Antioxidants & redox signaling最新文献

Aims: Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the aggregation of alpha-synuclein (α-syn) in Lewy bodies. Emerging studies find that disruption of the Golgi structure and Golgi stress are involved in PD. Thioredoxin-1 (Trx-1) is a redox regulatory protein that protects DA neurons from methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) damage. However, whether Trx-1 can protect DA neurons against MPTP-induced Golgi stress is still unknown.

Results: We first made sure that MPTP led to the loss of DA neurons in the SNpc and motor impairment in mice, which was reversed in Trx-1 overexpression mice. Trx-1 overexpression suppressed Golgi apparatus fragmentation, α-syn aggregation, oxidative stress, and protein kinase C zeta expression increased by MPTP. Trx-1 overexpression restored the colocalization of Trx-1 and tyrosine hydroxylase with Golgi matrix protein 130 (GM130), decreased by MPTP. Moreover, Trx-1 overexpression suppressed the increased co-localization of Leucine-rich repeat kinase 2 and Ras-associated binding protein 29 with vacuolar protein sorting-associated protein 52 induced by MPTP. Trx-1 overexpression suppressed the expression changes of ADP-ribosylation factor 4 and heat shock protein 47, and their colocalization with GM130 induced by MPTP.

Innovation: Our study reveals a novel mechanism, whereby Trx-1 inhibits Golgi stress in DA neuron induced by MPTP.

Conclusions: These results suggest that Trx-1 may regulate the development of PD through inhibiting Golgi stress and is a potential new molecular target and therapeutic strategy for Golgi stress involved in PD. Antioxid. Redox Signal. 00, 000-000.

Background: To evaluate the impact of the composite dietary antioxidant index (CDAI) on the progression from hypertension (HT) to cardiovascular diseases (CVDs) and subsequent death.

Methods: This prospective study included 100,193 participants (median age 55) initially free of HT and CVDs from the UK Biobank. The CDAI was calculated from the intake of six dietary antioxidants, including manganese, selenium, zinc, and vitamins A, C, and E. Multivariable Cox regression analysis assessed the relationship between CDAI and the risks of HT, CVDs, and all-cause mortality. Multistate models were used to examine the impact of CDAI levels on CVD progression trajectories.

Results: During a median follow-up of 14.10 years, 11,998 participants developed HT, 3656 developed CVDs, and 4169 died. CDAI was inversely associated with the risk of adverse outcomes, including HT, CVDs, and death. Compared with the lowest CDAI quartile, the adjusted hazard ratios (HRs; confidence intervals [CIs]) for the highest quartile in transitions from baseline to HT, to CVDs, and to death were 0.913 (0.868-0.960), 0.890 (0.799-0.992), and 0.850 (0.767-0.942), respectively. An association between the highest quartile CDAI and reduced risk was also observed in transitions from HT to CVDs (HR: 0.698; 95% CI: 0.558-0.872) and from HT to death (HR: 0.803; 95% CI: 0.648-0.995). Mediation analysis indicates that the reduction in CVD and mortality risk associated with CDAI primarily depends on its direct effect rather than its indirect effect through HT.

Conclusions: The CDAI influences the progression of CVD trajectories, underscoring the need for dietary adjustments to elevate CDAI levels in CVD health management. Antioxid. Redox Signal. 00, 000-000.

Aims: Hypothyroidism frequently causes myocardial injury, but the role of thyroid hormone receptor alpha (THRA) remains unclear. This study investigated the function and mechanism of THRA in hypothyroidism-associated cardiac damage.

Methods: A propylthiouracil (PTU)-induced hypothyroid mouse model was utilized, incorporating wild-type and THRA-knockout (KO) groups with or without thyroxine (T4) treatment. Systemic parameters, cardiac injury, histopathology, and molecular pathways were analyzed using enzyme-linked immunosorbent assay, immunohistochemistry, Western blot, quantitative polymerase chain reaction, RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays.

