Accumulation Of Reactive Oxygen Species Research Articles

The wheat CC-NBS-LRR protein TaRGA3 confers resistance to stripe rust by suppressing Ascorbate peroxidase 6 activity

Abstract Nucleotide-binding leucine-rich repeat (NLR) proteins are intracellular immune receptors that activate innate immune responses upon sensing pathogen attack. However, the molecular mechanisms by which NLR proteins initiate downstream signal transduction pathways to counteract pathogen invasion remain poorly understood. In this study, we identified the wheat (Triticum aestivum) NLR protein Resistance Gene Analogs3 (TaRGA3), which was significantly up-regulated during Puccinia striiformis f. sp. tritici (Pst) infection. TaRGA3 and its coiled-coil (CC) domain, localized to the cytoplasm and nucleus, can induce cell death in Nicotiana benthamiana. Virus-induced gene silencing (VIGS) and overexpression suggested that TaRGA3 contributed to wheat resistance to stripe rust by facilitating reactive oxygen species (ROS) accumulation. Yeast two-hybrid, luciferase complementation imaging, and co-immunoprecipitation assays revealed that TaRGA3 interacted with wheat protein Ascorbate Peroxidase 6 (TaAPX6). Further analysis showed that TaAPX6 specifically targeted the CC domain of TaRGA3. The TaRGA3-TaAPX6 interplay led to reduced enzyme activity of TaAPX6. Notably, TaAPX6 negatively regulated wheat resistance to Pst by removing excessive ROS accompanying Pst-induced hypersensitive responses. Our findings reveal that TaRGA3 responding to Pst infection confers enhanced wheat resistance to stripe rust, possibly by suppressing TaAPX6-modulated ROS scavenging, and demonstrate that TaRGA3 can be used to engineer stripe rust resistance in wheat.

Vitamin C ameliorates D-galactose-induced senescence in HEI-OC1 cells by inhibiting the ROS/NF-κB pathway.

Cochlear hair cell senescence is one of the major causes of age-related hearing loss (ARHL) and is significantly related to reactive oxygen species (ROS) accumulation. Research shows that vitamin C (VC) can inhibit ROS accumulation; however, its association with cochlear hair cell senescence remains elusive. Firstly, a cellular senescence model was established using D-galactose (D-gal) induced HEI-OC1 cells for 24 h. Senescent HEI-OC1 cells were then continued to be treated with the addition of VC or ROS inhibitor (N-acetylcysteine; NAC) for another 24 h, and explored the impact of VC on senescent cochlear hair cell and the potential regulatory mechanisms. The results indicated that D-gal-induced senescent HEI-OC1 cells, manifested as decreased cell viability, increased β-galactosidase activity and p21 protein level, and ROS and pro-inflammatory factors were upregulated, and NF-κB p65 phosphorylation was enhanced. However, the use of VC or NAC can significantly ameliorate these effects and improve HEI-OC1 cell senescence. This research indicates that VC can ameliorate D-gal-induced senescence of HEI-OC1 cochlear hair cells, and its protective effect may be related to the inhibition of the ROS/NF-κB pathway, which provides a new research direction for the prevention and treatment of ARHL.

Amantadine against glioma via ROS-mediated apoptosis and autophagy arrest.

Glioma is a common primary nervous system malignant tumor with poor overall cure rate and low survival rate, yet successful treatment still remains a challenge. Here, we demonstrated that amantadine (AMT) exhibits the powerful anti-glioma effect by promoting apoptosis and autophagy in vivo and in vitro. Mechanistically, amantadine induces a large amount of reactive oxygen species (ROS) accumulation in glioma cells, and then triggers apoptosis by destroying mitochondria. In addition, amantadine induces the initiation of autophagy and inhibits the fusion of autophagosome and lysosome, consequently performing an anti-glioma role. Taken together, our findings suggest that amantadine could be a promising anti-glioma drug that inhibits glioma cells by inducing apoptosis and autophagy, which may provide a novel potential treatment option for patients.

