Glutathione Peroxidase Research Articles

Advances in understanding the role of lncRNA in ferroptosis.

LncRNA is a type of transcript with a length exceeding 200 nucleotides, which was once considered junk transcript with no biological function during the transcription process. In recent years, lncRNA has been shown to act as an important regulatory factor at multiple levels of gene expression, affecting various programmed cell death modes including ferroptosis. Ferroptosis, as a new form of programmed cell death, is characterized by a deficiency of cysteine or inactivation of glutathione peroxidase, leading to depletion of glutathione, aggregation of iron ions, and lipid peroxidation. These processes are influenced by many physiological processes, such as the Nrf2 pathway, autophagy, p53 pathway and so on. An increasing number of studies have shown that lncRNA can block the expression of specific molecules through decoy effect, guide specific proteins to function, or promote interactions between molecules as scaffolds. These modes of action regulate the expression of key factors in iron metabolism, lipid metabolism, and antioxidant metabolism through epigenetic or genetic regulation, thereby regulating the process of ferroptosis. In this review, we snapshotted the regulatory mechanism of ferroptosis as an example, emphasizing the regulation of lncRNA on these pathways, thereby helping to fully understand the evolution of ferroptosis in cell fate.

Effects of Dietary Bio-Fermented Selenium Supplementation on Growth, Immune Performance, and Intestinal Microflora of Chinese Mitten Crabs, Eriocheir sinensis.

Selenium is a vital trace mineral that is crucial for maintaining regular biological processes in aquatic animals. In this study, a four-week dietary trial was carried out to assess the impact of bio-fermented selenium (Bio-Se) on the growth and immune response of Chinese mitten crabs, Eriocheir sinensis. The crabs were randomly allocated to five dietary treatment groups, each receiving a different dose of Bio-Se. The doses included 0, 0.3, 0.6, 1.5, and 3.0 mg/kg and were accurately measured in basal diet formulations. The results showed the weight gain rate (WGR), specific growth rate (SGR), and survival rate (SR) in the 1.5 mg/kg Bio-Se group were the highest, and 3.0 mg/kg of Bio-Se has an inhibitory effect on the WGR, SGR, and SR. The activities of the immune enzymes, including glutathione peroxidase (GPX), superoxide dismutase (SOD), and acid phosphatase (ACP), of the hepatopancreas were significantly (p < 0.05) increased in the 1.5 mg/kg Bio-Se group, while they decreased (p < 0.05) in the 3.0 mg/kg feeding group compared to the 0 mg/kg feeding group. The concentration of maleic dialdehyde (MDA) exhibited the opposite pattern. Similarly, the mRNA expression levels of antimicrobial peptides (ALF-1, Crus-1, and LYS), ERK, and Relish genes were also observed to be the highest in the 1.5 mg/kg Bio-Se group compared with the other groups. Furthermore, the administration of 1.5 mg/kg of Bio-Se resulted in an increase in the thickness of the intestinal plica and mucosal layer, as well as in alterations in the intestinal microbial profile and bacterial diversity compared to the dose of 0 mg/kg of Bio-Se. Notably, the population of the beneficial bacterial phylum Fusobacteria was increased after crabs were fed the 1.5 mg/kg Bio-Se diet. In conclusion, the oral administration of 1.5 mg/kg of Bio-Se improved the growth efficiency, antioxidant capabilities, immunity, and intestinal health of E. sinensis. Through a broken-line analysis of the WGR against dietary Bio-Se levels, optimal dietary Bio-Se levels were determined to be 1.1 mg/kg. These findings contribute valuable insights to the understanding of crab cultivation and nutrition.

Lipid Peroxidation Regulators GPX4 and FSP1 as Prognostic Markers and Therapeutic Targets in Advanced Gastric Cancer.

Gastric cancer is one of the most common cancers worldwide, and new therapeutic strategies are urgently needed. Ferroptosis is an intracellular iron-dependent cell death induced by the accumulation of lipid peroxidation, a mechanism different from conventional apoptosis and necrosis. Therefore, induction of ferroptosis is expected to be a new therapeutic strategy. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) have been identified as the major inhibitors of ferroptosis. Herein, we performed immunohistochemistry for GPX4, FSP1, and 4-HNE using tissues from patients with gastric cancer and investigated the relationship between these factors and prognosis. Patients with high GPX4 expression or high GPX4 expression and low 4-HNE accumulation tended to have a poor prognosis (p = 0.036, 0.023), whereas those with low FSP1 expression and high 4-HNE accumulation had a good prognosis (p = 0.033). The synergistic induction of cell death by inhibiting GPX4 and FSP1 in vitro was also observed, indicating that the cell death was non-apoptotic. Our results indicate that the expression and accumulation of lipid peroxidation-related factors play an important role in the clinicopathological significance of gastric cancer and that novel therapeutic strategies targeting GPX4 and FSP1 may be effective in treating patients with gastric cancer who have poor prognosis.

