Reactive Oxygen Species Pathway Research Articles

AMn2O4 (A = Ni, Co, Cu) oxygen carrier chemical looping reforming of benzene: Migration pathways of reactive oxygen species by experimental and DFT investigations

Chemical looping reforming (CLR) provides a novel solution for clean and efficient utilization of biomass tar. The versatility of oxygen carrier (OC) is essential for improving reforming efficiency. The properties of Mn-based spinel OCs (AMn2O4, A = Ni, Co, Cu) were investigated in the CLR process using benzene as a tar model compound. Detailed characterization and experimental results demonstrate the excellent structural stability of Mn-based spinel. The NiMn2O4 showed the most prominent reforming effect on benzene with the highest conversion of 95.77 % at 850 °C, S/C = 1.0, and WHSV = 3.0 h−1. After 40 cycles, NiMn2O4 and CoMn2O4 maintained significant catalytic activity for benzene reforming, achieving conversions of 92.96 % and 90.07 %, respectively, in the final cycle. Density functional theory (DFT) calculations demonstrate that the addition of H2O increases the activity of NiMn2O4. Compared to benzene adsorption alone, the adsorption energy decreased from −2.20 eV to −2.54 eV after the addition of H2O. The migration path of NiMn2O4 (100) reactive oxygen species in the presence or absence of H2O is directly demonstrated. In the absence of H2O, the activation energy barrier for direct oxidation of C6H5* by NiMn2O4 lattice oxygen is dominant (0.98 eV), but OH* produced by dissociation of H2O exhibits high activity, and oxidation of C6H5* to produce the key intermediate product C6H5O* has an activation energy barrier of only 0.35 eV. In addition, H2O has a predominant role in the replenishment of oxygen vacancies. The elucidation of the oxygen migration mechanism provides new guidance for the design of efficient OCs for catalytic oxidation.

Morphological, physiological, and biochemical responses of rice (Oryza sativa L.) varieties to drought stress via regulating respiration and ROS metabolism during germination

Germination marks a pivotal and sensitive phase in the life cycle of crops, with drought stress, precipitated by water scarcity, posing a significant impediment to the germination process in rice. Despite this, the regulation mechanism of respiratory and reactive oxygen species (ROS) metabolism during rice germination under drought stress remains to be fully elucidated. This manuscript presents an integrative analysis encompassing morphological, physiological, biochemical, and molecular attributes of germinated seeds from a cultivated drought-sensitive rice variety (JN10) and a drought-resistant rice variety (NG36). Our findings revealed that drought stress adversely affected the germination of both rice varieties, with NG36 exhibiting a more rapid germination rate compared to JN10 under such stress conditions. This differential response was attributed to the heightened activity of key enzymes, elevated levels of metabolic intermediates, and upregulated expression of genes encoding enzymes involved in ROS and respiratory metabolic pathways in NG36. To further dissect the interplay between these metabolic pathways, we selected specific enzyme activities for detailed examination. Notably, a robust positive linear correlation was established among phosphofructokinase (PFK), α-ketoglutarate dehydrogenase (KGDH), citrate synthase (CS), and isocitrate dehydrogenase (ICDH) in NG36. This correlation underscores the pivotal role of glycolytic pathways, particularly the tricarboxylic acid (TCA) cycle, in conferring drought resistance to NG36 during the germination phase under drought stress. To encapsulate our findings, the results of this investigation suggest that the rice cultivar NG36 manifests a heightened degree of drought tolerance relative to JN10. This is primarily achieved through the adept modulation of its respiratory metabolic pathways and the stringent preservation of ROS homeostasis during the germination phase under conditions of water deficit. These revelations provide unprecedented insights into the intricate regulatory mechanisms that subserve rice's drought resistance, potentially paving the way for the development of novel strategies in the breeding of rice cultivars with improved drought resilience.

