Elevated Levels Of Reactive Oxygen Species Research Articles

Impairing Ferroptosis Through the PI3K/Akt/Nrf2 Pathway: The Way for Nerve Growth Factor to Mitigate Hypoxia-induced Cardiomyocyte Damage.

Myocardial infarction (MI) is an acute cardiovascular diseases, distinguished primarily by cardiomyocyte damage due to ischemia and hypoxia. Nerve growth factor (NGF) is paramount in ischemic heart disease, it contributes to maintaining heart function and protecting the heart. Nonetheless, the effects of NGF on cardiomyocyte damage induced by hypoxia and the precise mechanisms involved are still to be elucidated. Utilizing western blot and immunofluorescence methods to quantify the NGF levels in cardiomyocytes (H9C2) of rats after hypoxia. Cell Counting Kit-8 (CCK-8) assay was employed to monitor the dynamic changes in cells vitality. The lactate dehydrogenase (LDH), Fe2+, malondialdehyde (MDA), superoxide dismutase (SOD) and reactive oxygen species (ROS) levels were evaluated by different kits. Moreover, the PI3K/Akt/Nrf2 pathway and ferroptosis-linked protein levels were analyzed using western blotting. In H9C2 cells, exposure to hypoxia for 24 h led to weakened NGF level, as well as lowered cell vitality and SOD activity, but elevated levels of LDH, Fe2+, MDA, and ROS, triggering ferroptosis. Overexpression NGF alleviated the ferroptosis in H9C2 cells caused by hypoxia, while NGF knockdown intensified this process. Additionally, overexpression NGF reinforced heme oxygenase-1 (HO-1) and Nrf2 levels, and Akt and PI3K phosphorylation, whereas NGF silencing produced contrary outcomes. Furthermore, the PI3K/Akt pathway inhibitor negated the elevation in HO-1 and Nrf2 levels mediated by NGF amplification. In contrast, the pathway activator reversed the lowering in Nrf2 and HO-1 levels caused by silencing NGF. This suggested that NGF mediates the activation of Nrf2 through the PI3K/Akt axis. Overall, by mediating the activation of Nrf2 through the PI3K/Akt axis, NGF reduced the damage to H9C2 cells caused by hypoxia and thus hindered ferroptosis.

Copper homeostasis and neurodegenerative diseases

Copper, one of the most prolific transition metals in the body, required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine (DPA), and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline (PBT2), along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

Synergistic effect of curcumin and Piperine loaded Niosomal nanoparticles on acute pulmonary toxicity induced by Paraquat in mice.

Paraquat (PQ), a widely used non-selective herbicide, induces severe lung toxicity by promoting cell death and tissue necrosis through the generation of reactive oxygen species (ROS) and free radicals. This study aimed to develop and evaluate novel niosomal nanoparticles (NPs) encapsulating curcumin and piperine to mitigate PQ-induced acute pulmonary toxicity in Balb/c mice. The NPs were prepared using non-ionic surfactants and cholesterol via the thin film hydration method. Characterization revealed high encapsulation efficiency (>85%), proper particle sizes (264-286nm), narrow polydispersity index (PDI) (0.19±0.04 to 0.23±0.02), and good stability over 90days. Thermal analysis confirmed successful encapsulation of curcumin and piperine within the niosomal NPs. In vivo studies showed that PQ exposure significantly elevated ROS, lipid peroxidation (LPO), and protein carbonylation (PC) levels, while reducing glutathione (GSH) levels and impairing mitochondrial function (P<0.001). However, co-treatment with curcumin- and piperine-loaded niosomal NPs effectively reversed these effects (P<0.001), improving mitochondrial function. The combined formulation of curcumin and piperine in niosomal NPs offers a promising therapeutic strategy for treating PQ-induced pulmonary toxicity, likely due to enhanced bioavailability and potent antioxidant activity.

Menthol as an effective inhibitor of quorum sensing and biofilm formation in Candida albicans and Candida glabrata by targeting the transcriptional repressor TUP1.

