Search Results (165)

Oxidative stress occurs within bovine when exposed to harmful stimuli, accompanied by substantial accumulation of reactive oxygen species. Without timely clearance, these reactive oxygen species attack vascular endothelial cells, concurrently inducing extensive production of lipid peroxides within the vascular endothelium, and thereby triggering ferroptosis. Aspirin eugenol ester (AEE) showed pharmacological activity against oxidative stress-induced vascular endothelial damage. However, whether it could alleviate vascular endothelial damage by inhibiting ferroptosis remains unclear. This study aimed to evaluate the effects of AEE on vascular endothelial ferroptosis and elucidate its underlying molecular mechanisms. This study established vascular endothelial damage models in vitro and in vivo to explore the ability of AEE to inhibit ferroptosis and oxidative stress by measuring ferroptosis- and oxidative stress-related biomarkers. Transcriptomic and network pharmacology analyses were performed to identify AEE-regulated pathways and key targets. Validation of the pathways were conducted using molecular docking, cellular thermal shift assay, and specific protein agonists/inhibitors. AEE inhibited oxidative stress and ferroptosis in bovine aortic endothelial cells induced by hydrogen peroxide (H₂O₂) or RSL3 via suppressing the upregulation of ferroptosis-related genes and enhancing the expression of antioxidant genes. Transcriptomic and network pharmacology analyses identified JNK as a core target of AEE in regulating ferroptosis. JNK agonists enhanced H₂O₂-induced ferritinophagy; on the contrary, JNK inhibitors alleviated it. AEE suppressed H₂O₂-induced phosphorylation of JNK/c-Jun and ferritinophagy. In a carrageenan-induced rat aortic vascular endothelial damage model, AEE alleviated vascular endothelial damage and ferroptosis-related gene changes, promoted antioxidant gene expression, and inhibited JNK/c-Jun phosphorylation and ferritinophagy. AEE inhibited vascular endothelial ferroptosis by enhancing antioxidant ability, blocking downstream ferritinophagy, and reducing ferrous ion release. Full article

The extensive distribution of quaternary sediments and the extraction of underground resources in the Yellow River Delta (YRD) have resulted in significant land subsidence, which accelerates relative sea level (RSL) rise and heightens the risk of coastal inundation. This study uses Sentinel-1A (S1A) imagery and the time-series synthetic aperture radar interferometry (TS-InSAR) method to obtain subsidence information for the YRD. By integrating data from groundwater level monitoring wells, hydrogeological conditions, extensometer monitoring, and drilling wells, we analyze the causes of subsidence and the deformation response to the groundwater level changes in the corresponding aquifers. For the first time in the YRD, this study introduces the high accuracy CoastalDEM v2.1 digital elevation model, combined with absolute sea level (ASL) data, to construct a coastal inundation simulation. This simulation maps the land inundation caused by RSL rise along the YRD in different scenarios. The results indicate significant subsidence bowls in coastal and inland regions, primarily attributed to shallow brine and deep groundwater extraction, respectively. The main subsidence layers in inland towns have been identified, and residual deformation has been observed. Currently, land subsidence has caused a maximum elevation loss of 141 mm/yr in coastal YRD areas, significantly contributing to RSL rise. Seawater inundation simulations suggest that if subsidence continues unabated, 12.84% of the YRD region will be inundated by 2100, with 8.74% of the built-up areas expected to be inundated. Compared to global warming-induced ASL rise, ongoing subsidence is the primary driver of inundation in the YRD coastal areas. Full article