Dietary β-hydroxybutyrate sodium alters rumen microbiome and nutrient metabolism in the rumen epithelium of young goats

The role of β-hydroxybutyric acid (BHBA) includes providing energy, regulating signaling pathways, and ameliorating the gut microbiota in the host, while its nutrient mechanism to improve rumen epithelium development in young ruminants is still unclear. In this study, a total of 12 female Haimen goats with 30 days of age were chosen and divided into two groups. One group was fed with basic diet (CON), and the other group was fed a basal diet supplemented with 6 g d-1 dietary β-hydroxybutyrate sodium (BHBA-Na). The experimental period was 30 days, and all goats were slaughtered at 60 days of age. The joint analysis of multi-omics, including rumen microbiota, rumen epithelial transcriptome and rumen epithelial metabolomics in young goat model, was performed to systematically investigate the effect of dietary BHBA-Na on rumen development in young goats. As the results, we found that dietary BHBA-Na improved the growth performance of young goat including body weight, average daily gain (ADG) and dry matter intake (DMI) (P<0.05). Dietary BHBA-Na also increased the weight of rumen, and promoted the growth of rumen epithelium development (P < 0.05). The abundance of several beneficial bacteria was increased (Fibrobacter, Succinivibrio, Clostridiales, etc.,). The rumen epithelium transcriptome and metabolomics indicated that BHBA-Na supplementation showed a remarkable effect on the nutrient metabolism of the rumen epithelium. Specifically, the pathways of “fatty acid metabolism”, “cholesterol homeostasis”, “reactive oxygen species (ROS) pathway” and “peroxisome” were activated in response to BHBA-Na addition (P < 0.05). Moreover, the genes (HMGCS2, ECSH1, ACAA2, ECH1, ACADS etc.) and metabolites (succinic acid, alpha-ketoisovaleric acid, etc.) involved in these pathways were also regulated positively (P < 0.05). The rumen epithelium obtained the energy for its development from the process of volatile fatty acids (VFAs) decomposition. Finally, we observed the close correlations among the phenotypes, ruminal microbiota, host genes and epithelial metabolites. Overall, our results revealed that the BHBA-Na promoted the growth and rumen development of young goats possibly by enhancing DMI and regulating the rumen microbiota and the metabolisms of VFA and amino acid in the rumen epithelium.

Metformin suppresses metabolic dysfunction-associated fatty liver disease by ferroptosis and apoptosis via activation of oxidative stress

Metformin is known for its antioxidant properties and ability to ameliorate metabolic dysfunction-associated fatty liver disease (MAFLD) and is the focus of this study. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is linked to MAFLD risk. This study investigated the effects of metformin on ferroptosis in free fatty acid (FFA)-treated Huh7 hepatoma cells and its association with MAFLD risk. Using Western blot, immunofluorescence, and ELISA, this study revealed that FFA treatment led to increased intracellular fat and iron accumulation, heightened Lp-PLA2 expression, reduced levels of the cysteine transporter SLC7A11 and glutathione peroxidase 4 (GPX4), altered glutathione (GSH)/oxidized glutathione (GSSG) ratios, generation of reactive oxygen species (ROS), and initiation of lipid peroxidation, which ultimately resulted in cell ferroptosis. Importantly, metformin reversed FFA-induced iron accumulation, and this effect was attenuated by ferrostatin-1 but enhanced by erastin, RSL3, and si-GPX4. Additionally, metformin activated antioxidant and antiapoptotic mechanisms, which reduced lipid peroxidation and suppressed Lp-PLA2 expression in FFA-treated Huh7 cells. In conclusion, our findings indicate that metformin may protect against MAFLD by inhibiting iron accumulation and Lp-PLA2 expression through the ROS, ferroptosis, and apoptosis signaling pathways. This study highlights potential therapeutic strategies for managing MAFLD-related risks and emphasizes the diverse roles of metformin in maintaining hepatocyte balance.

