Redox Report最新文献

Background: Idiopathic pulmonary fibrosis (IPF) carries high mortality and short survival, presenting significant clinical challenges. Current treatments primarily target to mitigate IPF progression, with insufficient focus on prevention.

Methods: We established bleomycin (BLM)-induced IPF model in mice and alveolar epithelial cells. Quercetin (QUE) was administered under two mutually exclusive dosing windows: preventive (pre-BLM only) and therapeutic (post-BLM only).

Results: Prophylactic QUE administration in mice prior to BLM challenge achieved fibrosis reduction comparable to post-injury treatment, while better mitigating peaks of epithelial damage, ferroptosis, and senescence. The preventive regimen also accelerated GSH and GPx4 recovery. Mechanistically, QUE triggers adaptive stress in healthy alveolar epithelial cells, evidenced by mild ROS elevation and oxidative stress response pathway activation. This adaptive stress minimally impacts cellular viability, proliferation, clonogenicity, apoptosis, or senescence in healthy cells. Instead, it primes 14-3-3γ-mediated phosphorylation to enhance NRF2 nuclear translocation, driving sustained elevation of GSH and GPx4 and conferring ferroptosis resistance, thereby limiting fibrogenesis. Crucially, co-administration of Mito-TEMPO or Z-VAD-FMK suppressed QUE-induced ROS but concurrently abolished prevention against BLM injury, confirming preconditioning via adaptive stress as the core mechanism.

Conclusions: Our findings unveil QUE as a promising preventive agent against IPF, mediated through alveolar epithelial preconditioning to enhance ferroptosis resistance.

Objectives: Tramadol, a clinically approved analgesic widely used for managing postoperative pain, has recently been shown to possess anticancer properties in several tumor models, especially in breast cancer. In this study, we explored the intricate molecular mechanisms by which tramadol induces cytotoxicity in breast cancer cell lines.

Methods: Two invasive ductal carcinoma lines MCF-7 and MDA-MB-231 were used to verify the molecular cytotoxicity of tramadol using cell viability analysis, flow cytometry analysis, real-time polymerase chain reaction, western blotting, Seahorse biogenetic, and transmission electron microscopy analyses.

Results: Our findings demonstrate that tramadol induces the normoxic stabilization and nuclear translocation of hypoxia-inducible factor- 1 alpha (HIF-1α) to activate hypoxia responsive genes. Concurrently, tramadol triggers endoplasmic reticulum (ER) stress and activates the p-eIF2α/ATF4/CHOP signaling axis, leading to the generation of reactive oxygen species, impaired autophagy, mitochondrial dysfunction, including mitochondrial membrane depolarization and the decline of ATP production, cytoplasmic vacuolization, and lipid droplet accumulation which is characteristics of paraptosis-like cell death. Notably, the knockout of HIF-1α or ATF4 significantly reduced tramadol-induced cytotoxicity, highlighting their crucial roles in mediating these cellular responses.

Conclusion: Tramadol induced breast cancer cell death via paraptosis which highlights its therapeutic potential in targeting resistant cancer subtypes such as triple-negative breast cancer.

Alzheimer's disease and Parkinson's disease are the two most prevalent neurodegenerative disorders worldwide, both characterized by progressive neuronal loss. Despite distinct pathophysiological features, they share cellular dysfunctions such as abnormal protein aggregation, oxidative stress, and neuroinflammation, research into which might be beneficial for developing novel therapeutic strategies that could tackle both conditions. This review highlights the emerging role of the gasotransmitters nitric oxide, carbon monoxide and hydrogen sulfide as modulators of adult neurogenesis and neuroprotection in Alzheimer's disease and Parkinson's disease. We have gathered recent evidence demonstrating that these endogenous gases exert anti-inflammatory, antioxidant, and anti-apoptotic effects, and, critically, promote neurogenesis - suggesting a dual neuroprotective and neuroregenerative therapeutic potential. The unique physicochemical features of these gasotransmitters, including their ability to cross the blood-brain barrier and diffuse rapidly throughout the neural tissue, further support their suitability as candidates for innovative neuroregenerative treatments. While clinical translation remains challenging, harnessing the neurogenic and neuroprotective actions of these gasotransmitters may offer transformative avenues for addressing the increasing burden of Alzheimer's disease and Parkinson's disease.

Objectives: Acid-sensing ion channel 1a (ASIC1a) functions as an extracellular acid sensor, with its activation frequently associated with age-related diseases. We aim to investigate the expression pattern of ASIC1a in the ferroptosis of degenerated nucleus pulposus (NP) tissues and NP cells (NPCs), and explore whether ASIC1a-mediated calcium influx regulates ferroptosis in NPCs through the calcium/calmodulin pathway during intervertebral disc degeneration (IVDD).

Methods: We use NP tissues, NPCs, and Transcriptome sequencing to investigate the effects and mechanism of ASIC1a in ferroptosis during the progression of IVDD.