Background/Objectives: Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and holds promise as a therapeutic strategy against cancers with elevated iron metabolism. However, many tumors evade ferroptosis through the upregulation of specialized antioxidant defense mechanisms. Here, we investigated ferroptosis susceptibility and resistance mechanisms in TSC models and in ovarian and breast cancer cell lines, aiming to identify potential therapeutic targets. Methods: Ferroptosis sensitivity was assessed using RSL3 and erastin. We explored the contribution of ferroptosis defense pathways using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA sequencing was performed to evaluate the expression of ferroptosis resistance genes and to explore NRF2-regulated transcriptional programs. Results: TSC2-deficient cells were resistant to RSL3- and erastin-induced ferroptosis. This resistance correlated with upregulation of ferroptosis defense genes, including NRF2 and its downstream targets. Pharmacological inhibition of NRF2 resensitized TSC2-deficient cells to ferroptosis, confirming a protective role for NRF2. However, FSP1 inhibition did not restore ferroptosis sensitivity in TSC2-deficient angiomyolipoma cells. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cells. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition to enhance ferroptosis sensitivity. FSP1 expression was not regulated by NRF2, suggesting that NRF2-targeted therapies alone may be insufficient to overcome ferroptosis resistance in certain cancer contexts. Conclusions: TSC2-deficient cells resist ferroptosis via an adaptive antioxidant response that protects against elevated iron-mediated lipid peroxidation. Our findings identify NRF2 and FSP1 as key, but mechanistically distinct, regulators of ferroptosis resistance. The differential efficacy of targeting these pathways across cancer types highlights the potential need for patient stratification. Dual targeting of NRF2 and FSP1 may offer an effective therapeutic strategy for iron-dependent, ferroptosis-resistant cancers. Full article

Soybean (Glycine max), as an important crop for both oil and grains, is a major source of high-quality plant proteins for humans. Among various natural disasters affecting soybean production, waterlogging is one of the key factors leading to yield reduction. It can cause root rot and seedling death, and in severe cases, even total crop failure. Given the significant differences in responses to waterlogging stress among different soybean varieties, traditional single-trait indicators are insufficient to comprehensively evaluate flood tolerance. In this study, relative seedling length (RSL) was used as a comprehensive evaluation index for flood tolerance. Using a chromosome segment substitution line (CSSL) population derived from SN14 and ZYD00006, we successfully identified seven quantitative trait loci (QTLs) associated with seed waterlogging tolerance. By integrating RNA-Seq transcriptome sequencing and phenotypic data, the functions of candidate genes were systematically verified. Phenotypic analysis indicated that Suinong14 had significantly better flood tolerance than ZYD00006. Further research revealed that the Glyma.05G160800 gene showed a significantly up-regulated expression pattern in Suinong14; qPCR analysis revealed that this gene exhibits higher expression levels in submergence-tolerant varieties. Haplotype analysis demonstrated a significant correlation between different haplotypes and phenotypic traits. The QTLs identified in this study can provide a theoretical basis for future molecular-assisted breeding of flood-tolerant varieties. Additionally, the functional study of Glyma.05G161800 in regulating seed flood tolerance can offer new insights into the molecular mechanism of seed flood tolerance. These findings could accelerate the development of submergence-tolerant rice varieties, enhancing crop productivity and stability in flood-prone regions. Full article

The olive oil-production sector engages with the environment on multiple levels, and the valorization of olive pomace (OP) has emerged as a key strategy to improve the entire system’s sustainability. Numerous studies have investigated the biological effects of OP phenolic fraction for nutraceutical applications, highlighting its antioxidant properties. This study aimed to assess the effect of an OP extract (OPE) and its phenolic content on ferroptosis induced by RAS-selective lethal 3 (RSL3), an inhibitor of glutathione peroxidase 4. After characterization of OPE phenolic composition, its antioxidant properties were confirmed through the Fenton reaction assay. Subsequently, we examined the effect of OPE on ter-butyl hydroperoxide-induced ROS generation and lipid peroxidation in TPH-1 and HIECs cells and found that OPE reduced ROS and lipid peroxidation. RSL3 decreased the number of vital cells, which was associated with an elevation in ROS and lipid peroxidation, and a reduction in GSH. Interestingly, all these detrimental effects were reversed by OPE. Furthermore, OPE was also found to significantly increase GSH and the GSH/GSSG ratio per se. In conclusion, the fact that OPE decreases ROS and lipid peroxidation induced by RSL3 and augments GSH and cell viability suggests that OPE has potential as a ferroptosis inhibitor. Full article