Menthol, a natural quorum sensing molecule, is derived from the Mentha species. Combating pathogenicity by inactivating quorum sensing is an emerging approach. Therefore, our objective was to investigate anti-quorum sensing and anti-biofilm potentials of menthol in Candida albicans and Candida glabrata. The antifungal properties of menthol were evaluated using a broth microdilution assay and a time-kill assay, and its effects on quorum sensing-mediated virulence factors, cellular reactive oxygen species (ROS), and biofilm formation were tested by evaluating TUP1 expression levels in both C. albicans and C. glabrata. Quorum sensing-mediated virulence factors and biofilm formation were inhibited by menthol in both C. albicans and C. glabrata. Furthermore, coinciding with elevated ROS levels, mRNAs of the quorum sensing-related gene TUP1 were upregulated in both C. albicans and C. glabrata. This study highlights the anti-quorum sensing potential of menthol through the inhibition of quorum sensing-mediated virulence factors, ROS generation, and biofilm development by targeting TUP1, which could have potential in the treatment of Candida infections.

Kinetic study and optimization of ginger mediated ochratoxin A reduction: An eco-friendly approach including toxicity evaluation

Ochratoxin A (OTA) is a toxic secondary metabolite synthesized by certain fungal strains of Penicillium and Aspergillus and is characterized as a Group 2B carcinogen. OTA infiltrates food and feeds through diverse chains, posing health risks to humans and animals. Herein, seven distinct edible plant materials were screened for their OTA reduction activity. Amidst them, ginger juice in aqueous (2.5%, v/v) showed the highest OTA reduction (95.63%), following first-order reaction kinetics (R2 = 0.92) with 0.72 d−1 rate constant. OTA reduction activity of ginger juice was substantially compromised in the presence of salt (> 2.5%) and temperature (> 40 °C). The response surface methodology-based approach employing Box–Behnken experimental design revealed an integrated effect of temperature, pH, and salt concentrations on OTA reduction (27.44–100%) by ginger juice. In addition, heat treatment (100 °C) and dialysis (12–14 kDa cutoff) of ginger juice implied the inclusion of heat-stable small molecules in reducing OTA. Ginger-treated OTA ameliorated hepatocellular carcinoma (HepG2) cell viability and diminished reactive oxygen species (ROS) levels compared to native OTA. In zebrafish embryos, OTA-induced teratogenic effects, diminished hatching (22.91%), and elevated ROS levels leading to embryo mortality (75%), which was significantly reversed by OTA treated with ginger, underscoring the curtailed toxicity of OTA-converted products by ginger.

Supplementation of Chlorogenic Acid Alleviates the Effects of H2O2-Induced Oxidative Stress on Laying Performance, Egg Quality, Antioxidant Capacity, Hepatic Inflammation, Mitochondrial Dysfunction, and Lipid Accumulation in Laying Hens

This research examined the impact of chlorogenic acid (CGA) on laying performance, antioxidant capacity, egg quality, hepatic inflammation, mitochondrial function, and lipid metabolism in hens subjected to hydrogen peroxide (H2O2)-induced oxidative stress (OS). Three hundred sixty healthy 43-wk-old Hy-Line brown hens were randomly assigned to six treatments: a basal diet + 0 (control and H2O2), 600 (600 mg/kg CGA and 600 mg/kg CGA + H2O2), and 800 (800 mg/kg CGA and 800 mg/kg CGA + H2O2) mg/kg CGA for 84 d. On the 64th and 78th days of the trial, hens in groups H2O2, 600 mg/kg CGA + H2O2, and 800 mg/kg CGA + H2O2 were injected intraperitoneally with 10% H2O2. The results demonstrated that 600 and 800 mg/kg CGA significantly improved the egg production rate (EPR) and egg quality and reduced lipid peroxidation compared to the control group. The 800 mg/kg CGA showed greater improvements in the EPR and average egg weight (AEW) compared to the 600 mg/kg dose. Conversely, H2O2 exposure significantly decreased the EPR, AEW, and egg quality and increased feed conversion rate and average daily feed intake. H2O2 exposure significantly decreased serum T-AOC and increased serum MDA levels while reducing hepatic T-SOD, GSH-Px, and CAT activities. Meanwhile, H2O2 exposure significantly elevated liver reactive oxygen species levels, pathological damage, and NF-κB, TNFα, and IL-1β gene expression. Additionally, H2O2 treatment disrupted hepatocyte mitochondrial structure and significantly increased the expression of VDAC1 protein, and IP3R, GRP75, MCU, Fis1, and MFF genes, while downregulating the expression of MFN2 protein and PGC1α gene. Oil Red O staining demonstrated that H2O2 induced significant lipid accumulation in hepatocytes. Concurrently, H2O2 significantly increased serum triglycerides, total cholesterol, and liver triglycerides levels while decreasing serum hepatic lipase activity. This was primarily attributed to the significant upregulation of liver SREBP1, FASN, and ACC genes and the downregulation of the liver CPT1 gene induced by H2O2. Furthermore, CGA pretreatment effectively prevented the degeneration in laying performance and egg quality, as well as OS, liver inflammation, pathological damage, and mitochondrial dysfunction induced by H2O2. CGA inhibited H2O2-induced hepatic lipid accumulation by upregulating fatty acid oxidation-related gene expression and downregulating fatty acid synthesis-related gene expression. These findings indicate that the dietary addition of 800 mg/kg of CGA is the optimum supplementation dose. CGA can enhance laying performance and egg quality while alleviating OS, hepatic inflammation, mitochondrial dysfunction, and lipid accumulation in H2O2-challenged laying hens.