Enhanced low-temperature methane oxidation over Pd supported Mn-doped NiO catalyst

This study introduces a novel catalyst system comprising Pd nanoparticles loaded onto Mn-doped NiO for the efficient oxidation of methane (CH4) at low temperatures. The loading of Pd nanoparticles onto the Mn-doped support has yielded a catalyst with exceptional activity and stability, as evidenced by the lowest T50 temperature of 276 °C and a CH4 conversion reaching 97% at 325 °C. The catalyst demonstrates optimized reaction kinetics with the lowest activation energy of 69.2 kJ mol–1. The catalyst's superior performance is attributed to the synergistic effects of the Pd/Mn-NiO composite, which include a higher Pd2+/Pd4+ ratio, increased adsorptive oxygen concentration (Oads/Ototal), and a reduced Ni3+/Ni2+ ratio. These characteristics collectively enhance the catalytic activity for CH4 oxidation. The Mars-van Krevelen mechanism underpins the oxidation process, with Pd2+ identified as the principal active site for CH4 adsorption and dissociation. Diffuse reflectance infrared Fourier transform spectroscopy coupled with mass spectrometry elucidates the pathway of surface reactive oxygen species in the formation of key intermediates, such as formates, and underscores the accelerated decomposition of carbonate facilitated by the Pd modification on the Mn-NiO surface. The findings signify a significant advancement in the development of catalysts for environmental and energy-related applications, particularly in the mitigation of CH4 emissions.

Quercetin inhibits cardiomyocyte apoptosis via Sirt3/SOD2/mitochondrial reactive oxygen species during myocardial ischemia–reperfusion injury

BackgroundMyocardial ischemia/reperfusion injury (MI/RI) can lead to impaired cardiac function. Quercetin (Que) has a positive effect and improves MI/RI. Sirtuin-3 (Sirt3) is a deacetylase that ameliorates oxidative stress and is associated with MI/RI. This study aimed to investigate the molecular mechanism by which Que protects cardiac function against MI/RI through the Sirt3 signaling pathway. MethodsWe conducted experiments by constructing hypoxia/reoxygenation (H/R) cardiomyocytes and MI/RI rat models. H9C2 cells were transfected with siRNA-Sirt3. Cardiomyocyte apoptosis was examined by TUNEL and Western blotting. The oxidative stress index was also determined. Mitochondrial reactive oxygen species (ROS) activity assays, ATP assays and mitochondrial membrane potential assays were performed. Evans Blue/TTC staining was used to examine surviving myocardial tissue. ResultsIn the constructed H/R cells and MI/RI animal models, it was found that myocardial cell apoptosis increased (Bcl-2 expression was downregulated; Bax and cleaved caspase-3/8/9 expression were upregulated). In addition, oxidative stress levels increased (MDA levels increased; SOD, CAT, GSH-Px levels decreased), myocardial tissue was damaged (LDH, CK content increased), Sirt3 expression was downregulated, acetylation levels of superoxide dismutase 2 (SOD2) increased (AC-SOD2), and mitochondrial ROS increased. Que treatment alleviated the effects of MI/RI on cardiomyocytes and rats. Sirt3 expression and activity were upregulated, SOD2 acetylation was decreased, and mitochondrial ROS production was reduced by Que treatment. After Sirt3 was knocked down, we found that AC-SOD2 expression was upregulated and mitochondrial ROS were increased in H/R cardiomyocytes, further increased the degree of injury, while Que treatment attenuated the effect of Sirt3 knockdown on H/R cardiomyocytes. ConclusionQue inhibits cardiomyocyte apoptosis, reduces oxidative stress levels, protects mitochondrial function and prevents the impairment of cardiac function during MI/RI via the Sirt3/SOD2/mitochondrial ROS pathway.

Aldosterone, mitochondria and regulation of cardiovascular metabolic disease.

Aldosterone is a mineralocorticoid hormone involved in controlling electrolyte balance, blood pressure, and cellular signaling. It plays a pivotal role in cardiovascular and metabolic physiology. Excess aldosterone activates mineralocorticoid receptors, leading to subsequent inflammatory responses, increased oxidative stress, and tissue remodeling. Various mechanisms have been reported to link aldosterone with cardiovascular and metabolic diseases. However, mitochondria, responsible for energy generation through oxidative phosphorylation, have received less attention regarding their potential role in aldosterone-related pathogenesis. Excess aldosterone leads to mitochondrial dysfunction, and this may play a role in the development of cardiovascular and metabolic diseases. Aldosterone has the potential to affect mitochondrial structure, function, and dynamic processes, such as mitochondrial fusion and fission. In addition, aldosterone has been associated with the suppression of mitochondrial DNA, mitochondria-specific proteins, and ATP production in the myocardium through mineralocorticoid receptor, nicotinamide adenine dinucleotide phosphate oxidase, and reactive oxygen species pathways. In this review, we explore the mechanisms underlying aldosterone-induced cardiovascular and metabolic mitochondrial dysfunction, including mineralocorticoid receptor activation and subsequent inflammatory responses, as well as increased oxidative stress. Furthermore, we review potential therapeutic targets aimed at restoring mitochondrial function in the context of aldosterone-associated pathologies. Understanding these mechanisms is vital, as it offers insights into novel therapeutic strategies to mitigate the impact of aldosterone-induced mitochondrial dysfunction, thereby potentially improving the outcomes of individuals affected by cardiovascular and metabolic disorders.

