Redox Report最新文献

Objectives: The objective of this study was to investigate whether skeletal muscle cystathionine γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (Cth^Δskm) mice.

Methods: The Cth^Δskm mice and littermate Cth-floxed (Cth^f/f) mice were fed with either HFD or chow diet for 13 weeks. Metabolomics and transcriptome analysis were used to assess the impact of CTH deficiency in skeletal muscle.

Results: Metabolomics coupled with transcriptome showed that Cth^Δskm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cth^f/f mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. Cth^Δskm+HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cth^f/f+HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in Cth^Δskm+HFD mice. Omics analysis showed differential pathways enriched between Cth^Δskm mice and Cth^f/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in Cth^Δskm+HFD mice compared to Cth^f/f+HFD mice.

Discussion: Our results indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.

Jaceosidin (JAC) is a natural flavonoid with anti-oxidant and other pharmacological activities; however, its anti-cancer mechanism remains unclear. We investigated the mechanism of action of JAC in gastric cancer cells. Cytotoxicity and apoptosis assays showed that JAC effectively killed multiple gastric cancer cells and induced apoptosis in human gastric adenocarcinoma AGS cells via the mitochondrial pathway. Network pharmacological analysis suggested that its activity was linked to reactive oxygen species (ROS), AKT, and MAPK signaling pathways. Furthermore, JAC accumulated ROS to up-regulate p-JNK, p-p38, and IκB-α protein expressions and down-regulate the p-ERK, p-STAT3, and NF-κB protein expressions. Cell cycle assay results showed that JAC accumulated ROS to up-regulate p21 and p27 protein expressions and down-regulate p-AKT, CDK2, CDK4, CDK6, Cyclin D1, and Cyclin E protein expressions to induce G0/G1 phase arrest. Cell migration assay results showed JAC accumulated ROS to down-regulate Wnt-3a, p-GSK-3β, N-cadherin, and β-catenin protein expressions and up-regulate E-cadherin protein expression to inhibit migration. Furthermore, N-acetyl cysteine pre-treatment prevented the change of these protein expressions. In summary, JAC induced apoptosis and G0/G1 phase arrest and inhibited migration through ROS-mediated signaling pathways in AGS cells.

Oxalate-induced damage to renal tubular epithelial cells (RTECs) is an essential factor in the incident kidney stone, but the specific mechanism is unclear. Recent research has pinpointed interacting areas within the endoplasmic reticulum and mitochondria, called mitochondria-associated membranes (MAMs). These studies have linked endoplasmic reticulum stress (ERS) and oxidative imbalance to kidney disease development. The sigma-1 receptor (S1R), a specific protein found in MAMs, is involved in various physiological processes, but its role in oxalate-induced kidney stone formation remains unclear. In this study, we established cellular and rat models of oxalate-induced kidney stone formation to elucidate the S1R's effects against ERS and apoptosis and its mechanism in oxalate-induced RTEC injury. We found that oxalate downregulated S1R expression in RTECs and escalated oxidative stress and ERS, culminating in increased apoptosis. The S1R agonist dimemorfan up-regulated S1R expression and mitigated ERS and oxidative stress, thereby reducing apoptosis. This protective effect was mediated through S1R inhibition of the CHOP pathway. Animal experiments demonstrated that S1R's activation attenuated oxalate-induced kidney injury and alleviated kidney stone formation. This is the first study to establish the connection between S1R and kidney stones, suggesting S1R's protective role in inhibiting ERS-mediated apoptosis to ameliorate kidney stone formation.

Purpose: To investigate the renal pathophysiological processes and protective effect of quercetin on contrast-induced acute kidney injury (CI-AKI) in mice with type 1 diabetic mellitus(DM) using diffusion tensor imaging(DTI).Methods: Mice with DM were divided into two groups. In the diabetic + contrast medium(DCA) group, the changes of the mice kidneys were monitored at 1, 24, 48, and 72 h after the injection of iodixanol(4gI/kg). The mice in the diabetic + contrast medium + quercetin(DCA + QE) group were orally given different concentrations of quercetin for seven days before injection of iodixanol. In vitro experiments, renal tubular epithelial (HK-2) cells exposed to high glucose conditions were treated with various quercetin concentrations before treatment with iodixanol(250 mgI/mL).Results: DTI-derived mean diffusivity(MD) and fractional anisotropy(FA) values can be used to evaluate CI-AKI effectively. Quercetin significantly increased the expression of Sirt 1 and reduced oxidative stress by increasing Nrf 2/HO-1/SOD1. The antiapoptotic effect of quercetin on CI-AKI was revealed by decreasing proteins level and by reducing the number of apoptosis-positive cells. In addition, flow cytometry indicated quercetin-mediated inhibition of M1 macrophage polarization in the CI-AKI.Conclusions: DTI will be an effective noninvasive tool in diagnosing CI-AKI. Quercetin attenuates CI-AKI on the basis of DM through anti-oxidative stress, apoptosis, and inflammation.

Objective: The study will be to observe the effect of Sodium butyrate (NaB) on bone loss in lipopolysaccharide (LPS)-treated rats.

Methods: In the rat model, we observed that changes in the expression of oxidative stress regulators, inflammatory markers and target genes were measured by immunofluorescence and RT-PCR after treatment. Changes in viability and osteogenesis of MC3T3-E1, osteoclast differentiation in RAW264.7 cells in the presence of LPS were evaluated using CCK-8, ALP staining, RES staining, and TRAP staining.

