pollution and induce oxidative damage in S. serrata.