Redox Report最新文献

Background: Alopecia is a global dermatological challenge. Adipose-derived stem cells (ADSC) show therapeutic potential, but their mechanisms in promoting hair regrowth, particularly under oxidative stress conditions, remain unclear..

Objective: To investigate ADSC's role in promoting hair regrowth by mitigating oxidative stress.

Methods: Using H₂O₂-stressed HaCaT cells, ADSC's protective effects were evaluated via conditioned medium (CM) and co-culture. Assessments included cell viability, colony formation, ROS, MDA, antioxidant enzymes, and 8-OHdG. Nrf2 activation was analyzed by immunofluorescence and Western blot. A mouse radiation injury model validated findings.

Results: Non-pretreated ADSC offered limited oxidative protection to HaCaT cells. Conversely, H₂O₂-pretreated ADSC significantly enhanced HaCaT viability and proliferation in both CM and co-culture systems. This involved paracrine activation of the Nrf2 pathway in HaCaT cells, boosting antioxidant enzymes, accelerating ROS clearance, and reducing lipid peroxidation. These effects were reversible with Nrf2 inhibition. In vivo, CM from H₂O₂-stimulated ADSC promoted hair regrowth in irradiated mice, outperforming CM from non-pretreated ADSC by activating Nrf2 and reducing tissue oxidative damage.

Conclusions: Oxidative stress potentiates the protective capacity of ADSC against oxidative via Nrf2-dependent paracrine mechanisms, offering a promising strategy for alopecia treatment.

Heatstroke (HS)-induced acute lung injury (ALI) has high morbidity and mortality with no specific therapies. Ferroptosis, a form of programmed cell death driven by lipid peroxidation due to reduced Glutathione Peroxidase 4 (GPX4) activity, is closely linked to HS-induced ALI. This study investigated the effect of alpha-linolenic acid (ALA), a plant-derived ω-3 fatty acid, on ferroptosis in a mouse model of HS-induced ALI. Histopathology analysis found that ALA can attenuate lung injury and improve the 7-day survival rate in mice with HS-induced ALI. In addition, ALA significantly reduced the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing the level of antioxidant glutathione (GSH). Further analysis showed that ALA upregulated the levels of SLC7A11 and GPX4 by promoting the nuclear translocation of Nrf2. This led to increased GSH synthesis but reduced ROS accumulation, which in turn suppressed ferroptosis and protected the mice against HS-induced ALI. Additionally, the protective effect of ALA was found to be diminished in Nrf2-deficient mice. In summary, ALA inhibits ferroptosis in macrophages by activating the Nrf2/SLC7A11/GPX4 pathway and attenuates HS-induced ALI.

Background: The adaptation of the redox system and bioenergetics is a major factor contributing to cancer metabolism. Redox therapy is promising but still requires molecular studies that consider the reactive species interactome (RSI) concept, which integrates reactive oxygen, nitrogen, sulfur, carbonyl species, and redox enzymes. Our aim was to decipher the role of the RSI in glioblastoma (GBM), including by challenging the RSI with the MnTBAP redox agent.

Methods: The effects of MnTBAP on the redox system and bioenergetics were investigated on several GBM models, namely in vitro 2D culture, in vitro 3D culture with two human GBM tumoroids, and in vivo preclinical model, which included male and female comparisons.

Results: We show - for the first time - that MnTBAP represses the sulfide:quinone oxidoreductase (SQOR) involved in the sulfur metabolism and bioenergetics, and targets the RSI through the sulfido-redox system. Through in vitro silencing and overexpression approaches, we also demonstrate that SQOR contributed to GBM cell growth and that its decrease is involved in the molecular effect of MnTBAP. Consequently, MnTBAP induces a switch between apoptosis, uncontrolled necrosis, and ferroptosis depending on the glioblastoma models.

Conclusion: Our findings represent the next step in establishing a better understanding of redox biology in the context of GBM.

Background: Ultraviolet B (UVB) radiation contributes to skin disorders such as photodamage, photoaging, and cancer. Natural antioxidants can mitigate UVB-induced damage. Pinus morrisonicola (Taiwan white pine), known for its anti-cancer, anti-inflammatory, and antioxidant properties, is used in health-promoting beverages, but its skin-protective effects remain underexplored.

Purpose: This study investigates the protective effects of P. morrisonicola leaf essential oil (PMLEO) against UVB-induced damage in HaCaT keratinocytes.

Methods: HaCaT cells were exposed to UVB and treated with PMLEO. Cell viability, reactive oxygen species (ROS) levels, and antioxidant enzyme expression were assessed. The role of Nrf2, a key antioxidant regulator, was evaluated through knockdown experiments. The effects on UVB-induced melanogenesis were examined via α-MSH secretion followed by p53-mediated POMC expression.