Numerous dark linear recurrent features called Recurring Slope Lineae (RSL) are observed on Martian surfaces, hypothesized as footprints of high-salinity liquid flow. This paper experimentally examined this “wet hypothesis” by analyzing the aspect ratios (length/width) of the flow traces on the granular material column to investigate how they vary with the granular material column, liquid and its flow rate, and inclination. While pure water produced low aspect ratios (<1.0) on the Martian regolith simulant column, high-salinity fluid (CaCl₂(aq)) traces exhibited significantly higher aspect ratios (>4.0), suggesting that pure water alone is insufficient to explain RSL formulation. Furthermore, the aspect ratios of high-salinity fluid traces on Martian regolith simulants were among the highest observed across all studied granular materials with similar particle sizes, aligning closely with actual RSL observed on Martian slopes. The results further suggest that variable ARs of actual RSL at the given slope can partly be explained by variable flow rates of high-salinity flow as well as salinity (i.e., viscosity) of flow. The results can be attributed to the unique granular properties of Martian regolith, characterized by the lowest permeability and Beavers–Joseph slip coefficient among the studied granular materials. This distinctive microstructure surface promotes surface flow over Darcy flow within the regolith column, leading to a narrow and long-distance feature with high aspect ratios observed in Martian RSL. Thus, our findings support that high-salinity flows are the primary driver behind RSL formation on Mars. Our study suggests the presence of salts on the Martian surface and paves the way for further investigation into RSL formulation processes. Full article

Multiple myeloma (MM) is an incurable malignancy of plasma cells that accounts for 10% of all haematological malignancies diagnosed worldwide. The poor outcome of patients with MM highlights the ongoing need for novel treatment strategies. Ferroptosis is a recently characterised form of non-apoptotic programmed cell death. Phospholipids (PLs) containing polyunsaturated fatty acids (PUFAs) play a crucial role as ferroptosis substrates when oxidised to form toxic lipid reactive oxygen species (ROS). Using a range of scientific techniques, we demonstrate a strong correlation between the PL profile of MM and diffuse large B cell lymphoma (DLBCL) cells with their sensitivity to ferroptosis. Using this PL profiling, we manufacture liposomes that are themselves composed of PL-PUFA ferroptosis substrates relatively deficient in MM cells, with and without the GPX4 inhibitor, RSL3, for investigation of their ferroptosis-inducing potential. PL-PUFAs were more abundant in DLBCL than MM cell lines, consistent with greater ferroptosis sensitivity. In contrast, MM cells generally contained a significantly higher proportion of PLs containing monounsaturated fatty acids. Altering the lipid composition of MM cells through exogenous supplementation with PL-PUFAs induced ferroptosis-mediated cell death and further sensitised these cells to RSL3. Liposomes predominantly comprising PL-PUFAs were subsequently manufactured and loaded with RSL3. Uptake, cytotoxicity and lipid ROS studies demonstrated that these novel liposomes were readily taken up by MM cells. Those containing RSL3 were more effective at inducing ferroptosis than empty liposomes or free RSL3, resulting in IC₅₀ values an average 7.1-fold to 14.5-fold lower than those for free RSL3, from the micromolar to nanomolar range. We provide a better understanding of the mechanisms associated with ferroptosis resistance of MM cells and suggest that strategies such as liposomal delivery of relatively deficient ferroptosis-inducing PL-PUFAs together with other targeted agents could harness ferroptosis for the personalised treatment of MM and other cancers. Full article