Differential sensitivity of hemocyte subpopulations (Mytilus edulis) to aged polyethylene terephthalate micro- and nanoplastic particles

Bivalve hemocytes, particularly granulocytes and hyalinocytes, play a crucial role in cell-mediated immunity. However, their interactions with aged plastic particles, exhibiting altered properties that more closely resemble those in natural environments, remain largely underexplored. This study assesses the differential responses of hemocyte subpopulations (Mytilus edulis) to chemically aged polyethylene terephthalate (PET) microplastic (MPs) and nanoplastic (NPs) particles across multiple cellular effect endpoints. Particle characteristics were analyzed using Single Particle Extinction and Scattering, Raman Spectroscopy, Scanning Electron Microscopy, and Dynamic Light Scattering. In vitro experiments with aged PET MPs (1.9 µm) and NPs (0.68 µm) were conducted at three internally relevant concentrations: 10 (C1), 10³ (C2), and 10⁵ particles/mL (C3). Cellular responses were assessed by measuring lysosomal content stability, reactive oxygen species (ROS) production, cellular mortality, and morphological parameters using flow cytometry at 6, 12, 24, and 48 hours. Our findings provide mechanistic insights into the differential sensitivities of granulocytes and hyalinocytes to aged PET, influenced by particle size and concentration. Specifically, aged PET MPs and NPs induce distinct size and concentration-dependent patterns of lysosomal destabilization, coinciding with the loss of functional integrity. Elevated ROS levels were observed only in granulocytes and hyalinocytes exposed to high concentrations of aged PET NPs, underscoring the effects on oxidative stress. Both aged PET MPs and NPs induce significant increases in cellular mortality, particularly after 24 h of exposure at high concentrations. These findings reveal the complex cellular mechanisms underlying hemocyte functional impairment following exposure to aged PET particles under environmentally and biologically relevant conditions.

Di-(2-ethylhexyl) Phthalate Exposure Induces Developmental Toxicity in the Mouse Fetal Heart via Mitochondrial Dysfunction.

Congenital heart disease (CHD) is a major cause of infant mortality and morbidity, with growing interest in the role of environmental factors in its etiology. Di-(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, has been implicated in the development of CHD. This study aimed to investigate the effects of DEHP exposure on fetal heart development in mice. Pregnant mice exposed to DEHP exhibited increased fetal malformations, decreased fetal weight, and reduced crown-rump length.f Transcriptomic analysis revealed the downregulation of genes involved in aerobic respiration and mitochondrial ATP synthesis. Functional assays demonstrated reduced mitochondrial respiration, decreased ATP production, elevated reactive oxygen species levels, and lowered mitochondrial membrane potential in DEHP-exposed fetal cardiomyocytes. These findings underscore the detrimental effects of DEHP on fetal cardiac health and provide insights into the molecular mechanisms underlying DEHP-induced CHD. Understanding these mechanisms is crucial for developing preventive strategies against environmental toxicants that affect fetal cardiac development.