Circadian organization of clock factors, antioxidant defenses, and cognitive genes expression, is lost in the cerebellum of aged rats. Possible targets of therapeutic strategies for the treatment of age-related cerebellar disorders

Aging is a major risk factor for cognitive deficits, impaired locomotion, and gait disorders. Although oxidative stress and circadian disruption are involved in both normal aging and the pathogenesis of age‐associated diseases, just a very few studies explore the consequences of aging on circadian rhythms in the cerebellum. Here, we investigated age-dependent changes in the circadian organization of the molecular clock, antioxidant defenses and synaptic plasticity-related factors, in the rat cerebellum, and discussed the impact of that altered temporal organization on the cognitive function of this brain area. Particularly, we examined the circadian patterns of Brain and muscle ARNT-like 1 (BMAL1) protein levels, Glutathione peroxidase 4 (GPx4) gene expression, GPx and Catalase (CAT) enzymes activity, reduced glutathione (GSH) levels, and the Brain-derived neurotrophic factor (Bdnf) and its Tyrosine kinase receptor B (TrkB) circadian expression. Endogenously-driven circadian rhythms of BMAL1, GPx4, CAT, GSH, and Bdnf/TrkB factors, were observed in the young rat cerebellum. The rhythms’ acrophases show a circadian organization that might be crucial for the daily cerebellar-dependent cognitive functions. Notably, aging disrupted circadian rhythms and the temporal organization of BMAL1, antioxidant defenses, and cognitive Bdnf/TrkB gene expression. Increased oxidative stress and disruption of clock-controlled rhythms during aging, might precede and cause the loss of circadian organization in the aged cerebellum. We expect our results highlight circadian rhythms of the studied factors as new targets for the treatment of age-dependent cerebellar disorders.

Sea buckthorn extract mitigates chronic obstructive pulmonary disease by suppression of ferroptosis via scavenging ROS and blocking p53/MAPK pathways

Ethnopharmacological relevanceSea buckthorn (Hippophae rhamnoides), a traditional Tibetan medicinal herb, exhibits protective effects against cardiovascular and respiratory diseases. Although Sea buckthorn extract (SBE) has been confirmed to alleviate airway inflammation in mice, its therapeutic effect and underlying mechanism on chronic obstructive pulmonary disease (COPD) requires further clarification. Aim of the studyTo elucidate the alleviative effect and molecular mechanism of SBE on lipopolysaccharides (LPS)/porcine pancreatic elastase (PPE)-induced COPD by blocking ferroptosis. MethodsThe anti-ferroptotic effects of SBE were evaluated in human BEAS-2B bronchial epithelial cells using CCK8, RT-qPCR, western blotting, and transmission electron microscopy. Transwell was employed to detect chemotaxis of neutrophils. COPD model was induced by intranasally administration of LPS/PPE in mice and measured by alterations of histopathology, inflammation, and ferroptosis. RNA-sequencing, western blotting, antioxidant examination, flow cytometry, DARTS, CETSA, and molecular docking were then used to investigate its anti-ferroptotic mechanisms. ResultsIn vitro, SBE not only suppressed erastin- or RSL3-induced ferroptosis by suppressing lipid peroxides (LPOs) production and glutathione (GSH) depletion, but also suppressed ferroptosis-induced chemotactic migration of neutrophils via reducing mRNA expression of chemokines. In vivo, SBE ameliorated LPS/PPE-induced COPD phenotypes, and inhibited the generation of LPOs, cytokines, and chemokines. RNA-sequencing showed that p53 pathway and mitogen-activated protein kinases (MAPK) pathway were implicated in SBE-mediated anti-ferroptotic action. SBE repressed erastin- or LPS/PPE-induced overactivation of p53 and MAPK pathway, thereby decreasing expression of diamine acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15), and increasing expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Mechanistically, erastin-induced elevation of reactive oxygen species (ROS) was reduced by SBE through directly scavenging free radicals, thereby contributing to its inhibition of p53 and MAPK pathways. CETSA, DARTS, and molecular docking further showed that ROS-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) may be the target of SBE. Overexpression of NOX4 partially impaired the anti-ferroptotic activity of SBE. ConclusionOur results demonstrated that SBE mitigated COPD by suppressing p53 and MAPK pro-ferroptosis pathways via directly scavenging ROS and blocking NOX4. These findings also supported the clinical application of Sea buckthorn in COPD therapy.