Results: PTU-induced hypothyroidism significantly reduced body weight, impaired cardiac function, and dysregulated thyroid hormones. THRA KO exacerbated these effects and completely abolished the therapeutic response to T4. Crucially, group KO-M markedly elevated markers of ferroptosis, including iron overload, malondialdehyde, and reactive oxygen species, while suppressing the reduced-to-oxidized glutathione ratio (GSH/GSSG) and key antiferroptotic proteins like glutathione peroxidase 4 (GPX4), compared with group M. Mechanistically, we identified GATA binding protein 4 (GATA4) as an upstream transcriptional activator of THRA. Furthermore, THRA itself directly bound to the GPX4 promoter and transactivated its expression. This GATA4-THRA-GPX4 axis was essential for cardioprotection, alongside modulation of the phosphoinositide 3-kinase/protein kinase B signaling pathway.

Conclusion: This study defines the GATA4-THRA-GPX4 transcriptional axis as a crucial mechanism that protects the heart from hypothyroidism-driven ferroptosis, uncovering a previously unrecognized transcriptional axis that is crucial for cardioprotection during hypothyroidism. Antioxid. Redox Signal. 44, 236-250.

Aims: Ferroptosis shows promise as a cancer treatment due to lipid hydroperoxide accumulation in an iron-dependent manner. Isocitrate dehydrogenase 1 (IDH1) mutation is common in gliomas and D-2-hydroxyglutarate (D-2HG) sensitizes cancer cells to ferroptosis. However, the regulation of ferroptosis in IDH1 mutant gliomas remains unclear. We hypothesize that IDH1 mutations induce glioma ferroptosis by regulating iron metabolism and antioxidant systems through the heme-BACH axis.

Results: IDH1 mutation induces ferroptosis in astrocytes and glioma cells demonstrated by growth inhibition, mitochondrial damage, and lipid peroxidation. In IDH1-mutant gliomas, both Fe²⁺ and reactive oxygen species accumulate due to impaired heme biosynthesis and thus BACH activation-dependent transcriptional repression of iron homeostasis and antioxidant response-related genes. The heme analogs zinc and tin protoporphyrin IX (ZnPP and SnPP) function as competitive inhibitors to reduce heme-dependent degradation of BACH and to exacerbate ferroptosis, especially for IDH1 mutants at extremely low concentrations. Primary mouse astrocytes and human glioma cell lines were used to determine the effect of IDH1 mutation on ferroptosis, while orthotopic xenograft models were used to evaluate heme analog efficacy. The drug affinity responsive target stability assay was used to determine the interaction between heme and its analog and BACH.

Innovation and conclusions: We discover that IDH1 mutation induces ferroptosis by activating the heme-BACH axis. ZnPP, previously believed to function exclusively as a heme oxygenase-1 inhibitor, can competitively bind to BACH to exacerbate ferroptosis and potently suppress IDH1-mutant gliomas. This study reveals a novel metabolic mechanism for inducing ferroptosis and provides a potential therapeutic target for IDH-mutant gliomas. Paraffin-embedded human glioma samples were collected from Xijing Hospital, the First Affiliated Hospital of the Fourth Military Medical University (China) (project number: KY20233192-1). Antioxid. Redox Signal. 44, 145-163.

Aims: This study aims to evaluate the protective effects of dexmedetomidine-loaded polypeptide nanomicrospheres (PNM@Dex) in a mouse model of intestinal ischemia/reperfusion (I/R) injury and investigate the underlying molecular mechanisms, focusing on autophagy activation in enteric neurons.

Results: PNM@Dex, synthesized via solid-phase peptide synthesis and coprecipitation, exhibited uniform spherical morphology (∼150 nm) and high drug encapsulation efficiency. In vitro studies demonstrated that PNM@Dex promoted autophagy in enteric neurons, attenuated oxidative stress and apoptosis, and improved cell viability. In vivo administration significantly mitigated intestinal injury, suppressed inflammatory cytokine production, and increased the expression of autophagy-related proteins. Autophagy inhibition assays confirmed the essential role of autophagy in mediating the protective effects of PNM@Dex.

Innovation: This study represents the first successful incorporation of dexmedetomidine into polypeptide nanomicrospheres for targeted delivery to enteric neurons. The nanoplatform achieved sustained release, enhanced autophagy, and exerted strong anti-inflammatory and antioxidant effects, offering a novel therapeutic approach for intestinal I/R injury and potential protection in intestinal transplantation.

Conclusion: PNM@Dex effectively alleviated intestinal I/R-induced damage through autophagy induction, oxidative stress reduction, and inflammation modulation, underscoring its promise as a therapeutic strategy for intestinal protection and transplantation. Antioxid. Redox Signal. 44, 213-235.