Atrial cardiomyopathy resulting from loss of plakophilin-2 expression: Response to adrenergic stimulation and implications for the exercise response.

Atrial arrhythmias occur in 20-40% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and are associated with an increased risk of sustained ventricular arrhythmias and inappropriate implantable cardioverter-defibrillator shocks. The pathophysiology of atrial arrhythmias in ARVC remains unclear. Most cases of gene-positive ARVC are linked to pathogenic variants in the desmosomal gene plakophilin-2 (PKP2). Here, we test the hypothesis that loss of PKP2 expression leads to pro-arrhythmic changes in atrial cardiomyocytes. Atrial cells/tissue were obtained from a cardiac-specific, tamoxifen-activated model of PKP2 deficiency (PKP2cKO). By contrast to PKP2cKO ventricular myocytes, PKP2cKO atrial cardiomyocytes presented no significant differences in intracellular calcium (Ca2+ i) transient dynamics, sarcoplasmic reticulum load or action potential morphology. PKP2cKO atrial cardiomyocytes showed elevated reactive oxygen species levels, increased frequency and amplitude of Ca2+ sparks, and increased diastolic [Ca2+]i compared to control; the latter two parameters were further increased by isoproterenol exposure and reversed by exposure to ryanodine receptor blocker dantrolene. We speculate that these isoproterenol-dependent effects may impact on the exercise-related atrial arrhythmia risk in ARVC patients. Despite absence of changes in Ca2+ i transient dynamics, PKP2cKO atrial cardiomyocytes showed enhanced sarcomere shortening and impaired sarcomere relaxation. Orthogonal transcriptomic analysis of human(GTEx) and PKP2cKO atrial tissue led to identification of 41 transcripts depending on PKP2 expression. Biochemical follow-up confirmed reduced abundance of sarcomeric protein myosin binding protein C, potentially playing a role in cellular shortening and relaxation changes observed. Our findings provide novel insights into the role of PKP2 in atrial myocardium with potential implications to therapeutic management of atrial fibrillation in patients with PKP2-related ARVC. KEY POINTS: Atrial arrhythmias occur in a large group of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a cardiac disease mostly caused by pathogenic variants in the desmosomal gene plakophilin-2 (PKP2). Exercise is considered to be an independent risk factor for arrhythmias consequent to PKP2 deficiency. Weshow that loss of PKP2 expression affects cellular calcium handling and electrophysiology differently in left atrial vs. ventricular myocardium and causes extensive atrial fibrosis. PKP2-deficient atrial cardiomyocytes present increased spontaneous sarcoplasmic reticulum calcium release events, furtherenhancedby isoproterenol exposure and reversiblebya ryanodine receptor blocker(dantrolene). In addition, PKP2-deficient atrial myocytes exhibit impaired relaxation and enhanced sarcomere shortening, most probably related to reduced abundance of myosin binding protein C. We speculate that cellular effects reported upon isoproterenol impact on the exercise-related atrial arrhythmia risk in ARVC patients. We further propose that therapeutic approaches aimed at mitigating ventricular damage may be effective to treat the atrial disease in ARVC.

Phthalate exposure induces cell death and ferroptosis in neonatal microglial cells.