Hypoxia-reoxygenation Extends the Lifespan of Caenorhabditis elegans via SKN-1- and DAF-16A-Dependent Stress Hormesis.

To study the role of hypoxia-reoxygenation and anoxia-starvation on the lifespan of C. elegans and elucidate the mechanism at molecular levels. Increasing evidence indicates that reactive oxygen species (ROS) act as signaling molecules that promote health. Hormesis occurs when a moderate stress level induces a beneficial adaptive response, protecting organisms against subsequent exposure to severe stress. Caenorhabditis elegans is a widely used model organism to study aging and displays a broad hormetic ability to couple with stress. To date, only few methods are available to induce stress hormesis in C. elegans. The objectives of this study were to explore the effects of hypoxia-reoxygenation and anoxia-starvation on the lifespan of C. elegans, exploring the involvement of ROS and oxidative stress-related pathways, and examining the hormetic property of H/R. The C. elegans were cultured in hypoxic conditions (1% O2) with OP50 bacteria for 24 h followed by reoxygenation (20% O2) (H/R) or in anoxic conditions (0% O2; 100% N2) without OP50 bacteria for 24 h followed by reoxygenation (20% O2) and food supplementation (A/S). Survivals were plotted and estimated for probability with Kaplan-Meier analysis. The H/R extended the lifespan of C. elegans, and H/R-pretreated worms showed improved resistance toward A/S compared to naïve worms. The C. elegans SKN-1 and DAF-16 are important oxidative stress response factors homologous to mammalian Nrf2 and FOXO3, respectively. Mutations in SKN-1 and DAF-16 blocked H/R-induced life extension. Next, H/R treatment in C. elegans activated both SKN-1 and DAF-16, as indicated by the upregulation of putative target genes of SKN-1 (gcs-1 and gss-1) and DAF-16 (sod-3). Moreover, pre-treatment with antioxidants (N-acetylcysteine, chlorogenic acid, and sulforaphane) reduced ROS levels and diminished the lifespan extension effect of H/R, indicating their dependency on ROS. These results provide evidence that H/R is beneficial for lifespan and stress resistance by activating the adaptive cellular response pathway (SKN-1 and DAF-16A) toward oxidative stress.

Ablation of the Integrin CD11b Mac-1 Limits Deleterious Responses to Traumatic Spinal Cord Injury and Improves Functional Recovery in Mice.

Spinal cord injury (SCI) triggers microglial/monocytes activation with distinct pro-inflammatory or inflammation-resolving phenotypes, which potentiate tissue damage or facilitate functional repair, respectively. The major integrin Mac-1 (CD11b/CD18), a heterodimer consisting of CD11b and CD18 chains, is expressed in multiple immune cells of the myeloid lineage. Here, we examined the effects of CD11b gene ablation in neuroinflammation and functional outcomes after SCI. qPCR analysis of C57BL/6 female mice showed upregulation of CD11b mRNA starting from 1 d after injury, which persisted up to 28 d. CD11b knockout (KO) mice and their wildtype littermates were subjected to moderate SCI. At 1 d post-injury, qPCR showed increased expression of genes involved with inflammation-resolving processes in CD11b KO mice. Flow cytometry analysis of CD45intLy6C-CX3CR1+ microglia, CD45hiLy6C+Ly6G- monocytes, and CD45hiLy6C+Ly6G+ neutrophils revealed significantly reduced cell counts as well as reactive oxygen species (ROS) production in CD11b KO mice at d3 post-injury. Further examination with NanoString and RNA-seq showed upregulation of pro-inflammatory genes, but downregulation of the ROS pathway. Importantly, CD11b KO mice exhibited significantly improved locomotor function, reduced cutaneous mechanical/thermal hypersensitivity, and limited tissue damage at 8 weeks post-injury. Collectively, our data suggest an important role for CD11b in regulating tissue inflammation and functional outcome following SCI.