Results: PMLEO and P. morrisonicola bark essential oil (PMBEO) were non-cytotoxic up to 200 µg/mL. UVB reduced cell viability to 43%, but PMLEO co-treatment significantly restored viability and reduced ROS levels via Nrf2 activation, increasing NQO-1 and HO-1. Nrf2 knockdown impaired PMLEO's protection. PMLEO also inhibited UVB-induced α-MSH secretion by downregulating p53-mediated POMC expression, suggesting an anti-melanogenic effect.

Conclusion: PMLEO protects dermal keratinocytes against UVB-induced oxidative stress, cell death, and melanogenesis via Nrf2 activation, highlighting its potential as a natural skin protectant.

Background: Mitochondrial division is one of the main characteristics for the initiation of myogenic differentiation. However, the role and mechanism of Dynamin-related protein 1 (Drp1), the most important protein that regulates mitochondrial fission in mammals, in regulating myogenic differentiation are not well understood.

Methods: Drp1 siRNAs were transfected to C2C12 cells, or AAV9-shDrp1 were injected to C57BL/6J mice to knockdown Drp1 expression. Then, mitochondrial damage, ROS level, myogenic differentiation, mitophagy and actin/MRTF-A/SRF pathway was detected by quantitative real-time PCR, western blotting, immunofluorescence staining and flow cytometry.

Results: The results showed that Drp1 was upregulated after C2C12 differentiation; Drp1 knockdown by siRNA transfection impaired myotube formation. ROS are the upstream activators for Drp1 expression, and Drp1 inversely reduces ROS by facilitating mitophagy to form a ROS-Drp1-mitophagy feedback loop during myogenic differentiation. Knockdown of Drp1 disrupted the ROS-Drp1-mitophagy feedback loop-mediated ROS homeostasis, thereby accelerating F-action depolymerization and blocking MRTF-A nuclear translocation by reducing the phosphorylation of cofilin. A decrease in MRTF-A nuclear translocation impaired SRF activity and hindered myogenic differentiation.

Conclusion: In summary, this study revealed the functional mechanism of Drp1 and clarified the interactions among ROS, Drp1-mediated mitophagy and actin cytoskeleton remodeling during myogenic differentiation.

Background: Iron continues to be linked to the pathogenesis of neurodegenerative disorders including HIV-1 associated neurocognitive disorders (HAND). People with HIV-1 who use opioids have a higher risk of developing HAND, and HIV-1 proteins and opioids disrupt endolysosome iron homeostasis, increase reactive oxygen species (ROS), and cause neural cell death. Endolysosomes are subcellular acidic organelles that regulate iron metabolism and redox homeostasis. HIV-1 gp120 and opioids induce endolysosome iron release, increasing cytosolic and in mitochondrial iron and ROS and inducing neurotoxicity. However, ROS represent only part of the reactive species interactome (RSI) and little is known about the extent to which HIV-1 proteins and opioids affect the RSI.

Results: In SH-SY5Y and U87MG cells, HIV-1 gp120, morphine, and iron supplementation de-acidified endolysosomes, decreased endolysosome Fe²⁺ and H₂S, and increased ROS, lipid peroxidation (LPO) and NO. These changes were accompanied by increased cytosolic and mitochondrial Fe²⁺, ROS, LPO, and NO, decreased H₂S, and increased cell death. All effects were blocked by the endolysosome-specific iron chelator deferoxamine.

Conclusion: Endolysosome iron dyshomeostasis induced by HIV-1 gp120, morphine and iron supplementation disrupts inter-organellar iron signaling and RSI homeostasis. Targeting endolysosome iron may mitigate neurotoxicity in HAND and other disorders associated with iron overload and redox imbalance.

Selenium (Se) is linked to physiological homeostasis. Male mice (n = 8/group) were fed control (AIN93G) or diets enriched in sodium selenite (NaSe, 5.6 ppm), methylselenocysteine (Met, 4.7 ppm), diphenyl diselenide (DPDS, 14.2 ppm), or nanoselenium (NanoSe, 2.7 ppm); dietary Se ascertained by inductively-coupled plasma mass spectrometry. At 4 weeks testes, sperm, thyroids, blood and stool were collected to assess histoarchitecture, circulating hormones (thyroxine, T4; triiodothyronine, T3; thyroid stimulating hormone, TSH) and gut microbiome (16S rRNAV3-V4 amplicon sequencing). Supplemented NaSe, Met, and NanoSe increased plasma testosterone and testis glutathione peroxidases (GPx-1/4) while testicular superoxide dismutase and catalase increased slightly in the NanoSe group indicating a selective antioxidant response. Overall, NanoSe and NaSe enhanced male reproductive factors. All thyroids isolated from Se-supplemented mice contained marginal vacuoles and a lower follicle area vs control. Nano-Se enhanced thyroidiodothyronine deiodinase-1 (DIO1) expression however, thyroid GPx-1/4 remained unchanged. Supplemented NaSe and DPDSl increased plasma T3/T4 ratio, while plasma TSH was unchanged. Microbiome analyses showed that NanoSe was most efficacious in altering composition (judged by α-diversity, Shannon index and taxon richness) while the NaSe diet showed the greatest overall change in α-diversity. Dietary Se supplementation, particularly encapsulated NanoSe, may improve male fertility factors by enhancing the gut-thyroid-fertility axis.