Epicatechin ameliorates glucose intolerance and hepatotoxicity in sodium arsenite-treated mice

Arsenic is a metalloid found in the environment that causes toxic effects in different organs, mainly the liver. This study aimed to investigate the protective effects of epicatechin (EC), a natural flavonol, on glucose intolerance (GI) and liver toxicity caused by sodium arsenite (SA) in mice. Our findings showed that SA exposure led to the development of GI. Liver tissue damage and decreased pancreatic Langerhans islet size were also observed in this study. Mice exposed to sodium arsenite (SA) exhibited hepatic oxidative damage, indicated by reduced antioxidant markers (such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione), along with elevated levels of thiobarbituric acid reactive substances. SA administration elevated the serum activities of liver enzymes alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. Furthermore, notable increases in the levels of inflammatory and apoptotic markers (Toll-like receptor 4, nuclear factor-kappa B, tumor necrosis factor-α, nitric oxide, B-cell lymphoma-2, and cysteine aspartate-specific protease-3) were observed in the liver. Treatment of SA-exposed mice with EC considerably reversed these biochemical and histological changes. This study demonstrated the beneficial effects of EC in ameliorating SA-induced hyperglycemia and hepatotoxicity due to its ability to enhance the antioxidant system by modulating inflammation and apoptosis.

Sudachitin Alleviates Paraquat Instigated Testicular Toxicity in Albino Rats via Regulating Nrf-2/Keap-1, Inflammatory, Steroidogenic, and Histological Profile.

Paraquat (PQ) is a noxious herbicide which adversely affects the vital organs including male reproductive system. Sudachitin (SCN) is a naturally occurring flavonoid that demonstrates a wide range of biological potentials. The current study was designed to investigate the alleviative potential of SCN to avert PQ-induced testicular toxicity in rats. Forty-eight male rats (Rattus norvegicus) were apportioned into four groups including control, PQ (5 mg/kg), PQ + SCN (5 mg/kg + 30 mg/kg), and SCN (30 mg/kg) only treated group. Our findings elucidated that PQ treatment reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2) and its antioxidant genes as well as the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSR) and glutathione peroxidase (GPx), while elevating the levels of reactive oxygen species (ROS), and malondialdehyde (MDA). Furthermore, PQ intoxication upregulated the expressions of Keap-1 while downregulating the expression of 3-beta hydroxysteroid dehydrogenase (3β-HSD), 17-beta hydroxysteroid dehydrogenase (17β-HSD), and steroidogenic acute regulatory protein (StAR). Moreover, sperm anomalies were increased following the exposure to PQ. Besides, PQ exposure decreased the levels of plasma testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) while increasing the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), interleukin-1beta (IL-1β), and cyclooxygenase-2 (COX-2). Additionally, PQ treatment escalated the expressions of cysteinyl aspartate-specific proteases-3 (Caspase-3) and Bcl-2-associated X-protein (Bax) while downregulating the expressions of B-cell lymphoma-2 (Bcl-2). Furthermore, PQ exposure disrupted the normal architecture of testicular tissues. However, SCN treatment remarkably protected the testicular tissues via regulating the aforementioned disruptions owing to its antioxidant, anti-inflammatory, and androgenic potential.

RBM15 Promotes High Glucose-Induced Lens Epithelial Cell Injury by Inducing PRNP N6-Methyladenine Modification During Diabetic Cataract

Purpose Diabetic cataract (DC) is a major cause of blindness worldwide. Prion protein (PRNP) was proved to be up-regulated and hypomethylated in DC samples. Here, we investigated whether PRNP was involved in DC progression in N6-methyladenosine (m6A)-dependent manner, and its potential mechanisms. Methods Levels of genes and proteins were assayed using qRT-PCR and western blotting. Cell proliferation and apoptosis were determined using Cell Counting Kit-8 assay, 5-thynyl-2’-deoxyuridine (EdU) assay, and flow cytometry, respectively. Oxidative stress was analyzed by measuring the production of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), and malondialdehyde (MDA). The m6A modification was determined by RNA immunoprecipitation (Me-RIP) assay. The interaction between RBM15 (RNA binding motif protein 15) and PRNP was probed using RIP assay. Results PRNP was highly expressed in DC patients and HG-induced HLECs. Functionally, PRNP deficiency reversed HG-induced apoptosis and oxidative stress in HLECs. Mechanistically, RBM15 induced PRNP m6A modification and directly bound to PRNP. Knockdown of RBM15 abolished HG-induced apoptotic and oxidative injury in HLECs, while these effects were rescued after PRNP overexpression. Conclusion RBM15 silencing suppressed HG-induced lens epithelial cell injury by regulating PRNP in an m6A-mediated manner, hinting a novel therapeutic strategy for DC patients.