Photosynthetic ROS and retrograde signaling pathways.

Sessile plants harness mitochondria and chloroplasts to sense and adapt to diverse environmental stimuli. These complex processes involve the generation of pivotal signaling molecules, including reactive oxygen species (ROS), phytohormones, volatiles, and diverse metabolites. Furthermore, the specific modulation of chloroplast proteins, through activation or deactivation, significantly enhances the plant's capacity to engage with its dynamic surroundings. While existing reviews have extensively covered the role of plastidial retrograde modules in developmental and light signaling, our focus lies in investigating how chloroplasts leverage photosynthetic ROS to navigate environmental fluctuations and counteract oxidative stress, thereby sustaining primary metabolism. Unraveling the nuanced interplay between photosynthetic ROS and plant stress responses holds promise for uncovering new insights that could reinforce stress resistance and optimize net photosynthesis rates. This exploration aspires to pave the way for innovative strategies to enhance plant resilience and agricultural productivity amidst changing environmental conditions.

Antioxidant enzyme Prdx1 inhibits osteoclastogenesis via suppressing ROS and NFATc1 signaling pathways.

Bone is a dynamic organ which continuously undergoes remodeling throughout one's lifetime. Cellular production of reactive oxygen species (ROS) is essential for regulating bone homeostasis. Osteoclasts, multinucleated giant cells differentiated from macrophage lineage, are responsible for osteolytic bone conditions which are closely linked to ROS signaling pathways. In this study, an anti-ROS enzyme, peroxiredoxin 1 (Prdx1) was found to be expressed both in bone marrow macrophages and osteoclasts. Recombinant Prdx1 protein was found to dose-dependently inhibit ROS production and osteoclast differentiation. Mechanistically, Prdx1 protein also attenuated NFATc1 activation as well as the expression of C-Fos, V-ATPase-d2, Cathepsin K, and Integrin αV. Collectively, Prdx1 is a negative regulator on osteoclast formation via inhibiting RANKL-mediated ROS activity, thus suggesting its potential application for treating osteoclast related disorders.

Quantitative proteomic analysis reveals hub proteins for high temperature-induced male sterility in bread wheat (Triticum aestivum L.).

High-temperature (HT) stress can induce male sterility in wheat; however, the underlying mechanisms remain poorly understood. This study examined proteomic alterations across three developmental stages between normal and HT-induced male-sterile (HT-ms) anthers in wheat. Utilizing tandem mass tags-based proteomics, we identified 2532 differentially abundant proteins (DAPs): 27 in the tetrad stage, 157 in the binuclear stage, and 2348 in the trinuclear stage. Analyses through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways indicated significant enrichment of these DAPs in seven pathways, namely phenylpropanoid biosynthesis, flavonoid biosynthesis, sphingolipid metabolism, MAPK signaling pathway, starch and sucrose metabolism, response to heat, and response to reactive oxygen species (ROS). Our results indicated the downregulation of DAPs associated with phenylpropanoid biosynthesis and starch and sucrose metabolism, which aligns with anther indehiscence and the lack of starch in HT-ms anthers. By contrast, DAPs in the ROS pathway were upregulated, which aligns with excessive ROS accumulation in HT-ms anthers. Additionally, we conducted protein-protein interaction analysis for the DAPs of these pathways, identifying 15 hub DAPs. The abundance of these hub proteins was confirmed through qRT-PCR, assessing mRNA expression levels of the corresponding transcripts. Collectively, these results offer insights into the molecular mechanisms underlying HT-induced male sterility in wheat at the proteomic level, providing a valuable resource for further research in plant sexual reproduction.