Class III peroxidase: An essential enzyme for enhancing plant physiological and developmental process by maintaining the ROS level: A review.

Since plants are sessile organisms, they are inevitably exposed to various environmental stresses, and the accumulation of reactive oxygen species (ROS) could affect the growth and development of plants. ROS play either positive or negative roles in various plant life activities as a two-edge sword. Class III peroxidase (CIII PRX) is a highly conserved antioxidant enzyme family specifically identified in plants, which is involved in maintaining ROS homeostasis in the cell and plays multiple functions in plant growth metabolism and stress response. In this review, the classification and structure of CIII PRXs are represented, and the roles of CIII PRXs in physiological and developmental processes such as plant growth, cell wall modification, loosening and stiffening, and lignin biosynthesis are described in detail. The molecular mechanisms of CIII PRXs in response to abiotic stress such as salt and drought, and biological stress such as pathogens invasion are introduced, with emphasis on the research results of PRX related genes in signal transduction. Furthermore, we summarize the difficulty in exploring the function of individual CIII PRX gene due to functional redundancy and promising technique that may break this research bottleneck.

Mutation of rice EARLY LEAF LESION AND SENESCENCE 1(ELS1), which encodes an anthranilate synthase α-subunit, induces ROS accumulation and cell death through activating the tryptophan synthesis pathway in rice.

Lesion-mimic mutants (LMMs) serve as valuable resources for uncovering the molecular mechanisms that govern programmed cell death (PCD) in plants. Despite extensive research, the regulatory mechanisms of PCD and lesion formation in various LMMs remain to be fully elucidated. In this study, we identified a rice LMM named early leaf lesion and senescence 1 (els1), cloned the causal gene through map-based cloning, and confirmed its function through complementation. ELS1 encodes an anthranilate synthase α-subunit involved in anthranilate biosynthesis. It is predominantly localized in chloroplasts and is primarily expressed in light-exposed tissues. Mutation of ELS1 triggers upregulation of its homologous gene, ASA1, via a genetic compensation response, leading to the activation of the tryptophan (Trp) synthesis pathway and amino acid metabolism. The accumulation of abnormal Trp-derived intermediate metabolites results in reactive oxygen species (ROS) production and abnormal PCD in the els1 mutant, ultimately causing the leaf lesion phenotype. The els1 mutant also exhibits reduced chlorophyll content, upregulation of genes related to chloroplast degradation and leaf senescence, and decreased activity of photosynthetic proteins, indicating that ELS1 plays a role in chloroplast development. These factors collectively contribute to the premature leaf senescence observed in the els1 mutant. Our findings shed light on the role of ELS1 in regulating ROS accumulation and PCD in rice, providing further genetic insights into the molecular mechanisms governing leaf lesions and senescence.

Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline.

Multidrug-resistant tuberculosis (MDR-TB), defined as resistance to the first-line drugs isoniazid and rifampin, is a growing source of global mortality and threatens global control of tuberculosis disease. The diarylquinoline bedaquiline has recently emerged as a highly efficacious drug against MDR-TB and kills Mycobacterium tuberculosis by inhibiting mycobacterialATP synthase. However, themechanisms underlying bedaquiline's efficacy against MDR-TB remain unknown. Here we investigate bedaquiline hyper-susceptibility in drug-resistant Mycobacterium tuberculosis using systems biology approaches. We discovered that MDR clinical isolates are commonly sensitized to bedaquiline. This hypersensitization is caused by several physiological changes induced by deficient catalase activity. These include enhanced accumulation of reactive oxygen species, increased susceptibility to DNA damage, induction of sensitizing transcriptional programs, and metabolic repression of several biosynthetic pathways. In this work we demonstrate how resistance-associated changes in bacterial physiology can mechanisticallyinduce collateral antimicrobial drug sensitivity and reveal druggable vulnerabilities in antimicrobial resistant pathogens.

Tanshinone IIA alleviates inflammation-induced skeletal muscle atrophy by regulating mitochondrial dysfunction.