High selenium diet attenuates pressure overload-induced cardiopulmonary oxidative stress, inflammation, and heart failure

Selenium (Se) deficiency is associated with the development of Keshan disease, a cardiomyopathy associated with massive cardiac immune cell infiltration that can lead to heart failure (HF). The purpose of this study was to determine whether high Se diet can attenuate systolic overload-induced cardiopulmonary inflammation and HF. Briefly, transverse aortic constriction (TAC)-induced cardiopulmonary oxidative stress, inflammation, left ventricular (LV) dysfunction, and pulmonary remodeling were determined in male mice fed with either high Se diet or normal Se diet. High Se diet had no detectable effect on LV structure and function in mice under control conditions, but high Se diet significantly protected mice from TAC-induced LV hypertrophy, dysfunction, increase of lung weight, and right ventricular hypertrophy. As compared with mice treated with normal Se diet, high Se diet also reduced TAC-induced LV cardiomyocyte hypertrophy, fibrosis, leukocyte infiltration, pulmonary inflammation, pulmonary fibrosis, and pulmonary micro-vessel muscularization. In addition, high Se diet significantly ameliorated TAC-induced accumulation and activation of pulmonary F4/80+ macrophages, and activation of dendritic cells. Interestingly, high Se diet also significantly attenuated TAC-induced activation of pulmonary CD4+ and CD8+ T cells. Moreover, we found that TAC caused a significant increase in cardiac and pulmonary ROS production, increases of 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT), as well as a compensatory increases of LV glutathione peroxidase 1 (GPX1) and 4 (GPX4) in mice fed with normal Se diet. Above changes were diminished in mice fed with high Se diet. Collectively, these data demonstrated that high Se diet significantly attenuated systolic pressure overload-induced cardiac oxidative stress, inflammation, HF development, and consequent pulmonary inflammation and remodeling.

Spermidine mitigates ferroptosis in free fatty acid-induced AML-12 cells through the ATF4/SLC7A11/GCLM/GPX4 pathway

Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of chronic liver disease worldwide. Spermidine (SPD), a naturally occurring polyamine, has shown potential in alleviating the accumulation of hepatic lipids and reducing NAFLD symptoms in overweight mice. Nonetheless, the specific mechanisms through which SPD exerts its effects remain largely unknown. This study seeks to explore the protective effects of SPD on NAFLD and to clarify the underlying mechanisms. An in vitro model of NAFLD was established by inducing steatosis in AML-12 cells through the use of free fatty acids (FFAs). Our experimental results demonstrate that SPD significantly reduces NAFLD development induced by FFAs. This reduction is primarily achieved through the inhibition of cellular ferroptosis, as evidenced by decreased levels of Fe2+, malondialdehyde (MDA), and reactive oxygen species (ROS). Additionally, SPD was found to enhance cellular activity and ameliorate mitochondrial dysfunction and oxidative stress caused by FFA exposure.Further mechanistic studies have revealed that SPD upregulates the expression of solute transporter family 7a member 11 (SLC7A11), glutamate-cysteine ligase modifier subunit (GCLM), and glutathione peroxidase (GPX4). This upregulation is mediated by the activation of activating transcription factor 4 (ATF4). Knockdown experiments of ATF4 confirmed that its inhibition reverses the upregulation of SLC7A11, GCLM, and GPX4, thereby negating the protective effects of SPD. In conclusion, our findings suggest that SPD mitigates NAFLD by modulating the ATF4/SLC7A11/GCLM/GPX4 signaling pathway, resulting in the suppression of ferroptosis and the improvement of cellular health. These insights provide a novel molecular mechanism and identify potential therapeutic targets for the treatment of NAFLD.

Avicularin Attenuated Lead-Induced Ferroptosis, Neuroinflammation, and Memory Impairment in Mice.