Cardamonin attenuates iron overload-induced osteoblast oxidative stress through the HIF-1α/ROS pathway

BackgroundOsteoporosis(OP) is a bone disease under research. Iron overload is a significant risk factor. Iron balance is crucial for bone metabolism and biochemical processes. When there is an excess of iron in the body, it tends to produce reactive oxygen species (ROS) which can cause oxidative damage to cells. The flavonoid compound, Cardamonin (CAR), possesses potent anti-inflammatory and anti-iron overload properties that can be beneficial in mitigating the risk of OP. PurposeThis study investigates the potential therapeutic interventions and underlying mechanisms of CAR for treating OP in individuals with iron overload. MethodsThe model of iron-overloaded mice was established by intraperitoneally injecting iron dextran(ID) into the mice. OP severity was evaluated with micro-CT and Hematoxylin-Eosin (HE) staining in vivo. In vitro, the iron-overloaded osteoblast model was induced by ferric ammonium citrate. Cell counting kit 8 assay to evaluate cell viability, Annexin V-FITC/PI assay to detect cell apoptosis. A range of cellular markers were detected, including the variation in mitochondrial membrane potential (MMP), levels of malondialdehyde (MDA), ROS, and lipid hydroperoxide (LPO). ResultsCAR can reverse bone loss in iron overload-induced OP mouse models in vivo.CAR attenuates the impairment of iron overload on the activity and apoptosis of MC3T3-E1 cells as well as the accumulation of ROS and LPO activation via HIF-1α/ROS pathways. ConclusionCAR downregulating HIF-1α pathways prevents inhibition of iron overload-induced osteoblasts dysfunctional by attenuating ROS accumulation, reducing oxidative stress, promotes bone formation, and alleviates OP.

Integrated multi-omics approaches reveal the neurotoxicity of triclocarban in mouse brain

Triclocarban (TCC) is an antimicrobial ingredient that commonly incorporated in many household and personal care products, raising public concerns about its potential health risks. Previous research has showed that TCC could cross the blood–brain barrier, but to date our understanding of its potential neurotoxicity at human-relevant concentrations remains lacking. In this study, we observed anxiety-like behaviors in mice with continuous percutaneous exposure to TCC. Subsequently, we combined lipidomic, proteomic, and metabolic landscapes to investigate the underlying mechanisms of TCC-related neurotoxicity. The results showed that TCC exposure dysregulated the proteins involved in endocytosis and neurodegenerative disorders in mouse cerebrum. Brain energy homeostasis was also altered, as evidenced by the perturbation of pyruvate metabolism, TCA cycle, and oxidative phosphorylation, which in turn caused mitochondrial dysfunction. Meanwhile, the changing trends of sphingolipid signaling pathway and overproduction of mitochondrial reactive oxygen species (mROS) could enhance the neural apoptosis. The in vitro approach further demonstrated that TCC exposure promoted apoptosis, accompanied by the overproduction of mROS and alteration in the mitochondrial membrane potential in N2A cells. Together, dysregulated endocytosis, mROS-related mitochondrial dysfunction and neural cell apoptosis are considered to be crucial factors for TCC-induced neurotoxicity, which may contribute to the occurrence and development of neurodegenerative disorders. Our findings provide novel perspectives for the mechanisms of TCC-triggered neurotoxicity.

The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax.

B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells. We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells. The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics. Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.

Hypothermic oxygenated machine perfusion influences the immunogenicity of donor livers in humans.

Hypothermic oxygenated machine perfusion (HOPE) is an organ preservation strategy shown to reduce ischemia-reperfusion-injury (IRI)-related complications following liver transplantation (LT). In animal models HOPE can also decrease alloimmune responses post-transplantation, but this remains to be evaluated in humans. Our study, involving 27 LT patients enrolled in 2 randomised controlled trials comparing static cold storage (SCS) with HOPE (14 HOPE- and 13 SCS-treated), delves into the impact of HOPE on the molecular profile of liver allografts and on the immune responses elicited post-transplantation. Following HOPE treatment, fewer intra-hepatic immune cells were observed in liver perfusates compared to SCS. Analysis of liver tissue transcriptome at reperfusion revealed an effect of HOPE on the reactive oxygen species pathway. Two weeks post-transplantation, HOPE recipients exhibited increased circulating CD4+FOXP3+CD127lo regulatory T cells (Tregs) (p<0.01), which corresponded to a higher frequency of donor specific Tregs (p<0.01) and was followed by reduced alloreactivity index of CD8+ T cells 3 months post-transplant. Our study provides novel mechanistic insight into the capacity of HOPE to influence liver IRI and to modulate effector and regulatory donor-specific T cell responses post-transplantation. These findings, which confirm observations made in animal models, help explain the decreased rejection rates reported in patients receiving HOPE-treated allografts.