Renal fibrosis is a key factor in the progression of chronic kidney disease (CKD), and current treatments remain inadequate. In this study, we investigated the therapeutic effects of cynaroside (Cyn), a natural flavonoid, in a mouse model of renal fibrosis induced by unilateral ureteral obstruction. Cyn treatment significantly ameliorated tubular injury and interstitial fibrosis while improving renal function. Mechanistically, Cyn inhibited the expression of fibrosis-related proteins and suppressed Smad2/3 phosphorylation. Additionally, Cyn reduced myofibroblast accumulation by inhibiting epithelial-mesenchymal transition, as indicated by increased E-cadherin expression and decreased levels of mesenchymal markers. Cyn also reduced oxidative stress by downregulating the prooxidant enzyme NADPH oxidase 4 and restoring antioxidant enzymes. Furthermore, Cyn attenuated ferroptosis by regulating key proteins, including acyl-CoA synthetase long-chain family member 4, transferrin receptor 1, and glutathione peroxidase 4, while also restoring glutathione levels. Cyn alleviated endoplasmic reticulum stress, as evidenced by the downregulation of key markers such as glucose-regulated protein 78 and activating transcription factor 6, and reduced inflammation, as confirmed by decreased macrophage infiltration and lower cytokine production. Overall, Cyn demonstrated broad protective effects against renal fibrosis by modulating oxidative stress, ferroptosis, ER stress, and inflammation, positioning it as a potential therapeutic agent for CKD management.

Inflammation is associated with a wide range of medical conditions, most leading causes of death, and high healthcare costs. It can thus benefit from new insights. Here we extended previous studies and found that oxidation of human native mtRNA to 'mitoxRNA' strongly potentiated IFNβ and TNFα immunostimulation in human cells, and that this newly identified type 1 interferon potentiation was transcriptional. This potentiation was significantly greater than with mtDNA oxidation, and t-butylhydroperoxide (tBHP) oxidation of RNA was more proinflammatory than hydrogen peroxide (HP). mtRNA triggered a modest increase in apoptosis that was not potentiated by oxidation, and mtDNA triggered a much greater increase. For native mtRNA, we found that chloroquine-inhibitable endosomes and MDA5 are key signaling pathways for IFNβ and TNFα production. For mitoxRNAs, RNAseq revealed a major increase in both tBHP- and HP-mitoxRNA modulated genes compared with native mtRNA. This increase was very prominent for interferon-related genes, identifying them as important mediators of this powerful oxidation effect. Moderately different gene modulations and KEGG pathways were observed for tBHP- versus HP-mitoxRNAs. These studies reveal the profound effect that mitochondrial RNA oxidation has on immunostimulation, providing new insights into DAMP inflammation and identifying potential therapeutic targets to minimize DAMP mtRNA/mitoxRNA-mediated inflammation.

Background: Diabetic nephropathy (DN) is the most common complication of diabetes mellitus. It has shown that the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) could attenuate DN. To identifiy novel Nrf2 activators targeting DN, we explored drynachromoside A (DCSA) from Drynaria fortunei in vitro and in vivo.

Methods: To determine the effects of DCSA, the proliferation of mesangial cells induced by high glucose was evaluated. And the renal function of db/db mice was evaluated. Meanwhile, oxidative stress and renal fibrosis in vitro and in vivo were further investigated. To elucidate the mechanism of DCSA, Nrf2 activation and its role in these effects were explored, and the interaction between Kelch-like ECH-associated protein 1 (Keap1) and DCSA was examined.

Results: DCSA inhibited the proliferation of mesangial cells resulting from high glucose and improved renal function in db/db mice. DCSA attenuated oxidative stress and fibrosis in vitro and in vivo, which was closely associated with Nrf2 activation in a Keap1-dependent manner.

Conclusion: DCSA identified in Drynaria fortunei is a Keap1-dependent Nrf2 activator with the potential to attenuate DN. This investigation could provide novel insights into the discovery of Nrf2 activators and new therapeutic approaches for DN.