Ferroptosis, a regulated form of iron-dependent lipid peroxidation-induced cell death, has emerged as a compelling therapeutic strategy to overcome treatment resistance in head and neck cancer (HNC). Glutathione peroxidase 4 (GPX4), a selenoenzyme responsible for detoxifying phospholipid hydroperoxides, plays a central role in blocking ferroptosis and is frequently upregulated in therapy-resistant HNC subtypes. In this review, we examine the multifaceted regulation of GPX4 expression and function, including transcriptional, post-transcriptional, epigenetic, and proteostatic mechanisms. We explore how GPX4 suppression through pharmacologic inhibitors (e.g., RSL3, withaferin A, statins), metabolic stress, or combined therapies (e.g., radiotherapy, EGFR inhibitors, immunotherapy) induces ferroptosis and resensitizes resistant tumors. We also summarize emerging biomarkers, including GPX4, ACSL4, SLC7A11, and NCOA4, that predict ferroptosis sensitivity and may guide patient selection for ferroptosis-targeted therapies. Single-cell and spatial transcriptomics reveal significant intratumoral heterogeneity in ferroptosis susceptibility, underscoring the need for precision approaches. Despite promising preclinical data, challenges such as drug delivery, toxicity, and resistance mechanisms remain. Nevertheless, the ferroptosis-GPX4 axis represents a unique vulnerability in HNC that can be therapeutically exploited. Integrating ferroptosis modulation into personalized oncology may transform outcomes for patients with refractory disease. Full article

In the continuous pursuit of minimally invasive interventions while ensuring a radical excision of lesions, Radio-Guided Surgery (RGS) has been for years the standard for image-guided surgery procedures, such as the Sentinel Lymph Node biopsy (SLN), Radio-guided Seed Localization (RSL), etc. In RGS, the lesion has to be identified precisely, in terms of position and extension. In such a context, going beyond the current one-point probes, introducing portable but high-resolution cameras, handholdable by the surgeon, would be highly beneficial. We developed and tested a novel compact, low-power, handheld gamma camera for radio-guided surgery. This is based on a particular position-sensitive Silicon Photomultiplier (SiPM) technology—the FBK linearly graded SiPM (LG-SiPM). Within the camera, the photodetector is made up of a 3 × 3 array of 10 × 10 mm² SiPM chips having a total area of more than 30 × 30 mm². This is coupled with a pixelated scintillator and a parallel-hole collimator. With the LG-SiPM technology, it is possible to significantly reduce the number of readout channels to just eight, simplifying the complexity and lowering the power consumption of the readout electronics while still preserving a good position resolution. The novel gamma camera is light (weight), and it is made to be a fully stand-alone system, therefore featuring wireless communication, battery power, and wireless recharge capabilities. We designed, simulated (electrically), and tested (functionally) the first prototypes of the novel gamma camera. We characterized the intrinsic position resolution (tested with pulsed light) as being ~200 µm, and the sensitivity and resolution when detecting gamma rays from Tc-99m source measured between 134 and 481 cps/MBq and as good as 1.4–1.9 mm, respectively. Full article

Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is regulated by key mediators including glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (Nrf2). Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes latency-associated nuclear antigen (LANA), a multifunctional protein critical for viral persistence. Although studies reported that KSHV infection enhanced cellular resistance to ferroptosis, the specific role of LANA in this process remains unexplored. Here, we demonstrate that LANA unexpectedly promotes ferroptosis. In KSHV-positive iSLK.219 cells, LANA knockdown significantly attenuated RSL-3-induced ferroptosis, whereas LANA overexpression sensitized HeLa cells to ferroptotic death. Quantitative analysis revealed that LANA-depleted cells exhibited significantly elevated ROS accumulation (p < 0.01), whereas LANA-overexpressing cells maintained reduced ROS levels during challenge with the ferroptosis inducer RSl-3. Mechanistically, LANA suppressed glutathione peroxidase 4 (GPX4) expression, reduced nuclear factor erythroid 2-related factor 2 (Nrf2) expression and impaired its nuclear translocation, and upregulated mouse double minute 2 homolog (MDM2) expression. Pharmacological inhibition of Nrf2 (ML385) or MDM2 (nutlin3a) reversed the ferroptotic effects of LANA knockdown or overexpression, respectively. These findings reveal a pro-ferroptotic role of LANA via Nrf2/GPX4 suppression and MDM2 activation. Full article