Identification and Verification of the Oxidative Stress-Related Signature Markers for Intracranial Aneurysm-Applied Bioinformatics.

Intracranial aneurysm (IA) is a localized abnormal dilation of the cerebral vascular wall, the degeneration of which is closely related to high oxidative stress. Clinical information and RNA-seq data from five public datasets were downloaded from the Gene Expression Omnibus (GEO). Using the "GSVA" package, enrichment analysis was performed on the gene sets of the oxidative stress, reactive oxygen species (ROS), metabolism, and inflammatory pathways retrieved from the MsigDB and Kyoto encyclopedia of genes and genomes (KEGG) databases. Weighted gene co-expression network analysis (WGCNA) was conducted using the "WGCNA" package, followed by using the "limma" R package to select differentially expressed genes (DEGs). Key genes were determined by applying three machine learning algorithms (random forest, Lasso, and SVM-RFE). The expression levels of the key genes were verified by the quantitative real-time polymerase chain reaction (qRT-PCR) in IA. Finally, ESTIMATE and CIBERPSORT algorithms were used for immune infiltration analysis. The enrichment score of the oxidative stress, ROS, metabolism, and inflammatory pathways was calculated, and we found that these pathways were significantly activated in IA samples with higher immune infiltration. The intersection between the blue module related to oxidative stress (610 genes identified by WGCNA) and 380 upregulated DEGs contained a total of 209 key genes, which were further processed by machine learning algorithms to obtain four crucial diagnostic markers (FLVCR2, SDSL, TBC1D2, and SLC31A1) for IA. These key genes are highly expressed in human brain vascular smooth muscle cells. The expressions of the four markers were significantly positively correlated with the abnormal activation phenotypes of oxidative stress, the ROS and glucometabolic pathways, and suppressive immune infiltration. This study employed WGCNA combined with three machine learning algorithms to identify four oxidative stress-related signature markers for IA, providing novel insights into the clinical management of IA patients.

A Low Expression of NRF2 Enhances Oxidative Stress and Autophagy in Myofibroblasts, Promoting Progression of Chronic Obstructive Pulmonary Disease.

The inflammation phenotypes are often closely related to oxidative stress and autophagy pathway activation, which could be developed as a treatment target. The aim of this study was to explore the underlying mechanism of inflammation in chronic obstructive pulmonary disease (COPD). The lung tissue single-cell RNA-seq (scRNA-seq) dataset of GSE171541 was downloaded from the Gene Expression Omnibus (GEO) database. The marker genes were obtained from the CellMarker database. "Seurat" and "harmony" R packages were used for single-cell profiling analysis. Then, the "AUCell" R package was employed to calculate the reactive oxygen species (ROS) and autophagy pathway scores. Gene regulation network analysis was performed by applying the "SCENIC" package, followed by conducting correlation analysis with Spearman's rank correlation method. The cigarettes were used to develop a traumatic model in mice, and the expression of relevant genes was measured by qRT-PCR. The scRNA-seq analysis classified 12 cell subgroups in which the contractility of myofibroblasts was closely associated with the progression of COPD. Further analysis showed that ROS and autophagy pathways were significantly activated in myofibroblasts and that the nuclear factor erythroid 2-related factor 2 (NRF2) and its mediated oxidative stress pathway were inhibited in myofibroblasts. In addition, the downregulated NRF2 gene was negatively correlated with the expression of autophagy and ROS activation. In the traumatic mice model, NRF2 was downregulated in COPD mice but further elevated in the COPD+NRF2 mice group. Interestingly, the mRNA levels of Kelchlike ECH-associated protein 1 (Keap1), NADPH oxidase (NOX), and Cathepsin B (CTSB) were upregulated in COPD group in comparison to the control group but they were downregulated by NRF2. These results suggested that low-expressed NFR2 promoted autophagy and ROS pathway activation in myofibroblasts for COPD progression. We identified a cell myofibroblast cluster closely associated with COPD progression using the scRNA-seq analysis. The downregulated NFR2, as a key risk factor, mediated myofibroblast death by activating the oxidative stress and autophagy pathway for COPD progression.

