Redox Report最新文献

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.

Background: Diabetic cataract (DC) is a major cause of blindness, with its pathogenesis involving oxidative stress and ferroptosis, according to recent studies.

Methods: We performed a Mendelian Randomization (MR) study using GWAS data to select SNPs and assess the causal link between diabetes and cataracts. DC datasets were analyzed for differential gene expression, WGCNA, and protein-protein interactions to identify key oxidative stress and ferroptosis genes. An SVM-RFE algorithm developed a diagnostic model, and ImmuCellAI analyzed immune infiltration patterns.

Results: MR analysis confirmed diabetes as a cataract risk factor and identified core genes related to oxidative stress and ferroptosis in DC. Four key genes (Hspa5/Nfe2l2/Atf3/Stat3) linked to both processes were discovered. Immune infiltration analysis revealed an imbalance associated with these genes.

Conclusions: A functional interaction between oxidative stress and ferroptosis genes in DC is suggested, with a 4-gene model, indicating their potential as a 'bridge' in DC pathogenesis.

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.

Gasotransmitters play crucial roles in regulating many physiological processes, including cell signaling, cellular proliferation, angiogenesis, mitochondrial function, antioxidant production, nervous system functions and immune responses. Hydrogen sulfide (H₂S) is the most recently identified gasotransmitter, which is characterized by its biphasic behavior. At low concentrations, H₂S promotes cellular bioenergetics, whereas at high concentrations, it can exert cytotoxic effects. Cystathionine β-synthetase (CBS), cystathionine-γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST), and cysteinyl-tRNA synthetase 2 (CARS2) are pivotal players in H₂S biosynthesis in mammalian cells and tissues. The focus of this review is the regulation of the various pathways involved in H₂S metabolism in various forms of cancer. Key enzymes in this process include the sulfide oxidation unit (SOU), which includes sulfide:quinone oxidoreductase (SQOR), human ethylmalonic encephalopathy protein 1 (hETHE1), rhodanese, sulfite oxidase (SUOX/SO), and cytochrome c oxidase (CcO) enzymes. Furthermore, the potential role of H₂S methylation processes mediated by thiol S-methyltransferase (TMT) and thioether S-methyltransferase (TEMT) is outlined in cancer biology, with potential opportunities for targeting them for clinical translation. In order to understand the role of H₂S in oncogenesis and tumor progression, one must appreciate the intricate interplay between H₂S-synthesizing and H₂S-catabolizing enzymes.

Objectives: Necrotizing enterocolitis (NEC) is a common and sometimes fatal disease affecting premature infants. Elevated formate has been found in the stool of patients with NEC. Sodium formate (NaF) is used to explore the role of formate in the intestinal epithelial injury.

Methods: In this study, 150 mM NaF solution was intraluminally injected in 14-day-old and 28-day-old mice. Mice were sacrificed after 24 h of feces collection, and the blood and small intestinal tissues were collected to detect the pathological damage of intestinal tissue, intestinal permeability, oxidative stress indicators including SOD, HO-1, MDA, and 4-HNE, inflammatory cytokines including IL-1β, TNF-α and IL-6, mitochondrial function such as ATP and PGC-1α in mice intestinal tissue, indicators of the cell death modes including necroptosis-related protein RIPK1 and p-MLKL, and apoptosis- related protein cleaved-caspase-3 and p-AKT (S473).

Results: NaF treatment significantly damaged intestinal epithelial tissue and barrier function, caused mitochondrial dysfunction, manifesting as decreased ATP and PGC-1α levels, increased lipid peroxidation products MDA and 4-HNE, depleted antioxidant enzyme SOD, and upregulated the expression of HO-1. Furthermore, NaF treatment induced inflammatory responses by promoting the release of IL-1β, IL-6 and TNF-α in a development-dependent manner, eventually inducing necroptosis and apoptosis.

Conclusions: Formate may be a source of metabolic intestinal injury contributing to the pathogenesis of NEC in human newborns.

Objectives: The molecular mechanism underlying the protective effects of DEX against sepsis-induced acute kidney injury (SAKI) remains to be elucidated.

Methods: We established S-AKI models in vivo via CLP and in vitro with LPS-induced HK-2 cells.

Results: The Nrf2/SLC7A11/FSP1/CoQ10 pathway was inhibited in S-AKI both in vitro and in vivo. The overexpression of Nrf2 inhibited LPS-induced ferroptosis by activating the SLC7A11/FSP1/CoQ10 pathway. DEX ameliorated kidney tissue damage, as determined by a decrease in BUN, Cr, and inflammatory factor levels, along with renal tubule vacuolation and inflammatory cell infiltration in S-AKI mice. Additionally, DEX treatment significantly ameliorated ferroptosis in S-AKI in vitro and in vivo, as indicated by an improvement in mitochondrial shrinkage and disruption of cristae, a decrease in iron, ROS, MDA, and 4-HNE levels, and an increase in GSH and GPX4 levels. Mechanistically, DEX treatment restored the reduction of Nrf2 expression and nuclear translocation in S-AKI, as well as, the levels of downstream SLC7A11, FSP1, and CoQ10. Knocking down Nrf2 in vitro and administering brusatol in vivo eliminated the protective effect of DEX against S-AKI.

Conclusions: DEX mitigated ferroptosis and attenuated S-AKI by activating the Nrf2/SLC7A11/FSP1/CoQ10 pathway. Abbreviation: CLP: Cecal ligation puncture; LPS: Lipopolysaccharide; Nrf2: Nuclear factor-erythroid- 2-related factor 2; SLC7A11: Solute carrier family 7 member 11; FSP1: Ferroptosis suppressor protein 1; CoQ10: Coenzyme Q10; BUN: Blood urea nitrogen; Cr: Serum creatinine; ROS: Reactive oxygen species; MDA: Malondialdehyde; 4-HNE: 4-hydroxynonenal; GSH: Hlutathione; GPX4: Glutathione peroxidase 4.

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.

Objectives: Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes and is the most common cause of end-stage renal disease. Tripartite motif-containing (TRIM) proteins are a large family of E3 ubiquitin ligases that contribute to protein quality control by regulating the ubiquitin - proteasome system. However, the detailed mechanisms through which various TRIM proteins regulate downstream events have not yet been fully elucidated. The current research aimed to determine the function and mechanism of TRIM22 in DN.

Methods: DN models were established by inducing HK-2 cells using high glucose (HG) and diabetic mice (db/db mice). Cell viability, apoptosis, mitochondrial reactive oxygen species, and mitochondrial membrane potential were detected by Cell Counting Kit-8 and flow cytometry, respectively. Pathological changes were evaluated using hematoxylin and eosin, periodic acid schiff and Masson staining. The binding between TRIM22 and optic atrophy 1 (OPA1) was analyzed using co-immunoprecipitation. The m⁶A level of TRIM22 5'UTR was detected using RNA immunoprecipitation.

Results: TRIM22 was highly expressed in patients with DN. TRIM22 silencing inhibited HG-induced apoptosis and mitochondrial dysfunction in HK-2 cells. Promoting mitochondrial fusion alleviated TRIM22 overexpression-induced cell apoptosis, mitochondrial dysfunction in HK-2 cells, and kidney damage in mice. Mechanistically, TRIM22 interacted with OPA1 and induced its ubiquitination. Wilms tumor 1-associating protein (WTAP) promoted m⁶A modification of TRIM22 through the m⁶A reader insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).

Discussion: TRIM22 silencing inhibited the progression of DN by interacting with OPA1 and inducing its ubiquitination. Furthermore, WTAP promoted m⁶A modification of TRIM22 via IGF2BP1.