Results: Elevated expression of ASIC1a was associated with the progression of ferroptosis in human degenerated NP tissues. Meanwhile, the expression of ASIC1a remarkably increased as acid-induced ferroptosis progressed in human NPCs. Besides, transcriptomic analysis identified that inhibition of ASIC1a attenuates ECM degradation and ferroptosis. We then confirmed the overexpression of ASIC1a promoted the progression of ferroptosis and ECM degradation in human NPCs in vitro. Moreover, the ferroptosis of NPCs induced by ASIC1a overexpression was ameliorated by the treatment of BAPTA-AM (the intracellular calcium chelator) or calmidazolium (the calmodulin antagonist). ASIC1a mediated acid-induced ferroptosis via calcium/calmodulin signaling in human NPCs. The in vivo study further indicated that the inhibition of ASIC1a activation ameliorated the IVDD by suppressing ferroptosis in the rat model.

Conclusion: This study demonstrated that ASIC1a increased as ferroptosis progressed in human NP tissues and human NPCs. The acid-induced ASIC1a upregulation caused increased calcium levels and contributed to the ferroptosis in NPCs partially mediated by calcium/calmodulin signaling.

Exposure to fine particulate matter smaller than 2.5 μm in diameter (PM2.5) has emerged as a critical environmental factor contributing to skin injury. As the skin is the body's primary barrier against the external environment, it is directly susceptible to PM2.5, which induces oxidative stress, inflammation, premature aging, and disruption of skin barrier function. Increasing evidence demonstrates that PM2.5 damages both epidermal keratinocytes and dermal fibroblasts, leading to cellular dysfunction through alterations in major signaling pathways, including the aryl hydrocarbon receptor (AhR), nuclear factor kappa B (NF-κB), activator protein 1 (AP-1), mitogen-activated protein kinase (MAPK), and nuclear factor erythroid 2-related factor 2 (Nrf2). These molecular perturbations accelerate skin aging and impair protective functions, highlighting the need for effective intervention strategies. Botanicals and their bioactive phytochemicals have attracted growing interest for their antioxidant and anti-inflammatory properties, which may counteract PM2.5-induced damage. By targeting redox imbalance and inflammatory signaling, natural compounds represent a promising approach for protecting skin health. This review highlights the role of PM2.5 in skin injury and critically examines botanical strategies that may mitigate PM2.5-induced skin damage and premature aging.

Background: Sepsis-induced myocardial injury (SIMI) contributes significantly to morbidity and mortality in sepsis, but its molecular mechanisms are not fully understood. Hydrogen sulfide (H₂S), an endogenous signaling molecule, regulates inflammation, oxidative stress, and cell death in cardiovascular diseases, with protein sulfhydration as a key mechanism.

Methods: We used in vitro and in vivo sepsis models we investigated the protective to examine the effects of H₂S donors (GYY4137 and Allicin) on SIMI. We focused on ferroptosis and the HIF1α/BNIP3 axis, and applied transcriptomic, proteomic, and molecular biology approaches.

Results: Sepsis suppressed the CSE/H₂S pathway, increasing ferroptosis and myocardial injury. Exogenous H₂S attenuated cardiac dysfunction, inflammation, and cell death. Mechanistically, H₂S promoted HSPA8 sulfhydration at Cys574, enhancing HIF1α degradation and inhibiting BNIP3, thereby reducing oxidative stress, ferroptosis, and myocardial damage. Allicin, a natural H₂S donor, induced endogenous H₂S production, restored HSPA8 sulfhydration, and provided cardioprotection without toxicity.

Conclusion: This study reveals a novel H₂S-HSPA8-HIF1α-BNIP3 axis in regulating ferroptosis and myocardial injury during sepsis. Protein sulfhydration mediates the cardioprotective effects of H₂S, and Allicin emerges as a promising therapeutic agent for septic cardiomyopathy.

Objectives: Alzheimer's disease (AD) is characterized by cognitive impairment and neuropsychiatric disturbances, including depression, both tightly linked to redox imbalance and neuroinflammatory activation. This study investigated whether the selenium-containing compound 7-chloro-4-(phenylselanyl)quinoline (4-PSQ) mitigates behavioral and biochemical alterations in a β-amyloid (Aβ)-induced mouse model of AD through modulation of redox-regulated pathways.

Methods: Male Swiss mice received intracerebroventricular Aβ (25-35) or saline (3 µL/site) and were treated orally for seven days with 4-PSQ (1 mg/kg), paroxetine (1 mg/kg), or donepezil (1 mg/kg). Depressive-like behavior and memory performance were assessed, followed by determination of plasma corticosterone, reactive species levels, lipid peroxidation, antioxidant enzyme activities, neuroinflammatory mediators, and acetylcholinesterase (AChE) activity in the hippocampus and prefrontal cortex of mice.