Aims: Endogenous hydrogen sulfide (H₂S) is involved in the occurrence and development of breast cancer, while its underlying mechanism is not yet clear. Here, we aimed to focus on the molecular mechanism of endogenous H₂S promoting the proliferation and metastasis of breast cancer.

Results: In this study, four major findings were revealed: (1) Inhibition of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) increased the content of glucose in the supernatant of breast cancer cell and decreased the production of intracellular lactic acid and adenosine triphosphate. (2) Phosphoglycerate kinase 1 (PGK1) was persulfidated at Cys108 and Cys316, and its persulfidation level in breast cancer tissue was significantly higher than that in paracancerous tissue. (3) Blocking the persulfidation of PGK1 inhibited glycolysis and malignant biological behaviors of breast cancer cell. (4) The CSE inhibitor reduced the persulfidation of PGK1 and inhibited the growth and metastasis of xenograft tumors, whereas sodium hydrosulfide reversed the effect of CSE inhibitor. Preface PGK1 is not the only potential target for persulfidation.

Innovation and conclusion: This study revealed a novel mechanism involved in the upregulation of endogenous H₂S in breast cancer. Endogenous H₂S regulates glycolysis of breast cancer cells by mediating PGK1 persulfidation modification at Cys108 and Cys316, thereby promoting tumor proliferation and metastasis. This study offers a potential therapeutic strategy through targeting the upregulated endogenous H₂S and persulfidation of PGK1. Antioxid. Redox Signal. 44, 164-181.

Aims: Ferroptosis has been implicated in the pathogenesis of lupus nephritis (LN), yet its precise role and mechanisms remain unclear. This study aimed to clarify the role of ferroptosis in LN progression and its underlying mechanisms.

Methods: Transmission electron microscopy (TEM) was used to assess mitochondrial morphology in renal tissues from LN patients and MRL/lpr mice. Multidimensional mass spectrometry-based shotgun lipidomics was applied to analyze lipid alterations in renal cortex, medulla, and isolated renal tubules. Immunoblotting and reverse transcription quantitative PCR were performed to evaluate ferroptosis-related proteins and their messenger RNAs (mRNAs). Primary renal tubular epithelial cells (RTECs) from the distinct renal regions (cortex/medulla) were isolated and exposed to oxidative stress in vitro. Ferroptosis inducer erastin and inhibitor ferrostatin-1 (Fer-1) were used in vivo to determine causal effects.

Results: TEM revealed typical ferroptotic mitochondrial changes in renal tissues from both LN patients and lupus-prone mice. In MRL/lpr mice, ferroptosis occurred as early as the pre-LN stage (8 weeks) and worsened by 14 weeks, with cortical tubules showing more severe damage than medullary tubules. Lipidomics demonstrated significant increases in lysophospholipids (e.g., 22:4 lysophosphatidylethanolamine, p < 0.001; 20:4 lysophosphatidylcholine, p < 0.01) and HNE species (p < 0.05), along with reductions in plasmalogens (e.g., 18:1-20:4 plasmenylcholine, p < 0.001). Mechanistically, ferroptosis was driven by downregulation of glutathione peroxidase 4 (p < 0.001) and solute carrier family 7 member 11 (p < 0.01) and upregulation of Acyl-CoA synthetase long chain family member 4 (p < 0.05), consistent with mRNA changes. Functionally, cortical RTECs cultured in vitro exhibited higher lipid reactive oxygen species (p < 0.001) and ferrous ion (Fe²⁺) accumulation (p < 0.01). In vivo, erastin accelerated LN progression, whereas Fer-1 significantly reduced proteinuria, renal pathology, and inflammatory cytokines.

Innovation and conclusion: The study provided direct evidence of ferroptosis markers in renal tissues of LN patients. RTECs exhibited the intrinsic abnormalities that trigger ferroptosis, greatly contributing to the progression of LN. Our findings highlighted the critical role of region-specific tubular ferroptosis in driving renal pathology. Early intervention targeting ferroptosis of RTECs in the renal cortex might be an effective strategy for treating LN. Antioxid. Redox Signal. 44, 197-212.

Background: The aim of this study was to construct a machine learning (ML) model to predict the effect of dietary antioxidants on cardiovascular-arthritis comorbidity.