Lead (Pb) is a common environmental neurotoxicant that results in abnormal neurobehavior and impaired memory. Avicularin (AVL), the main dietary flavonoid found in several plants and fruits, exhibits neuroprotective and hepatoprotective properties. In the present study, the effects of AVL on Pb-induced neurotoxicity were evaluated using ICR mice to investigate the molecular mechanisms behind its protective effects. Our study has demonstrated that AVL treatment significantly ameliorated memory impairment induced by lead (Pb). Furthermore, AVL mitigated Pb-triggered neuroinflammation, ferroptosis, and oxidative stress. The inhibition of Pb-induced oxidative stress in the brain by AVL was evidenced by the reduction in malondialdehyde (MDA) levels and the enhancement of glutathione (GSH) and glutathione peroxidase (GPx) activities. Additionally, in the context of lead-induced neurotoxicity, AVL mitigated ferroptosis by increasing the expression of GPX4 and reducing ferrous iron levels (Fe2+). AVL increased the activities of glycogenolysis rate-limiting enzymes HK, PK, and PYG. Additionally, AVL downregulated TNF-α and IL-1β expression while concurrently enhancing the activations of AMPK, Nrf2, HO-1, NQO1, PSD-95, SNAP-25, CaMKII, and CREB in the brains of mice. The findings from this study suggest that AVL mitigates the memory impairment induced by Pb, which is associated with the AMPK/Nrf2 pathway and ferroptosis.

Neurotoxicity and intestinal microbiota dysbiosis induced by per- and polyfluoroalkyl substances in crucian carp (Carassius auratus)

Per- and polyfluoroalkyl substances (PFAS) have been called "forever chemicals" due to their inherent chemical stability. Their potential toxic effects on aquatic animals and health risk assessments have not been fully elucidated. In this study, we investigated the toxic effects of PFASs at environmentally relevant concentrations (200 ng/L) on crucian carp (Carassius auratus). The results showed that PFAS reduced the comfort behaviour of crucian carp and was associated with reduced levels of acetylcholinesterase and dopamine in the brain. PFAS exposure also decreased the activities of total superoxide dismutase, catalase and glutathione peroxidase, while increasing the levels of malondialdehyde. PFAS caused over-expression of the pro-inflammatory cytokines TNF-α, IFN-γ and stress-related genes Caspase-3, HSP-70 in the fish brain. Pathological staining showed that PFAS caused multifocal demyelination and perineural vacuolization in brain, intestinal tissue also showed reduced villus length and focal damage. PFASs altered the composition of the gut microbiota of crucian carp, significantly increasing the abundance of potentially pathogenic bacteria and the potential pathogenicity of the microbiota. It is suggested that PFASs may cause varying degrees of tissue damage by destabilising the gut microbiota. These results provide insights for assessing the toxicity of PFAS contaminants at aquatic environmental concentrations.

Oxidative stress markers in brain and gonads of rabbit bucks fed herbal supplements

BackgroundCurrently, there is an increase in the usage of phytogenic feed additives to help improve animal welfare and productivity, while less emphasis is now placed on metabolic and oxidative stability of neuronal and testicular tissues. This study aims at investigating the effects of Moringa oleifera, Phyllanthus amarus and Viscum album as feed additives on some metabolic indicators and oxidative status of rabbit testis and brain. Isonitrogenous and isocaloric diets were formulated with 5% supplementation of each of the phytogenic additive to 3 treatment groups and basal diet group.ResultsIt was revealed that moringa, mistletoe, and phyllanthus can modulate oxidative status in both the brain and gonads of rabbit bucks through their unique phytochemical compositions, thereby affecting reproductive and cognitive functions. Moringa, rich in crude protein, saponins, glycosides, and steroids, enhances protein and lactate dehydrogenase levels but increases lipid peroxidation in the testis. Mistletoe, with high crude fiber, ash, and antioxidants like flavonoids and tannins, boosts total antioxidant activity in several brain regions and reduces lipid peroxidation, indicating its potential for reducing oxidative stress. Phyllanthus, having the least fiber and ash but effective antioxidant properties, notably affects the oxidative balance in both the testis and brain, with varied impacts on different tissues. The result obtained showed that total antioxidant activity of the left testis was enhanced (p < 0.05) by inclusion of the phytogenic additives, while total antioxidant activity of the right testis in bucks fed on phytogenic additives were similar (p > 0.05) to bucks on basal diet. Bucks fed on moringa and phyllanthus additives had higher (p < 0.05) testicular lipid peroxidation, lowered testicular protein and/or lactate dehydrogenase. Result also shows that lipid peroxidation of hypothalamus, cerebrum, olfactory lobe and cerebellum were lowest in bucks fed on mistletoe, phyllanthus, phyllanthus and phyllanthus, respectively. High catalase activity of optic lobe, olfactory lobe and cerebellum were observed in bucks fed on mistletoe, moringa and mistletoe, respectively, while glutathione peroxidase activity in hypothalamus, cerebrum, olfactory lobe and pineal was enhanced (p < 0.05) in bucks fed on moringa and mistletoe compared to bucks on other treatment.ConclusionM. oleifera, P. amarus and V. album leaves as phytogenic feed additives in rabbit diets have negative effect on the metabolic activity of the testis, enhancing antioxidant activity in the brain.