Skeletal muscle atrophy, characterized by loss of muscle mass and function, is often linked to systemic inflammation. Tanshinone IIA (Tan IIA), a major active constituent of Salvia miltiorrhiza, has anti-inflammatory and antioxidant properties. However, the effect of Tan IIA on inflammation-induced skeletal muscle atrophy remains unclear. Here, a mice model of the inflammatory muscle atrophy was established using lipopolysaccharide (LPS). Tan IIA intervention significantly increased muscle mass and strength, improved muscle fiber size, and maintained the integrity of skeletal muscle mitochondrial morphology in LPS-treated mice. Myotubes derived from myosatellite cells (MUSCs) were exposed to LPS in vitro. Tan IIA treatment inhibited LPS-induced muscle protein degradation and increased myotube diameter. Notably, Tan IIA attenuated LPS-induced inflammatory response and hyperactive mitophagy both in vivo and in vitro. In addition, Tan IIA treatment effectively diminished oxidative stress, inhibited the accumulation of mitochondrial reactive oxygen species (mtROS), and attenuated mitochondrial fission in LPS-treated myotubes. Reducing mtROS production helped to inhibit LPS-induced excessive mitophagy and myotubes atrophy. Together, our results reveal that Tan IIA can protect against inflammation-induced skeletal muscle atrophy by regulating mitochondrial dysfunction, presenting innovative potential therapeutics for skeletal muscle atrophy.

Acid Sphingomyelinase Activation and ROS Generation Potentiate: Antiproliferative Effects of Mitomycin in HCC

Sphingolipids play a major role in the regulation of hepatocellular apoptosis and proliferation. We have previously identified sphingolipid metabolites as biomarkers of chronic liver disease and hepatocellular carcinoma. Human hepatocellular carcinoma cell lines were transfected with a plasmid vector encoding for acid sphingomyelinase. Overexpressing cells were subsequently treated with mitomycin and cell proliferation, acid sphingomyelinase activity, sphingolipid concentrations, and generation of reactive oxygen species were assessed. The stimulation of acid sphingomyelinase-overexpressing cell lines with mitomycin showed a significant activation of the enzyme (p < 0.001) followed by an accumulation of various ceramide species (p < 0.001) and reactive oxygen radicals (p < 0.001) as compared to control transfected cells. Consequently, a significant reduction in cell proliferation was observed in acid sphingomyelinase-overexpressing cells (p < 0.05) which could be diminished by the simultaneous application of antioxidant agents. Moreover, the application of mitomycin induced significant alterations in mRNA expression levels of ceramidases and sphingosine kinases (p < 0.05). Our data suggest that the overexpression of the acid sphingomyelinase in human hepatoma cell lines enhances the in vitro antiproliferative potential of mitomycin via accumulation of ceramide and reactive oxygen species. The selective activation of acid sphingomyelinase might offer a novel therapeutic approach in the treatment of hepatocellular carcinoma.

Revealing mitochondrial microenvironmental changes triggered by ferroptosis regulation.

Ferroptosis is a unique form of iron-dependent cell death characterized by dramatic ultrastructural changes in mitochondria. Since mitochondria are intracellular energy factories and binding sites for producing reactive oxygen species, there is increasing evidence that mitochondria are closely related to ferroptosis and play a crucial role in the regulation and execution of ferroptosis. The pH of the mitochondrial microenvironment is an important parameter for cellular physiological activities. Its abnormal fluctuations are commonly thought to be associated with cancers and other diseases. Herein, a surface-enhanced Raman scattering (SERS)-based pH nanosensor with high sensitivity and targeting function was utilized to quantify and monitor mitochondrial pH value. This nanosensor was constructed by gold nanorods (AuNRs) functionalized with pH-responsive molecules (4-mercaptopyridine, MPy) and mitochondrion-targeting peptides (AMMT) that can precisely deliver AuNRs to mitochondria. Super-resolution fluorescence imaging was employed to evidence the mitochondrial targeting feature of this nanosensor. Ferroptosis regulation induces intracellular accumulation of lipid peroxide (LPO) and reactive oxygen species (ROS), which cause changes in the mitochondrial pH. This method reveals that ferroptosis leads to the gradual acidification of the mitochondrial internal environment. The conclusion deduced by this study will be helpful for the evaluation and diagnosis of diseases according to intracellular abnormal microenvironments.