Methods: In this study, 44 dietary antioxidants were selected based on the National Health and Nutrition Examination Survey data from 2007 to 2010 and from 2017 to 2018, and demographic covariates such as gender and age were included for analysis. In addition, 10 mainstream ML models were investigated for the evaluation, and a comprehensive evaluation system of the multi-indicator empowerment algorithms was constructed to comprehensively measure the model performance. To further enhance the model interpretability, SHapley Additive exPlanations (SHAP) values and Local Interpretable Model-agnostic Explanation (LIME) methods were introduced to deeply analyze the prediction mechanism.

Results: A total of 8046 participants were included in this study, of whom 380 had cardiovascular disease and arthritis comorbidities. After multiple covariates were eliminated, 34 indicators of nutritional antioxidant intake and 11 demographic baseline characteristics were selected as key predictors. The multicriteria-based assessment system demonstrated excellent performance of the logistic regression machine model. It performed optimally on the validation set with an area under the receiver operating characteristic curve of 0.871. Notably, the study of SHAP and LIME algorithms revealed the opposite biological effects of total and single flavonoid intake as well as the heterogeneity of dietary antioxidants in different age-sex characterized populations.

Conclusion: This study suggests that future strategies should consider antioxidant types and individual traits, promoting diverse natural foods over single supplements to advance precision nutrition. Antioxid. Redox Signal. 44, 251-270.

Aims: Radiation therapy is a crucial treatment modality for head and neck squamous cell carcinomas (HNSCCs). However, acquired radiation resistance due to various mechanisms poses a major clinical challenge for therapeutic strategies. Intriguingly, reactive oxygen species (ROS) are versatile signaling molecules that promote various cellular functions at low concentrations but induce cell death at above-critical threshold levels.

Results: Here, we found that radioresistant (RR) cancer cells exhibited reduced ROS levels and activation of the mesenchymal-epithelial transition factor/signal transducer and activator of transcription 3 (c-MET/STAT3) pathway. To target common vulnerabilities in RR cancers, we applied ROS enhancement therapy using nonthermal plasma-activated media (NTPAM), a novel approach that effectively inhibits the viability of RR cancer cells and is associated with inactivation of the c-MET/STAT3 pathway. Mechanistically, the downregulation of total c-MET is related to ROS-mediated lysosomal degradation. In addition, NTPAM suppressed tumor growth in a mouse model of RR cancer, concurrently reducing the levels of both the total and activated forms of c-MET and decreasing STAT3 phosphorylation.Innovations and Conclusions:These findings suggest that ROS enhancement therapy can overcome radiation resistance, thereby offering a compelling rationale for considering NTPAM as a stand-alone or complementary therapeutic approach for treating patients with HNSCCs. Antioxid. Redox Signal. 44, 182-196.

Aims: Cataracts are the leading cause of blindness worldwide, and the mechanism underlying cataract formation is linked to the oxidative damage and the apoptosis of lens epithelial cells. Retinoic acid Receptor-related orphan receptor α (RORα), a transcription factor, prevents oxidative stress and cell apoptosis. RORα is decreased in the lens from patients with cataract, but it remains unclear whether decreases in RORα are attributed to cataract formation.

Results: Here, rat models of selenite-induced cataracts were used for in vivo experiments. In vitro, human lens epithelial cells (SRA01-04) were treated with selenite. RORα was downregulated in the lens from rat models of selenite-induced cataracts. The RORα agonist SR1078 significantly mitigated the degree of lens opacity. SR1078 reduced oxidative stress, cell apoptosis, and mitochondrial dysfunction and promoted the peroxisome proliferative activated receptor gamma coactivator (PGC-1α) and the nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 pathways in the lens from rat models of selenite-induced cataracts and lens epithelial cells upon selenite stimulation. RORα overexpression showed a similar protective effect on lens epithelial cells in vitro. Nerve growth factor (NGF) expression was up-regulated by RORα overexpression. Although RORα overexpression prevented selenite-induced damage to lens epithelial cells, the damage recurred following NGF knockdown.

Conclusion: RORα protects against selenite-induced oxidative stress and cellular apoptosis. In the context of cataractogenesis, NGF is newly identified as a transcriptional target of RORα, and its reduction is related to mitochondrial dysfunction in lens epithelial cells. Our study highlights the translational potential of RORα activation as a nonsurgical cataract intervention. Antioxid. Redox Signal. 00, 000-000.