METTL14-Mediated m6A Modification of TUG1 Represses Ferroptosis in Alzheimer's Disease via Inhibiting GDF15 Ubiquitination.

Alzheimer's disease (AD) is a neurodegenerative disease that remains a serious global health issue. Ferroptosis has been recognized as a vital driver of pathological progression of AD. However, the detailed regulatory mechanisms of ferroptosis during AD progression remain unclear. This study aimed to explore the regulatory role and mechanism of methyltransferase like 14 (METTL14) in ferroptosis in AD models. Serum samples were collected from 18 AD patients and 18 healthy volunteers to evaluate clinical correlation. Scopolamine-treated mice and Aβ1-42-stimulated SH-SY5Y cells were served as the in vivo and in vitro models of AD. Ferroptosis was detected by reactive oxygen species (ROS), Fe2+, total iron levels, and ferroptosis-related proteins glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The N6-methyladenosine (m6A) modification was detected by RNA methylation quantification kit and methylated RNA immunoprecipitation sequencing-quantitative real-time polymerase chain reaction (MeRIP-qPCR). Molecular mechanisms were investigated by RNA pull-down, RNA immunoprecipitation (RIP), and co-immunoprecipitation (Co-IP) assays. Cognitive disorder of AD mice was measured by Morris water maze test. METTL14 was down-regulated, while lncRNA taurine upregulated gene 1 (TUG1) was up-regulated in clinical patients and experimental models of AD. Functional experiments demonstrated that METTL14 overexpression or TUG1 silencing effectively attenuated Aβ1-42-induced ferroptosis and neurotoxicity in SH-SY5Y cells. Mechanistically, METTL14-mediated m6A modification reduced the stability of TUG1. Moreover, TUG1 promoted the ubiquitination and degradation of growth differentiation factor 15 (GDF15) by directly interacted with Smad ubiquitin regulatory factor 1 (SMURF1), which consequently inactivated nuclear factor erythroid 2-related factor 2 (NRF2). Rescue experiments indicated that GDF15 depletion reversed sh-TUG1-mediated protection against ferroptosis and neurotoxicity. Finally, Mettl14 overexpression repressed ferroptosis to ameliorate the cognitive disorder via modulating Tug1/Gdf15/Nrf2 pathway in vivo. METTL14 inhibited ferroptosis to ameliorate AD pathological development by m6A modification of TUG1 to activate GDF15/NRF2 axis, providing a novel therapeutic target for AD.

Research on the Anti-Fatigue Effects and Mechanisms of Arecoline in Sleep-Deprived Mice.

This research aims to estimate the anti-fatigue effects of arecoline and explore its underlying mechanisms using a murine model of central fatigue precipitated by sleep deprivation (SD). Seventy-two male C57BL/6 mice were randomly assigned to six groups: a control group, an SD-induced fatigue model group, a group that received Rhodiola Rosea capsules (2.5 mg/kg), and three arecoline groups, which were administered at low, medium, and high doses (10, 20, and 40 mg/kg, respectively). Following 28 days of continuous administrations, the effects of arecoline on mouse fatigue-related behaviors were assessed by behavioral tests, including grip strength, rotarod performance, and weight-bearing swimming endurance. The release levels of the related biochemical markers were measured by enzyme-linked immunosorbent assays (ELISAs). Western blotting was employed to quantify the expression levels of nuclear factor erythroid 2-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase 1 (HO-1), sequestosome-1 (p62), and NADPH quinone oxidoreductase 1 (NQO1) in the gastrocnemius muscle. Arecoline administration notably enhanced grip strength, delayed the onset of fatigue as evidenced by extended latencies in rotarod tests, and increased the duration of weight-bearing swimming in mice. In the elevated plus maze, arecoline obviously decreased both the number of entries and the total distance traveled in the open arms. Arecoline markedly decreased the contents of creatine kinase, blood urea nitrogen, lactate dehydrogenase, triglycerides, and cholesterol in the serum, while it elevated the levels of total testosterone, lactate dehydrogenase, and immunoglobulin G. Furthermore, it significantly increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase in the gastrocnemius muscle, reduced malondialdehyde levels, augmented hippocampal SOD and CAT activity, and elevated glycogen stores in both liver and muscle tissues. Neurotransmitter levels showed significant increases, cytokine levels were markedly reduced, and the expressions of Nrf2, Keap1, NQO1, p62, and HO-1 in brain tissues were significantly upregulated. This study demonstrates that arecoline has anti-fatigue activity, and the specific mechanisms are associated with elevating glucose and lipid metabolism levels, relieving oxidative stress damage, inhibiting neuroinflammatory response, and regulating neurotransmitter levels and the Keap1/Nrf2/HO-1 signaling pathway. The research provides a new direction for arecoline's potential in preventing and improving fatigue.