Inhibition of CISD2 enhances sensitivity to doxorubicin in diffuse large B-cell lymphoma by regulating ferroptosis and ferritinophagy

BackgroundCDGSH iron-sulfur domain 2 (CISD2), an iron-sulfur protein with a [2Fe-2S] cluster, plays a pivotal role in the progression of various cancers, including Diffuse Large B-cell Lymphoma (DLBCL). However, the mechanisms by which CISD2 regulates the occurrence and development of DLBCL remain to be fully elucidated.MethodsThe potential role of CISD2 as a predictive marker in DLBCL patients treated with the R-CHOP regimen was investigated through bioinformatics analysis and clinical cohort studies. DLBCL cell lines (SUDHL-4 and HBL-1) were employed in this research. Adenoviral (AV) plasmids were used to either silence or overexpress CISD2 in these DLBCL cell lines. Additionally, the induction of ferroptosis in DLBCL cell lines was assessed. Various parameters, including cell proliferation, intracellular free iron levels, lipid peroxides, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP), were measured. Furthermore, the expression of proteins associated with ferroptosis and ferritinophagy was analyzed. Drug-resistant DLBCL cell lines were developed by gradually increasing doxorubicin (DOX) concentration over 6 months. The biological role of CISD2 in these drug-resistant DLBCL cell lines was subsequently assessed.ResultsElevated CISD2 levels were found to be associated with decreased sensitivity of DLBCL patients to the R-CHOP regimen, as indicated by bioinformatics and clinical cohort analysis. Silencing CISD2 significantly reduced cell proliferation, increased iron accumulation, depleted glutathione (GSH), and elevated malondialdehyde (MDA) levels, alongside the accumulation of ROS and increased MMP. Additionally, BECN1 and NCOA4 expressions were upregulated, while p62, FTH1, and GPX4 expressions were downregulated. Conversely, overexpression of CISD2 reversed these effects. Treatment of DLBCL cell lines with Erastin led to decreased CISD2 levels. Notably, in drug-resistant DLBCL cell lines, CISD2 knockdown promoted ferroptosis and ferritinophagy, restoring sensitivity to DOX and enhancing the efficacy of Erastin treatment.ConclusionOur findings suggest that CISD2 may play a role in the drug resistance observed in DLBCL patients. Inhibition of CISD2 could enhance ferroptosis and ferritinophagy, potentially improving the sensitivity of DLBCL cells to DOX treatment.

E'jiao and Cubilose Formula Induced Antioxidant Activity and Improved Collagen Expression of Human Skin Fibroblasts During Oxidation Damage.

As traditional Chinese medicinal materials, E'jiao and cubilose are rich in various bioactive substances with good antioxidant, anti-inflammatory, and immune-regulating effects. To obtain the optimal ratio of synergistic effect between E'jiao and cubilose. The antioxidant capacity of E'jiao and cubilose digestive fluid was evaluated invitro, as well as the intracellular oxidation balance between HSF cells and 3D whole-skin model induced by H2O2. E'jiao, cubilose, and their different ratios of composites had better scavenging ability against free radicals such as DPPH (2,2-Diphenyl-1-picrylhydrazyl). Using HSF cells induced by H2O2 as an oxidative damage model, it was found that the combination of E'jiao and cubilose in a ratio of 2:3 significantly enhanced the activities of SOD, GSH-PX, and CAT enzymes compared to the separate treatments of E'jiao and cubilose, as well as other combination ratios. It effectively reduced the accumulation of reactive oxygen species caused by H2O2 in HSF (Human Skin Fibroblast)cells and protected the integrity of the cells. Further analysis using flow cytometry and a 3D full-thickness skin model revealed that the combination ratio of 2:3 increased the proportion of H2O2-treated cells in the S%+G2% phase from 19.1% + 7.4%-22.1% + 28.8%, helping oxidatively damaged cells partially recover their proliferative capacity. It also promoted the expression of collagen I and collagen IV in the 3D full-thickness skin model, with improvement rates reaching 168.00% and 123.68%, respectively. These findings indicate that the combination of E'jiao and cubilose in a ratio of 2:3 exhibits good synergistic effects, enhancing the ability of cells to resist oxidative damage, promoting cellular renewal and metabolism, and improving skin antiwrinkle capacity.