Results: In vitro experiments have shown that LPS-induced inhibition of JC-1, SIRT1, GPX1 and SOD2 is associated with increased levels of inflammation and oxidative stress. In addition, NaB has been found to suppress oxidative stress, inflammation and Mito SOX, promote osteogenic differentiation, and inhibit osteoclast differentiation. In addition, NaB significantly promoted SITR1 expression, repaired impaired bone metabolism, and improved bone strength and bone mineral density.

Conclusion: Given all this experimental evidence, the results strongly suggest that NaB can restore osteogenic activity in the presence of LPS by reducing intracellular ROS, inhibiting osteoclast differentiation and reducing bone loss in LPS-treated rat models.

Objective: This study investigates how astaxanthin (AST) counters tert-butyl hydroperoxide (tBHP)-induced cellular damage in C28/I2 chondrocytes, focusing on the circ-HP1BP3/miR-139-5p/SOD1 signaling pathway and its use in sustained-release microspheres for osteoarthritis treatment.

Methods: We employed a variety of techniques including real-time quantitative PCR, Western blot, ELISA, and dual-luciferase reporter gene assays to explore AST's molecular effects. Additionally, the efficacy of AST-loaded sustained-release microspheres was evaluated in vitro and in a mouse model of osteoarthritis.

Results: AST significantly enhanced SOD1 expression, reducing apoptosis and inflammation in damaged cells. The AST-loaded microspheres showed promising in vitro drug release, improved cell viability, and reduced oxidative stress. In the osteoarthritis mouse model, they effectively decreased joint inflammation and increased the expression of chondrocyte markers.

Conclusion: Astaxanthin effectively mitigates oxidative stress and inflammation in chondrocytes via the circ-HP1BP3/miR-139-5p/SOD1 pathway. The development of AST-loaded microspheres offers a novel and promising approach for osteoarthritis therapy, potentially extending to osteoarthritis treatment.

Objectives: Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism.

Methods: The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot.

Results: An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385.

Discussion: Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.

Alzheimer's disease is a neurodegenerative disease involving memory impairment, confusion, and behavioural changes. The disease is characterised by the accumulation of amyloid beta plaques and neurofibrillary tangles in the brain, which disrupt normal neuronal function. There is no known cure for Alzheimer's disease and due to increasing life expectancy, occurrence is projected to rise over the coming decades. The causes of Alzheimer's disease are multifactorial with inflammation, oxidative stress, genetic and epigenetic variation, and cerebrovascular abnormalities among the strongest contributors. We review the current literature surrounding inflammation and epigenetics in Alzheimer's disease, with a focus on how oxidants from infiltrating immune cells have the potential to alter DNA methylation profiles in the ageing brain.

Objectives: To investigate the role of selenium and selenium-containing proteins in the etiology and pathogenesis of kidney stones.Methods: The HK-2 cell line was subjected to supersaturation oxalate treatment to establish an in vitro model of calcium oxalate kidney stones, while SD rats were administered with ethylene glycol to establish an in vivo model of calcium oxalate kidney stones. qPCR analysis was employed to investigate the alterations in selenoproteins within the models, and subsequently, genes exhibiting significant changes were identified. Subsequently, based on the functions of these genes, their regulatory effects on endoplasmic reticulum stress (ERS) and apoptosis during the disease progression were examined both in HK-2 cells and rat kidneys. Finally, Selenomethionine (SeMet) supplementation was introduced to explore its therapeutic potential for kidney stone management.Results: The involvement of Selenoprotein K in the pathogenesis of calcium oxalate kidney stone disease has been confirmed, exhibiting significant alterations. Manipulation of its expression levels through overexpression and knockdown techniques resulted in a corresponding reduction or increase in oxidative stress, ERS, and apoptosis within renal tubular epithelial cells. SelK regulates ERS and apoptosis by controlling the IRE1-ASK1-JNK pathway. In addition, SeMet treatment, which contains selenium, effectively reduced the levels of oxidative stress, ERS, and apoptosis in vivo and in vitro models, thereby alleviating tubular epithelial cell damage and reducing the formation of kidney stones in experimental rats.Discussion: Selenium is involved in the occurrence and development of kidney stones by regulating oxidative damage to renal tubular epithelial cells. The results suggest that dietary selenium supplementation in daily life may be of great significance for the prevention and treatment of kidney stones.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe disease with a poor prognosis, whose clinical treatment is still limited to therapeutic hypothermia with limited efficacy. Perillyl alcohol (POH), a natural monoterpene found in various plant essential oils, has shown neuroprotective properties, though its effects on HIE are not well understood. This study investigates the neuroprotective effects of POH on HIE both in vitro and in vivo. We established an in vitro model using glucose deprivation and hypoxia/reperfusion (OGD/R) in PC12 cells, alongside an in vivo model via the modified Rice-Vannucci method. Results indicated that POH acted as an indirect antioxidant, reducing inducible nitric oxide synthase and malondialdehyde production, maintaining content of antioxidant molecules and enzymes in OGD/R-induced PC12 cells. In vivo, POH remarkably lessened infarct volume, reduced cerebral edema, accelerated tissue regeneration, and blocked reactive astrogliosis after hypoxic-ischemic brain injury. POH exerted antiapoptotic activities through both the intrinsic and extrinsic apoptotic pathways. Mechanistically, POH activated Nrf2 and inactivated its negative regulator Keap1. The use of ML385, a Nrf2 inhibitor, reversed these effects. Overall, POH mitigates neuronal damage in HIE by combating oxidative stress, reducing inflammation, and inhibiting apoptosis via the Nrf2/Keap1 pathway, suggesting its potential for HIE treatment.