Oxidative stress plays a critical role in regulating sperm function, yet species-specific antioxidant mechanisms remain poorly understood. This study compared hydrogen peroxide (H₂O₂) tolerance in horse and human sperm and investigated the roles of catalase and glutathione peroxidase (GPx) in horses. A H₂O₂ dose–response assay (0–2000 µM) showed that horse sperm were significantly more resistant to oxidative damage, with an IC₅₀ for progressive motility over 14-fold higher than that of human sperm (391.6 µM vs. 27.3 µM). Horse sperm also accumulated more intracellular H₂O₂ without loss of motility or viability. DNA damage assays (Halo and SCSA) revealed H₂O₂-induced fragmentation in human but not horse sperm. Enzyme inhibition experiments in horse sperm using 3-amino-1,2,4-triazole (catalase inhibitor) and (1S,3R)-RSL3 (GPx inhibitor) at 250 µM H₂O₂ showed that catalase inhibition severely impaired motility and increased intracellular H₂O₂ > 100-fold, while GPx inhibition had a milder effect (~5-fold increase). Immunocytochemistry localized catalase to the sperm head, particularly the post-acrosomal region, challenging the notion that sperm lack peroxisomes. The dependence of horse sperm on oxidative phosphorylation may drive the need for enhanced antioxidant defenses. These findings reveal species-specific oxidative stress adaptations and highlight catalase as a key antioxidant in equine sperm. Full article

Robotics has widespread applications throughout industrial automation, autonomous vehicles, agriculture, and more. For these reasons, undergraduate education has begun to focus on preparing engineering students to directly contribute to the design and use of such systems. However, robotics is inherently multi-disciplinary and requires knowledge of controls and automation, embedded systems, sensors, signal processing, algorithms, and artificial intelligence. This makes training the future robotics workforce a challenge. In this paper, we evaluate our experiences with project-based learning approaches to teaching robotics at the undergraduate level at Miami University. Specifically, we analyze three consecutive years of capstone design projects on increasingly complex robotics design problems for multi-robot systems. We also evaluate the laboratories taught in our course “ECE 314: Elements of Robotics”. We have chosen these four experiences since they focus on the use of “cheap” first-principled robots, meaning that these robots sit on the fringe of embedded system design in that much of the student time is spent on working with a micro-controller interfacing with simple and cheap actuators and sensors. To contextualize our results, we propose the Robotic System Levels (RSL) model as a structured way to understand the levels of abstraction in robotic systems. Our main conclusion from these case studies is that, in each experience, students are exposed primarily to a subset of levels in the RSL model. Therefore, the curriculum should be designed to emphasize levels that align with educational objectives and the skills required by local industries. Full article