A mechanistic integration of hypoxia signaling with energy, redox and hormonal cues.

Oxygen deficiency (hypoxia) occurs naturally in many developing plant tissues but can become a major threat during acute flooding stress. Consequently, plants as aerobic organisms must rapidly acclimate to hypoxia and the associated energy crisis to ensure cellular and ultimately organismal survival. In plants, oxygen sensing is tightly linked with oxygen-controlled protein stability of group VII ETHYLENE-RESPONSE FACTORs (ERFVII) which, when stabilized under hypoxia, act as key transcriptional regulators of hypoxia-responsive genes (HRGs). Multiple signaling pathways feed into hypoxia signaling to fine-tune cellular decision making under stress. First, ATP shortage upon hypoxia directly affects the energy status and adjusts anaerobic metabolism. Secondly, altered redox homeostasis leads to reactive oxygen and nitrogen species (ROS and RNS) accumulation, evoking signaling and oxidative stress acclimation. Finally, the phytohormone ethylene promotes hypoxia signaling to improve acute stress acclimation, while hypoxia signaling in turn can alter ethylene, auxin, abscisic acid, salicylic acid and jasmonate signaling to guide development and stress responses. In this Update, we summarize the current knowledge on how energy, redox and hormone signaling pathways are induced under hypoxia and subsequently integrated at the molecular level to ensure stress-tailored cellular responses. We show that some HRGs are responsive to changes in redox, energy and ethylene independently of the oxygen status, and propose an updated HRG list that is more representative for hypoxia marker gene expression. We discuss the synergistic effects of hypoxia, energy, redox and hormone signaling and their phenotypic consequences in the context of both environmental and developmental hypoxia.

CSIG-14. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS THROUGH THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION

Abstract Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.

TMET-22. OVERCOMING RESISTANCE: PANOBINOSTAT SENSITIZES 2DG-RESISTANT PEDIATRIC HIGH-GRADE GLIOMAS WITH H3.3 K27M/G34R MUTATIONS TO APOPTOSIS

Abstract BACKGROUND Pediatric high-grade gliomas (pHGG) harboring H3.3 K27M/G34R mutations present formidable challenges in treatment due to their aggressiveness and resistance to standard chemotherapy. Our preliminary investigations have shown promising results, indicating that combining 2-deoxyglucose (2DG), a glycolytic inhibitor, with DNA-damaging agents synergistically inhibits pHGG growth. However, prolonged exposure to 2DG induces resistance, necessitating the exploration of alternative therapies. This study aims to investigate the potential of panobinostat, a histone deacetylase inhibitor, in sensitizing 2DG-resistant pHGG with H3.3 K27M/G34R mutations to apoptosis. METHODS Transcriptomic analysis via Illumina NovaSeq 6000 and metabolomic profiling employing Liquid Chromatography-High-Resolution Mass Spectrometry was used to delineate the molecular landscape of naive and 2DG-resistant pHGG cell lines. Functional assays, including the Agilent Seahorse Mito Stress Test and flow cytometry, assessed bioenergetics and mitochondrial dynamics. Intracellular NAD+ and NADH levels were quantified utilizing NAD+/NADH Glo assays, while apoptotic markers and metabolic stress were measured using the Annexin V-FITC Conjugates for Apoptosis Detection kit and western blot. RESULTS Comparative analysis revealed increased transketolase activity in 2DG-resistant cells, augmenting the interaction between the pentose phosphate pathway and glycolysis, resulting in elevated levels of NADPH and ATP. Additionally, these resistant cells displayed enhanced reliance on mitochondrial energy metabolism, as evidenced by substantial increases in mitochondrial membrane potential and mass, coupled with elevated NAD+ levels. Subsequent treatment with panobinostat induced a significant decrease in NAD+ biosynthesis and ATP generation. Furthermore, this intervention triggered the upregulation of pro-apoptotic BCL-2 family proteins, particularly BAX and BAK, concomitant with a notable reduction in mitochondrial membrane potential and the accumulation of reactive oxygen species. Consequently, heightened caspase-3 activity ensued, leading to significantly elevated cell death rates in 2DG-resistant gliomas. CONCLUSION Our findings highlight panobinostat as a promising therapy to resensitize 2DG-resistant pHGG cells to apoptosis, offering hope for treating these aggressive tumors with H3.3 K27M/G34R mutations.