Phthalates are the materials used for plasticizing polyvinyl chloride. Di-(2-Ethylhexyl) phthalate (DEHP) is one of the phthalates most frequently used in a wide range of applications, including medical equipment such as endotracheal and feeding tubes, intravenous catheters, central lines, extracorporeal membrane oxygenation sets, total parenteral nutrition bags, blood product sets, and intravenous pump lines, respiratory sets in neonatal intensive care units (NICUs). Studies have shown that phthalates, including DEHP, can cross the placenta and blood-brain barrier, possibly leading to neurodevelopmental impairment in vitro and in vivo. However, the molecular mechanisms affected by phthalate exposure have not been explored in depth. This study aimed to illuminate the effects of DEHP on neuroinflammation at the molecular level using neonatal microglial cells as the model. Mouse BV-2 neonatal microglia cells were exposed to DEHP under controlled conditions. Cellular toxicity was assessed via a cell viability assay and specific markers were used to evaluate the apoptosis/necrosis, cellular iron content, reactive oxygen species (ROS), and organelle integrity. Proinflammatory proteins were quantified using enzyme-linked immunosorbent assay, while ferroptosis was assessed using a ferroptosis blocker, and affected gene expressions were determined using quantitative reverse-transcriptase real-time polymerase chain reaction (RT-PCR). The results revealed that high concentrations of DEHP exposure increased toxicity via increased levels of ROS and inflammation. Elevated ROS levels were observed to increase the tendency for mitochondrial-lysosomal disruption, bringing about apoptosis or necrosis. Moreover, iron homeostasis was dysregulated by DEHP, which putatively triggered ferroptosis in a dose-dependent manner. This study indicates that neonatal exposure to DEHP may be linked to neurodevelopmental impairment via inflammation-related cell death and ferroptosis. The prevalence of DEHP in NICU medical devices raises concerns about potential neurodevelopmental deficits, including disorders like autism and mental retardation. These findings highlight the urgency of addressing DEHP exposure in neonatal care.

Borosilicate bioactive glass synergizing low-dose antibiotic loaded implants to combat bacteria through ATP disruption and oxidative stress to sequentially achieve osseointegration

Bone infection is a catastrophe in clinical orthopedics. Despite being the standard therapy for osteomyelitis, antibiotic-loaded polymethyl methacrylate (PMMA) cement has low efficiency against bacteria in biofilms. Furthermore, high-dose antibiotic-loaded implants carry risks of bacterial resistance, tissue toxicity, and impairment of local tissue healing. By incorporating borosilicate bioactive glass (BSG) into low-dose gentamicin sulfate (GS)-loaded PMMA cement, an intelligent strategy that synergistically eradicates bacteria and sequentially promotes osseointegration, was devised. Results showed that BSG did not compromises the handling properties of the cement, but actually endowed it with an ionic and alkaline microenvironment, thereby damaging the integrity of bacterial cell walls and membranes, inhibiting ATP synthesis by disrupting the respiratory chain in cell membranes and glycogen metabolism, and elevating reactive oxygen species (ROS) levels by weakening antioxidant components (peroxisomes and carotenoids). These antibacterial characteristics of BSG synergistically reinforced the effectiveness of GS, which was far below the actual clinical dosage, achieving efficient bacterial killing and biofilm clearance by binding to the 30S subunit of ribosomes. Furthermore, the released GS and the ionic and alkaline microenvironment from the implants fostered the osteogenic activity of hBMSCs in vitro and coordinately enhanced osseointegration in vivo. Collectively, this study underscores that BSG incorporation offers a promising strategy for reducing antibiotic dosage while simultaneously enhancing the antibacterial activity and osteogenesis of implants. This approach holds potential for resolving the conflict between bacterial resistance and bone infection.

Gaultheria procumbens essential oil longevity and oxidant/antioxidant status of silver catfish Rhamdia quelen experimentally infected by Aeromonas caviae

The increase in bacterial resistance in animals and the buildup of antimicrobials in animal meat pose significant nutritional and economic challenges. Given this context, this study explored the potential of Gaultheria procumbens essential oil (GPEO) as a sustainable alternative for aquaculture, focusing on its effects against Rhamdia quelen infected with Aeromonas caviae. Longevity tests revealed that R. quelen, when treated with 5 and 10 µL/L of GPEO, displayed significantly improved survival rates compared to both the untreated infected control group and those treated with ethanol. To understand the mechanisms behind the increased survival, a subsequent experiment with a 10 µL/L GPEO treatment aimed to investigate the oxidative stress pathway. This involved measuring levels of thiobarbituric acid reactive substances (TBARS) and reactive oxygen species (ROS), alongside enzyme activities for superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. Our findings showed elevated TBARS and ROS levels in the non-infected control group treated with GPEO, suggesting an increase in these enzymes as a response to ROS balance. Therefore, our data indicate that the mechanism leading to enhanced longevity in R. quelen infected and treated with GPEO does not involve the oxidative stress pathway.

Vitamin E supplementation prevents obesogenic diet-induced developmental abnormalities in SR-B1 deficient embryos.