Results: 4-PSQ significantly reversed Aβ-induced depressive behavior and memory impairment. The compound normalized plasma corticosterone levels, reduced reactive species and lipid peroxidation, and restored antioxidant enzyme activity. It also decreased the expression of inflammatory markers while regulating AChE activity, indicating concomitant modulation of redox, neuroimmune, and cholinergic pathways.

Conclusion: By restoring redox homeostasis and attenuating neuroinflammatory responses, 4-PSQ effectively counteracted behavioral and biochemical disruptions associated with Aβ toxicity. These findings support 4-PSQ as a promising selenium-based therapeutic candidate targeting redox-driven features of AD, including comorbid depression and cognitive decline.

Background: Mitochondria and lysosomes are pivotal in dictating cell survival or death outcomes. While mitochondrial damage and ROS production are key events in mitochondrial cell death, lysosome membrane permeabilization and cathepsin B release mark lysosomal cell death. We aimed to generate a live-cell approach to concurrently monitor mitochondrial redox alterations and lysosomal permeabilization. This would provide mechanistic insight into their dynamic interplay during cell death and enable the discovery of organelle-specific death inducers.

Methods: A dual cell sensor, stably expressing tdTomato-CathepsinB and mitochondria-targeted redox GFP (mt-roGFP), was successfully engineered, and simultaneous imaging of both events by real-time confocal imaging was carried out with selected drugs.

Results: This platform faithfully reported the chronological sequence of organelle-specific events with the progression of cell death, with good temporal and spatial resolution at the single-cell level. Moreover, we have identified and categorised potential lead compounds that predominantly induce lysosomal cell death or mitochondrial cell death, as well as a subset that elicit both events concomitantly.

Conclusion: The study provided evidence that both organelles contribute to cell death in a context-dependent manner, and the temporal analysis of both events is critical in understanding unique organelle-centred cell death.

Uterine fibroids are benign tumors with high incidence and recurrence rates that still pose significant treatment challenges. Traditionally, it has been believed that estrogen and progesterone primarily drive the development and progression of uterine fibroids. Recent studies have revealed that hormonal imbalance can affect reactive oxygen species production and trigger a significant oxidative stress (OS) state. The OS status in uterine fibroids can further amplify the pathological effects caused by hormonal imbalance. This suggests that estrogen, progesterone, and OS may interact to form an estrogen-progesterone-oxidative stress (E-P-OS) network, collectively promoting the progression of uterine fibroids. This network model provides a theoretical basis for the high recurrence rates following hormone monotherapy or surgery. Therefore, we reviewed the molecular mechanisms underlying hormone-OS interactions within the E-P-OS network and elucidated its pathological effects in promoting uterine fibroid progression. The integrated perspective lays the theoretical foundation for developing novel therapies that simultaneously block hormone signaling and counteract oxidative damage. Additionally, we summarized current clinical strategies for hormone therapy and antioxidant treatment, identified potential combination therapy approaches, and explored key challenges in their clinical translation. This aims to provide new directions and evidence for advancing the precision treatment of uterine fibroids.

Objectives: The efficacy of cellular therapies has been disappointing in solid tumors. A major barrier that contributes to the low success rate, is hypoxia within the tumor microenvironment. In this study, we investigated the influence of hypoxia on natural killer (NK) cell function and to evaluated a strategy to restore their activity in hypoxia.

Methods: Unarmed or CAR NK cells were placed in normoxia (21% O₂) or hypoxia (1% O₂) prior to experimental readouts. Mitochondrial content and morphology were assessed by confocal microscopy, membrane potential and reactive oxygen species (ROS) by flow cytometry, and global transcriptional changes by RNA sequencing. Cytotoxicity was evaluated against tumor cell lines and patient-derived cancer organoids, which were characterized by RNA sequencing. DRP1 function was inhibited pharmacologically or through CRISPR-Cas9-mediated knockout.

Results: Hypoxia reduced NK cell mitochondrial content and membrane potential, while increasing mitochondrial ROS and inducing broad transcriptional changes in stress response pathways. Their cytotoxic activity was drastically impaired, which could not be prevented by CD70-CAR-IL-15 engineering. Pharmacological inhibition of DRP1 restored mitochondrial content and cytotoxic function. To confirm the role of DRP1, CRISPR-Cas9-mediated DRP1 knockout (KO) NK cells preserved mitochondrial load and membrane potential under hypoxia, and DRP1^KO CAR NK cells retained cytotoxic activity under hypoxic conditions against cancer cell lines. Patient microtumor models with distinct transcriptomic profiles exhibited divergent responses to DRP1^WT and DRP1^KO CAR NK cells.

Conclusion: These findings indicate that DRP1 inactivation supports NK cell function in hypoxia and metabolic engineering may enhance CAR-NK efficacy in solid tumors.