CSIG-15. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS VIA THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION

Abstract Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.

The histone deacetylase RhHDA15 represses petal senescence by epigenetically regulating reactive oxygen species homeostasis in rose.

Epigenetic modifications play vital roles in many biological processes. Flower senescence involves epigenetic factors that influence the chromatin state and gene expression. However, the molecular mechanism underlying the role of histone deacetylation in regulating flower senescence has not been elucidated. Here, we demonstrate that histone deacetylation is involved in flower senescence by fine-tuning reactive oxygen species (ROS) homeostasis in rose (Rosa hybrida). Our data reveal that the histone lysine deacetyltransferase RhHDA15 inhibits ROS accumulation and petal senescence by downregulating the expression of NADPH OXIDASE/RESPIRATORY BURST OXIDASE HOMOLOG (RhRboh) genes. Furthermore, the transcription factor RELATED TO ABI3/VP1 2 (RhRAV2) recruits RhHDA15 and the co-repressor TOPLESS (RhTPL) to suppress flower senescence by reducing H3 lysine 9 acetylation (H3K9ac) at the RhRbohA1/2 promoter and thus directly inhibiting precocious RhRbohA1/2 expression. Our work sheds light on an epigenetic mechanism in which histone deacetylation plays a crucial role in controlling petal senescence by precisely fine-tuning ROS homeostasis, providing insights into the regulatory network of organ senescence.

Research progress of ferroptosis in brain injury

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, has emerged as a key contributor to neuronal damage in various types of brain injury, including traumatic brain injury (TBI) and ischemic brain injury caused by brian ischemia (BI). This review summarizes the underlying mechanisms of ferroptosis in brain injuries and highlights its role in exacerbating neuronal loss, inflammation, and secondary damage. After TBI, the release of free iron and oxidative stress after injury triggers ferroptosis, contributing to long-term neurological deficits. Similarly, in BI, ferroptosis is initiated by the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction during ischemia and reperfusion, further amplifying neuronal damage. The current review provides a comprehensive overview of the interplay between ferroptosis and brain injury, with an emphasis on the potential of targeting ferroptosis to improve recovery outcomes in patients. Future research directions include the development of novel ferroptosis inhibitors and the integration of ferroptosis-targeting strategies with existing treatment modalities.

Processes independent of nonphotochemical quenching protect a high-light-tolerant desert alga from oxidative stress.

Non-photochemical quenching (NPQ) mechanisms are crucial for protecting photosynthesis from photoinhibition in plants, algae, and cyanobacteria, and their modulation is a long-standing goal for improving photosynthesis and crop yields. The current work demonstrates that Chlorella ohadii, a green micro-alga that thrives in the desert under high light intensities that are fatal to many photosynthetic organisms does not perform nor require NPQ to protect photosynthesis under constant high light. Instead of dissipating excess energy, it minimizes its uptake by eliminating the photosynthetic antenna of photosystem II. In addition, it accumulates antioxidants that neutralize harmful reactive oxygen species (ROS) and increases cyclic electron flow around PSI. These NPQ-independent responses proved efficient in preventing ROS accumulation and reducing oxidative damage to proteins in high-light-grown cells.