Proteomic insights into adventitious root formation in Larix kaempferi

The adventitious root formaton (ARF) in excised plant parts is essential for the survival of isolated plant fragments. In this study, we explored the complex mechanisms of ARF in Larix kaempferi by conducting a comprehensive proteomic analysis across three distinct stages: the induction of adventitious root primordia (C1, 0–25 d), the formation of adventitious root primordia (C2, 25–35 d), and the elongation of adventitious roots (C3, 35–45 d). We identified 1976 proteins, with 263 and 156 proteins exhibiting increased abundance in the C2/C1 and C3/C2 transitions, respectively. In contrast, a decrease in the abundance of 106 and 132 proteins suggests a significant demand for metabolic processes during the C2/C1 phase. The abundance of IAA-amino acid hydrolase and S-adenosylmethionine synthase were increased in the C2/C1 phase, underscoring the role of auxin in adventitious root induction. The decrease in abundance of photosynthesis-related proteins during the C2/C1 phase highlights the significance of initial light conditions in adventitious root induction. Moreover, variation in cell wall synthesis and metabolic proteins in the C2/C1 and C3/C2 stages suggests that cell wall metabolism is integral to adventitious root regeneration. Gene Ontology enrichment analysis revealed pathways related to protein modification enzymes, including deubiquitinases and kinases, which are crucial for modulating protein modifications to promote ARF. Furthermore, the increased abundance of antioxidant enzymes, such as peroxidases and glutathione peroxidases, indicates a potential approach for enhancing ARF by supplementing the culture medium with antioxidants. Our study provides insights into metabolic changes during ARF in L. kaempferi, offering strategies to enhance adventitious root regeneration. These findings have the potential to refine plant propagation techniques and expedite breeding processes. SignficanceThe main challenge in the asexual reproduction technology of Larix kaempferi lies in adventitious root formation (ARF). While numerous studies have concentrated on the efficiency of ARF, proteomic data are currently scarce. In this study, we collected samples from three stages of ARF in L. kaempferi and subsequently performed proteomic analysis. The data generated not only reveal changes in protein abundance but also elucidate key metabolic processes involved in ARF. These insights offer a novel perspective on addressing the challenge of adventurous root regeneration.

Effects of dietary Jatropha gossypiifolia leaves extract on growth performance, antioxidant capacity, immune response, and disease resistance of African sharptooth catfish (Clarias gariepinus) infected with Aeromonas hydrophila

ABSTRACT This study investigated the effects of Jatropha gossypiifolia leaf extract (JGE) on the performance and immune response of African sharptooth catfish. Fish (6.43 ± 0.26 g, n = 450, 30/replicate) were fed diets supplemented with 0, 0.5, 1.0, 1.5, or 2.0 g JGE/kg in triplicate for 84 days. Thereafter, the fish were injected with Aeromonas hydrophila and observed for 14 days. Fish fed 1.0–1.5 g JGE had higher (P < 0.05) weight gain, protein efficiency ratio, and villi absorption area, with highest performance at 1.0 g JGE. All the fish fed JGE-supplemented diets had enhanced (P < 0.05) activities of glutathione-s-transferase and glutathione peroxidase, compared to fish fed control diet, while the variations in erythrocyte and leucocyte counts were insignificant (P > 0.05). The post-challenge fish fed JGE-supplemented diets had higher lysozyme, phagocytic, and respiratory burst activities and survival than the control treatment.