Genetic and environmental factors influence the risk of neural tube defects (NTD), congenital malformations characterized by abnormal brain and spine formation. Mouse embryos deficient in Scavenger Receptor Class B Type 1 (SR-B1), which is involved in the bidirectional transfer of lipids between lipoproteins and cells, exhibit a high prevalence of exencephaly, preventable by maternal vitamin E supplementation. SR-B1 knock-out (KO) embryos are severely deficient in vitamin E and show elevated reactive oxygen species levels during neurulation. We fed SR-B1 heterozygous female mice a high-fat/high-sugar (HFHS) diet and evaluated the vitamin E and oxidative status in dams and embryos from heterozygous intercrosses. We also determined the incidence of NTD. HFHS-fed SR-B1 HET females exhibited altered glucose metabolism and excess circulating lipids, along with a higher incidence of embryos with developmental delay and NTD. Vitamin E supplementation partially mitigated HFHS-induced maternal metabolic abnormalities and completely prevented embryonic malformations, likely through indirect mechanisms involving the reduction of oxidative stress and improved lipid handling by the parietal yolk sac.

Mesoporous cerium oxide nanoenzyme for Efficacious impeding tumor and metastasis via Conferring resistance to anoikis

Tumor cells can survive when detached from the extracellular matrix or lose cell-to-cell connections, leading to a phenomenon known as anoikis resistance (AR). AR is closely associated with the metastasis and proliferation of tumor cells, enabling them to disseminate, migrate, and invade after detachment. Here, we have investigated a novel composite nanoenzyme comprising mesoporous silica/nano-cerium oxide (MSN-Ce@SP/PEG). This nanoenzyme exhibited satisfactory catalase (CAT) activity, efficiently converting high levels of H2O2 within tumor cells into O2, effectively alleviating tumor hypoxia. Furthermore, MSN-Ce@SP/PEG nanoenzyme demonstrated high peroxidase (POD) activity, elevating reactive oxygen species (ROS) levels and attenuating AR in hepatocellular carcinoma (HCC) cells. The MSN-Ce@SP/PEG nanoenzyme exhibited satisfactory dual bioactivity in CAT and POD and was significantly enhanced under favorable photothermal conditions. Through the synergistic effects of these capabilities, the nanoenzyme disrupted the epithelial-mesenchymal transition (EMT) process in detached HCC cells, ultimately inhibiting the recurrence and metastasis potential of anoikis-resistant HCC cells. This study represents the first report of a novel nanoenzyme based on mesoporous silica/nano-cerium oxide for treating AR in HCC cells, thereby suppressing HCC recurrence and metastasis. The findings of this work offer a pioneering perspective for the development of innovative strategies to prevent the recurrence and metastasis of HCC.

IL-11-Engineered Macrophage Membrane-Coated Reactive Oxygen Species-Responsive Nanoparticles for Targeted Delivery of Doxorubicin to Osteosarcoma.

Osteosarcoma (OS) is a lethal malignant orthotopic bone tumor that primarily affects children and adolescents. Biomimetic nanocarriers have attracted wide attention as a new strategy for delivering chemotherapy agents to the OS. However, challenges such as rapid clearance and limited targeting hinder the effectiveness of OS chemotherapy. In this study, we designed reactive oxygen species (ROS)-responsive nanoparticles (NPs) coated with an interleukin (IL)11-engineered macrophage membrane (MM). The camouflage by MMs prevents clearance of IL-11-engineered MM-coated NPs loaded with doxorubicin (IL-11/MM@NPs/Dox) by the immune system. Moreover, the macrophage membrane combined with surface-expressed IL-11 not only directed IL-11/MM@NPs/Dox to OS tissues but also selectively identified IL-11 receptor alpha (IL-11Rα)-enriched OS cells. Within these cells, elevated levels of ROS triggered the controlled release of Dox from the ROS-responsive NPs. The synergistic modification of targeted ligand conjugation and cell membrane coating on the ROS-responsive NPs enhanced drug availability and reduced toxic side effects, thereby boosting the efficacy of OS chemotherapy. In summary, our findings suggest that IL-11/MM@NPs/Dox represents a promising approach to improving OS chemotherapy efficacy while ensuring excellent biocompatibility.