Background: Acute kidney injury (AKI), characterized by high morbidity and mortality, is primarily caused by renal ischemia–reperfusion injury (RIRI). Ferroptosis plays a key role in RIRI, yet its underlying mechanisms remain unclear. The drug pair of Astragali Radix–Ligustri Lucidi Fructus (DAL) shows promise in renal diseases, but its protective effects against RIRI and associated molecular pathways via ferroptosis inhibition are unknown. This study aimed to investigate DAL’s therapeutic effects on RIRI and its mechanisms. Methods: A mouse model of bilateral renal ischemia–reperfusion was established. Renal function (serum creatinine, Scr; blood urea nitrogen, BUN), inflammatory cytokines (TNF-α, IFN-γ, IL-6), ferroptosis markers (GPX4, MDA, GSH, tissue iron), and pathological damage were evaluated. Transcriptomic sequencing and electron microscopy analyzed gene pathways and mitochondrial structure. In HK-2 cells, oxygen–glucose deprivation/reoxygenation (OGD/R) and RSL3-induced ferroptosis models were used to assess DAL-containing serum effects via cell viability, GPX4 expression, and mitochondrial morphology. LC-MS analyzed DAL’s chemical components, and network pharmacology predicted ferroptosis-related targets. Results: DAL significantly reduced Scr/BUN levels, alleviated tubular injury, fibrosis, and apoptosis, and downregulated inflammatory cytokines and damage markers. It inhibited ferroptosis by upregulating GPX4, decreasing MDA/tissue iron, and increasing GSH. Transcriptomics revealed enrichment in lipid metabolism pathways. DAL restored the mitochondrial cristae structure; DAL-containing serum improved cell viability, blocked RSL3-induced GPX4 downregulation, and mitigated mitochondrial dysfunction. Network pharmacology identified DAL’s potential active components and targets. Molecular docking validated binding affinity and interaction patterns of active components with targets. Conclusions: DAL protects against RIRI by upregulating GPX4, preserving the mitochondrial structure, and inhibiting ferroptosis, highlighting its therapeutic potential for AKI prevention and treatment. Full article

Background: Combination therapies for cancer have gained considerable attention due to their potential for enhancing therapeutic efficacy and decreasing drug resistance. Introducing nanodrug delivery systems in this context may further improve the therapy due to targeted delivery, improved drug stability, sustained drug release, and prevention of rapid clearance from circulation. This study evaluates the combinatorial effects of two cytotoxic drugs, cabazitaxel (CBZ) and RSL3 (RAS-selective lethal 3), in free form as well as encapsulated within poly(2-ethyl butyl cyanoacrylate) (PEBCA) nanoparticles (NPs) in breast cancer cell lines. Methods: Cell proliferation was assessed using IncuCyte technology, and synergistic drug effects were determined with SynergyFinder Plus. Cell viability was measured with the MTT assay. Additionally, we investigated whether the combinatorial effects were reflected in alterations of metabolic activity or reactive oxygen species (ROS) production using Seahorse technology and the CM-H₂DCFDA assay, respectively. Results: The data presented reveal, for the first time, that CBZ and RSL3 exhibit synergistically or additively combinatorial effects on various breast cancer cell lines. The pattern of cytotoxic effects was consistent, whether the drugs were in free form or encapsulated in NPs. Moreover, the combinatorial effects were not observed to be associated with early changes in metabolic activity or ROS production. Conclusion: This study highlights the potential of CBZ and RSL3 in combinatorial nanomedicine as they may act synergistically. Further studies are warranted to better understand the mechanisms behind these combinatorial effects. Full article

Glutathione peroxidase 4 (GPX4) plays a crucial role in regulating lipid peroxidation and is associated with infection and inflammation, particularly in terms of its effects on inflammatory cytokines and ferroptosis. This study aimed to investigate the regulatory effects of Gpx4 on the inflammatory response and ferroptosis in blunt snout bream (Megalobrama amblycephala), a significant freshwater fish species in China, after Aeromonas hydrophila infection. Using a bioinformatics analysis, we discovered that Gpx4 has a conserved protein structure and high amino acid identity in various carp species, indicating functional conservation across species and through involution. RT-qPCR analysis revealed that gpx4 mRNA increased after the neuroembryonic stage during early development and was particularly highly expressed in the liver of healthy adult fish. Upon A. hydrophila infection, gpx4 expression decreased significantly and rapidly in the liver. In L8824 cells, overexpression of gpx4 suppressed inflammatory cytokines and inhibited ferroptosis in response to both A. hydrophila infection and induction of ferroptosis-inducer RSL3. These findings highlight the regulatory role of Gpx4 in cellular ferroptosis and inflammation, providing insights into the complex mechanisms of disease resistance and potentially aiding in the development of strategies for disease control in fish. Full article