Fish gut-derived probiotic Pediococcus pentosaceus alleviates gossypol-induced intestinal inflammation by inhibiting NLRC3/NF-κB/IL-1β signal pathway in Nile tilapia

Cottonseed meal (CSM) and cottonseed protein concentrate (CPC) serve as protein alternatives to fish meal and soybean meal in the feed industry. However, the presence of gossypol residue in CSM and CPC can potentially trigger severe intestinal inflammation, thereby restricting the widespread utilization of these two protein sources. Probiotics are widely used to prevent or alleviate intestinal inflammation, but their efficacy in protecting fish against gossypol-induced enteritis remains uncertain. Here, the protective effect of Pediococcus pentosaceus, a strain isolated from the gut of Nile tilapia (Oreochromis niloticus), was evaluated. Three diets, control diet (CON), gossypol diet (GOS) and GOS supplemented with P. pentosaceus YC diet (GP), were used to feed Nile tilapia for 10 weeks. After the feeding trial, P. pentosaceus YC reduced the activity of myeloperoxidase (MPO) in the proximal intestine (PI) and distal intestine (DI). Following a 7-day exposure to Aeromonas hydrophila, the addition of P. pentosaceus YC was found to increase the survival rate of the fish. P. pentosaceus YC significantly inhibited the oxidative stress caused by gossypol, which was evidenced by lower reactive oxygen species (ROS) and malondialdehyde (MDA), as well as higher activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in PI and DI. Addition of P. pentosaceus YC significantly inhibited enteritis, with the lower expression of pro-inflammatory cytokines (il-1β, il-6, il-8) and higher expression of anti-inflammatory cytokines tgf-β. RNA-seq analysis indicated that P. pentosaceus YC supplementation significantly inhibited nlrc3 and promoted nf-κb expression in PI and DI, and the siRNA interference experiment in vivo demonstrated that intestinal inflammation was mediated by NLRC3/NF-κB/IL-1β signaling pathway. Fecal bacteria transplantation experiment demonstrated that gut microbiota mediated the protective effect of P. pentosaceus YC. These findings offer valuable insights into the application of P. pentosaceus YC for alleviating gossypol-induced intestinal inflammation in fish.

Cairo pentagon tessellated covalent organic frameworks with mcm topology for near-infrared phototherapy

Despite the prevalent of hexagonal, tetragonal, and triangular pore structures in two-dimensional covalent organic frameworks (2D COFs), the pentagonal pores remain conspicuously absent. We herein present the Cairo pentagonal tessellated COFs, achieved through precisely chosen geometry and metrics of the linkers, resulting in unprecedented mcm topology. In each pentagonal structure, porphyrin units create four uniform sides around 15.5 Å with 90° angles, while tetrabiphenyl unit establish a bottom edge about 11.6 Å with 120° angles, aligning precisely with the criteria of Cairo Pentagon. According to the narrow bandgap and strong near-infrared (NIR) absorbance, as-synthesized COFs exhibit the efficient singlet oxygen (1O2) generation and photothermal conversion, resulting in NIR photothermal combined photodynamic therapy to guide cancer cell apoptosis. Mechanistic studies reveal that the good 1O2 production capability upregulates intracellular lipid peroxidation, leading to glutathione depletion, low expression of glutathione peroxidase 4, and induction of ferroptosis. The implementation of pentagonal Cairo tessellations in this work provides a promising strategy for diversifying COFs with new topologies, along with multimodal NIR phototherapy.

Gene Polymorphisms of the antioxidant enzymes NOX, GSTP, and GPX and diabetic nephropathy risk in Saudi patients with type 2 diabetes

Oxidative stress has been hypothesized to play a crucial role in the complications of type 2 diabetes (T2D). Hyperglycaemia-mediated increases in free radicals have a deleterious effect on cellular compartments and nucleic acids, leading to imbalances between free radicals and antioxidant enzymes. This case–control study comprised two groups with 100 participants (50 T2D and 50 DN patients) and aimed to examine the association between single-nucleotide polymorphisms (SNPs) in the genes encoding nicotinamide adenine dinucleotide phosphate oxidase (NOX), glutathione S-transferase P (GSTP1), and glutathione peroxidase 1(GPX1) and diabetic nephropathy (DN) risk in patients with T2D. An SNP genotyping assay was performed using TaqMan assay and real-time PCR to identify the SNPs (NOX rs4673, GSTP rs1695, GPX1 rs1050450). The Sanger method was used to validate our findings. Fisher chi-square analyses revealed no significant differences in these genes when comparing T2D patients with and without DN. Our findings suggest no association between the rs4673, rs1695, and rs1050450 SNPs and DN in Saudi patients with T2D.