53BP1 regulates the self-renewal ability of neural stem/progenitor cells through modulating mitochondrial homeostasis

The regulation of intracellular reactive oxygen species (ROS) levels is important for maintaining the self-renewal ability of neural stem/progenitor cells (NSCs). In this study, we demonstrate that 53BP1, a DNA damage response factor known to facilitate the repair of DNA double-strand breaks, supports the maintenance of NSC stemness. ReNcell VM human NSCs with depleted 53BP1 exhibited reduced self-renewal ability compared with control NSCs, as revealed by a decrease in neurosphere size and an increase in differentiation into neural or glial cells within an NSC culture. Furthermore, 53BP1 depletion elevated cellular ROS levels, accompanied by mitochondrial abnormalities. The reduced self-renewal ability and elevated ROS levels in 53BP1-deficient NSCs were restored with the treatment of a radical scavenger, N-acetyl-l-cysteine. In addition, we investigated the functional relationship in the NSC self-renewal ability between 53BP1 and ataxia-telangiectasia mutated (ATM) or forkhead box O3a (FOXO3a), factors required for mitochondrial homeostasis, and the maintenance of NSC stemness. We found that ATM inhibition or FOXO3a deficiency, in addition to 53BP1 deficiency, did not induce further NSC stemness impairment. Collectively, our findings show that 53BP1, by cooperatively functioning with ATM and FOXO3a, supports the maintenance of NSC stemness by modulating mitochondrial homeostasis.

The effect of norepinephrine on ovarian dysfunction by mediating ferroptosis in mice model.

Studies have shown that stress is associated with ovarian dysfunction. Norepinephrine (NE), a classic stress hormone involved in the stress response, is less recognized for its role in ovarian function. In this study, an NE-treated mouse model is induced by intraperitoneal injection of NE for 4 weeks. Compared with normal control mice, NE-treated mice show disturbances in the estrous cycle, decreased levels of anti-Mullerian hormone (AMH) and estradiol (E2), and increased level of follicle-stimulating hormone (FSH). Additionally, the numbers of primordial follicles, primary follicles, secondary follicles, and antral follicles are decreased, whereas the number of atretic follicles is increased in NE-treated mice, indicating NE-induced ovarian dysfunction. RNA sequencing further reveals that genes associated with ferroptosis are significantly enriched in NE-treated ovarian tissues. Concurrently, the levels of reactive oxygen species (ROS), ferrous ions, and malondialdehyde (MDA) are increased, whereas the expression level of glutathione peroxidase 4 (GPX4) is decreased. To elucidate the mechanism of NE-induced ferroptosis in ovaries and the potential reversal by Coenzyme Q10 (CoQ10), an antioxidant, we conduct both in vitro and in vivo experiments. In vitro, the granulosa cell line KGN, when treated with NE, shows decreased cell viability, reduced expression of GPX4, elevated levels of ferrous ion and ROS, and increased MDA level. However, these NE-induced changes are reversed by the addition of CoQ10. Compared with the NE group, the NE-treated mice supplemented with CoQ10 present increased GPX4 level and decreased iron, ROS, and MDA levels. Moreover, the differential expression of genes associated with ferroptosis induced by NE is ameliorated by CoQ10 in NE-treated mice. Additionally, CoQ10 improves ovarian function, as evidenced by increased ovarian weight, more regular estrous cycles, and an increase in follicles at various stages of growth in NE-treated mice. In conclusion, NE induces ovarian dysfunction by triggering ferroptosis in ovarian tissues, and CoQ10 represents a promising approach for protecting reproductive function by inhibiting ferroptosis.

Nrf2 Activation in Keratinocytes: A Central Role in Diabetes-Associated Wound Healing.