Predictive role of oxidative stress-related genes in colon cancer: a retrospective cohort study based on The Cancer Genome Atlas

PurposeThis study aimed to elucidate the predictive role of an oxidative stress-related genes (OSRGs) model in colon cancer.Materials and methodsFirst, OSRGs that were differentially expressed between tumor and normal tissues were identified using The Cancer Genome Atlas (TCGA)—(Colorectal Adenocarcinoma) COAD dataset. Then, Lasso COX regression was performed to develop an optimal prognostic model patients were stratified into high- and low-risk groups based on the expression patterns of these genes. The model's validity was confirmed through Kaplan–Meier survival curves and receiver operating characteristic curve (ROC) analysis. Additionally, enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) to uncover underlying mechanisms.ResultsA totally of 115 differentially expressed OSRGs were identified within the TCGA cohort, with 17 significantly linked to overall survival. These 17 genes were used to formulate a prognostic model that differentiated patients into distinct risk groups, with the high-risk group demonstrating a notably inferior overall survival rate. The risk score, when integrated with clinical and pathological data, emerged as an independent prognostic indicator of colon cancer. Further analyses revealed that the disparity in prognostic outcomes between risk groups could be attributed to the reactive oxygen species pathway and the p53 signaling pathway.ConclusionA new prediction model was established based on OSRGs. CYP19A1, NOL3 and UCN were found to be highly expressed in tumor tissues and substantial clinical predictive significance. These findings offer new insights into the role of oxidative stress in colon cancer.

The identification of heterogeneous reactive oxygen subtypes in esophageal squamous cell carcinoma to aid patient prognosis and immunotherapy

IntroductionEsophageal cancer is increasingly recognized as a significant global malignancy. The main pathological subtype of this cancer is esophageal squamous cell carcinoma (ESCC), which displays a higher degree of malignancy and a poorer prognosis. Reactive oxygen species (ROS) play a critical role in modulating the immune response to tumors, and understanding the regulation of ROS in ESCC could lead to novel and improved therapeutic strategies for ESCC patients. MethodsA consensus matrix derived from genes involved in the ROS pathway revealed two subtypes of ROS. These subtypes were categorized as ROS-active or ROS-suppressive based on their level of ROS activity. The heterogeneity among the different ROS subtypes was then explored from various perspectives, including gene function, immune response, genomic stability, and immunotherapy. In order to assess the prognosis and the potential benefits of immunotherapy, a ROS activity score (RAS) was developed using the identified ROS subtypes. In vitro experiments were performed to confirm the impact of core RAS genes on the proliferative activity of esophageal cancer cell lines. ResultsTwo distinctive subtypes of ROS were identified. The first subtype, referred to as ROS-active, exhibited elevated ROS activity, enhanced involvement in cancer-associated immune pathways, and increased infiltration of effector immune cells. The second subtype, named ROS-suppressive, demonstrated weaker ROS activity but displayed more pronounced dysregulation in the cell cycle and a denser extracellular matrix, indicating malignant characteristics. Genomic stability, particularly in terms of copy number variation (CNV) events, differed between the two ROS subtypes. By developing a RAS model, reliable risk assessment for overall survival (OS) in patients with ESCC was achieved, and the model demonstrated strong predictive capabilities in real-world immunotherapy cohorts. Moreover, the core gene LDLRAD1 within the RAS model was found to enhance proliferative activity in esophageal cancer cell lines. ConclusionBased on the ROS pathway, we successfully identified two distinct subtypes in ESCC: the ROS-active subtype and the ROS-suppressive subtype. These subtypes were utilized to evaluate prognosis and the sensitivity to immunotherapy.