Evaluation of antioxidant activity of 1,2,4-triazole derivatives in the initiation of free radical processes

The activation of lipid free radical oxidation is a key stage in the development of many diseases and can lead to the emergence of related complications. To identify new synthetic compounds with antioxidant properties, it is necessary to conduct studies on various models of experimental free radical oxidation of biomolecules. Literature sources indicate that among the derivatives of 1,2,4-triazole, there is a significant number that possess high antioxidant activity. The aim of the study to assess the antioxidant properties of newly synthesized S-derivatives of 1,2,4-triazole through the inhibition of reactive oxygen species accumulation in the superoxide dismutase system. Materials and methods. To achieve this goal, we used one of the methods for assessing antioxidant activity by initiating free radical processes in vitro, specifically by inhibiting the accumulation of reactive oxygen species. Results. Twenty-three S-derivatives of 5-(thiophene-3-ylmethyl)-4-R-1,2,4-triazole-3-thiols were investigated. The most effective compound was sodium 2-((4-phenyl-5-thiophene-3-ylmethyl)-1,2,4-triazole-3-yl)thio)acetate, which exceeded the activity of both reference drugs. Following in activity was compound 22, 1-phenyl-2-((4-phenyl-5-(thiophene-3-ylmethyl)-4H-1,2,4-triazole-3-yl)thio)ethanol, which demonstrated an effect similar to that of emoxipine, while compound 7, 1-(3-fluorophenyl)-2-((5-thiophene-3-ylmethyl)-4H-1,2,4-triazole-3-yl)thio)ethanone, was slightly less active. Conclusions. It was established that among the new S-derivatives of 1,2,4-triazole, some exhibit significant antioxidant effects that are comparable to or exceed the efficacy of reference drugs.

Deficiency of muscle-generated brain-derived neurotrophic factor causes inflammatory myopathy through reactive oxygen species-mediated necroptosis and pyroptosis

Idiopathic inflammatory myopathy (commonly known as myositis) is a group of immune-related diseases characterized by muscle damage, weakness, and fatigue with unknown causes. Although overactivated innate immunity is a widely believed cause of myositis onset, the mechanism that provokes and maintains a high immune response in myositis patients is still unclear. This study aims to test if brain-derived neurotrophic factor (BDNF) deficiency per se is sufficient to cause myositis and determine its underlying mechanism. We found that ablating BDNF production in skeletal muscle is sufficient to trigger myositis development in mice. Muscle-specific Bdnf knockout (MBKO) mice displayed extensive myocyte necrosis, mononuclear cell infiltration, and myophagocytosis. In association with these damages, elevated production of pro-inflammatory cytokines such as interleukin (IL) 23, IL-1β, IL-18, and tumor necrosis factor α (TNFα) was found in the muscle of MBKO mice. Disruption of sarcolemma integrity was also detected in MBKO mice, which is a result of necroptosis executioner Mixed lineage kinase domain-like protein (MLKL) and pyroptosis executioner Gasdermin D (GSDMD) activation. Mechanistically, diminishing BDNF synthesis in myotubes enhances the accumulation of mitochondrial reactive oxygen species (mtROS), which sensitizes the cells towards TNFα-induced receptor-interacting protein kinase (RIPs) activation and promotes the formation of NLR family pyrin domain containing 3 (NLRP3)-containing inflammasome. BDNF deficiency-induced cell death could be alleviated by scavenging mtROS, suppressing the activity of GSDMD, or inhibiting receptor-interacting kinase 3 (RIP3). Similarly, supplementation of BDNF mimetics, suppression of RIP3 activity, increasing the intramyocellular antioxidant, or enhancing mitophagy ameliorated the myopathies of MBKO mice and improved their muscle strength. Together, our study demonstrates that insufficient BDNF production in mouse muscle causes the development of pathological features of myositis via enhancing oxidative stress, necroptosis, and pyroptosis in myofibers.