Wound healing is a complex biological process crucial for tissue repair, wherein keratinocytes play a pivotal role in initiating, sustaining and completing the cascade. Various local and systemic factors, such as lifestyle, age metabolic disorders and vascular insufficiency, can influence this process, and in the context of diabetic wounds, disrupted biological mechanisms, including inflammation, tissue hypoxia, decrease in collagen production along with increased oxidative stress and keratinocyte dysfunction, contribute to delayed healing. During re-epithelialisation, keratinocytes undergo rapid multiplication and migration, forming a dense hyperproliferative epithelial layer that restores the epidermal barrier. Nuclear factor-erythroid 2-related factor (Nrf2), a vital transcription factor, emerges as a central regulator in managing antioxidant proteins and detoxifying enzymes, serving as a guardian against elevated reactive oxygen species (ROS) levels during stress. Nrf2 also orchestrates angiogenesis and anti-inflammatory responses crucial for wound repair. Studies demonstrate that under high-glucose conditions, Nrf2 activation promotes wound healing by enhancing cell proliferation and migration while reducing apoptosis. Nrf2 activators stimulate endogenous antioxidant production, thereby mitigating oxidative stress. Furthermore, Nrf2 upregulation is associated with decreased expression of cytokines such as TNF-α and IL- 6. Recent research underscores the potential of bioactive molecules, including dietary polyphenols, traditional medicinal compounds and pharmacological agents, in activating Nrf2 and preventing diseases such as diabetes due to their robust antioxidative properties. This review aims to investigate the activation of Nrf2 by these bioactive molecules in cultured keratinocytes and animal models, elucidating the key molecular regulatory mechanisms involved in alleviating oxidative stress and facilitating the diabetic wound healing process. Understanding these complex pathways may offer insights into novel therapeutic strategies for enhanced wound healing in diabetes-associated complications.

Impact of Diabetic Condition on the Remodeling of In Situ Tissue-Engineered Heart Valves.

Most in situ tissue-engineered heart valve (TEHV) evaluation studies are conducted in a healthy physical environment, which cannot accurately reflect the specific characteristics of patients. In this study, we established a diabetic rabbit model and implanted decellularized extracellular matrix (dECM) into the abdominal aorta of rabbits through interventional surgery with a follow-up period of 8 weeks. The results indicated that dECM implants in diabetic rabbits exhibited poorer endothelialization and more severe fibrosis compared to those in healthy animals. Furthermore, mechanistic studies revealed that high glucose induced endothelial cell (EC) apoptosis and impeded their proliferation and migration, accompanied by an increase in reactive oxygen species (ROS) concentration and a decrease in the nitric oxide (NO) level. High glucose also led to elevated ROS levels and an increased expression of inflammatory factors and transforming growth factor β1 (TGF-β1) in macrophages, contributing to fibrosis. These findings suggest that oxidative-stress-mediated mechanisms are likely the primary pathways affecting heart valve repair and regeneration under diabetic conditions. Therefore, future design and evaluation of TEHVs may concern more patient-specific circumstances.

Hepatitis B Virus X Protein Induces Reactive Oxygen Species Generation via Activation of p53 in Human Hepatoma Cells.

Hepatitis B virus (HBV), particularly through the HBx protein, induces oxidative stress during liver infections. This study reveals that HBx increases reactive oxygen species (ROS) via two distinct mechanisms. The first mechanism is p53-independent, likely involving mitochondrial dysfunction, as demonstrated by elevated ROS levels in p53-deficient Hep3B cells and p53-knocked-down HepG2 cells after HBx expression or HBV infection. The increase in ROS persisted even when p53 transcriptional activity was inhibited by pifithrin-α (PFT-α), a p53 inhibitor. The second mechanism is p53-dependent, wherein HBx activates p53, which then amplifies ROS production through a feedback loop involving ROS and p53. The ability of HBx to elevate ROS levels was higher in HepG2 than in Hep3B cells. Knocking down p53 in HepG2 cells lowered ROS levels, while ectopic p53 expression in Hep3B cells raised ROS. HBx-activated p53 downregulated catalase and upregulated manganese-dependent superoxide dismutase, contributing to ROS amplification. The transcriptional activity of p53 was crucial for these effects, as cells with a p53 R175H mutation or those treated with PFT-α generated less ROS. Additionally, HBx variants with Ser-101 increased p53 and ROS levels, whereas variants with Pro-101 did not. These dual mechanisms of HBx-induced ROS generation are likely significant in the pathogenesis of HBV and may contribute to liver diseases, including hepatocellular carcinoma.