Free Radical Biology and Medicine最新文献

Ferroptosis is a mode of programmed cell death that plays an important role in an increasing number of diseases. Recently, ferroptosis was found to be involved in the pathology of acute pancreatitis (AP). We determined that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the ferroptosis process in AP. By inhibiting Nrf2 expression, the death of acinar cells in AP can be increased. Therefore, to help treat AP to a certain extent, we analyzed the effects of astaxanthin and found that it can activate Nrf2 and reduce the pathological process of AP. The activation of Nrf2 improves defective autophagy in AP and inhibits ferroptosis in acinar cells. Specifically, Nrf2 can promote the expression of Gpx4 and ferritin, and can inhibit the formation of Beclin-Slc7a11 complex by improving autophagy, thereby increasing the membrane expression of Slc7a11. Slc7a11/Gpx4 is an important anti-ferroptosis pathway; Slc7a11 can promote the synthesis of glutathione, while Gpx4 can utilize glutathione to exert antioxidative effects. Thus, we demonstrated that Nrf2 activation not only ameliorated defective autophagy at the time of AP but also promoted membrane expression of Slc7a11 to inhibit ferroptosis in acinar cells, thereby alleviating AP.

Chemotherapy-induced alopecia (CIA), commonly associated with agents such as cyclophosphamide (CYP), is a prevalent and distressing side effect of numerous chemotherapeutic treatments, significantly impacting patients' quality of life. S100A8, a calcium-binding protein involved in inflammatory responses and oxidative stress regulation, plays a pivotal role in cellular homeostasis. In this study, we investigated the involvement of S100A8 in ferroptosis within a CYP-induced CIA mouse model. We found that CYP treatment upregulated S100A8, NCF2, and NOX2 while reducing GPX4 levels in hair follicles, indicating elevated oxidative stress and ferroptosis. Administration of the S100A8 inhibitor paquinimod (PAQ) alleviated alopecia and decreased markers of oxidative stress and ferroptosis. In vitro experiments using human outer root sheath keratinocytes (ORSKs) confirmed that S100A8 promotes ferroptosis via the NCF2/NOX2 pathway, as inhibition of NCF2 or NOX2 reversed these effects. These findings suggest that targeting the S100A8-NCF2/NOX2 axis may provide a novel therapeutic strategy for mitigating CIA induced by various chemotherapeutic agents.

Tumor hypoxia determines tumor growth, metastasis, drug resistance, and tumor heterogeneity through multiple mechanisms, largely dependent on the extent of hypoxia, further modulated by re-oxygenation events. In order to track the cell fates under hypoxia and re-oxygenation, we have developed a sensor cell for real-time tracking of apoptotic, necrotic, and surviving mitophagy cells under hypoxia and re-oxygenation. The study using this sensor revealed a cell death switch from apoptosis to necrosis by hypoxia-exposed cells under re-oxygenation, where mitophagy plays a key role in acquiring temporally evolving functional phenotypes, including metabolic heterogeneity and mitochondrial redox heterogeneity. RNA transcriptomics also revealed a temporally evolving genomic landscape supporting the complex transcriptional plasticity of cells as a non-genetic adaptive event. Interestingly, cells regained from these distinct stages retained their metastatic potential despite slow growth in animal models. Overall, the study demonstrated that cells acquire distinct functions by tumor hypoxia and re-oxygenation, secondarily acquiring transient functional traits and metabolic heterogeneity governed by cell inherent mitochondrial dynamics. Such cell autonomous temporal alterations in cell states governed by organelle integrity with distinct cell proliferation and apoptosis-necrosis switch may be advantageous for the growing tumor to evolve under complex microenvironmental stress, further contributing to tumorigenesis.

The clinical use of the anticancer drug doxorubicin (DOX) is limited due to its time- and dose-dependent cardiotoxicity. Therefore, there is an urgent need to explore the molecular mechanism and coping strategies for alleviating DOX-induced cardiotoxicity (DIC) and solve the difficulties in clinical application. The role and mechanism of androgen receptor (AR), which is the target of androgen, in DIC remain unclear. Here, we elucidated the molecular mechanisms of AR in DOX-induced cardiotoxicity. Inhibition of AR aggravated the DOX-induced cardiac function impairment, while the activation of AR showed obvious therapeutic effect and rescued cardiac function of rats. AR can physically interact with SERCA2a. Activation of AR participates in the regulation of DOX-induced myocardial injury by modulating SERCA2a, attenuating DOX-induced endoplasmic reticulum stress, improving calcium (Ca²⁺) cycling homeostasis, and inhibiting ROS levels and apoptosis, thereby participating in the regulation of DOX induced myocardial injury. Altogether, these findings reveal for the first time the relationship and role between AR and SERCA2a in regulating the progression of DIC, suggesting that AR may play a therapeutic role as a new target against DIC.

Adults older than 45 years old are at higher risk of developing venous blood clotting known as venous thrombosis/thromboembolism than a cohort < 45 years old. Complement activation, which can be mediated by oxidative stress, plays a central role in venous thrombosis. Yet, whether RBCs contribute to complement activation triggering thrombosis in aging and in patients with venous thrombosis/thromboembolism remains an open question. RBCs from healthy Mid-life stage (55-68 years old) adults and patients with venous thrombosis/thromboembolism showed higher deposition of the complement C3 and the anaphylatoxin C3a, and NADPH oxidase (Nox)1 expression than a younger cohort (21-30 years old). Increased C3/C3a deposition on RBCs from mid-life stage adults and patients with venous thrombosis/thromboembolism triggered prothrombin activation via Nox1-dependent reactive oxygen species (ROS) generation, and G protein-coupled receptor kinase 2 (GRK2) activation. Interaction of C3/C3a positive RBCs from mid-life stage adults with endothelial cells led to increased endothelial ROS production. TGF-β1-stimulated GRK2 and Nox1 activation in RBCs from the younger and older adults exacerbated RBC C3/C3a deposition and C3/C3a-mediated prothrombotic activation, which appears to result from ROS-mediated increased RBC phosphatidylserine exposure. Using human RBCs, and Rpl13a snoRNA knockout aged mice, we show that Rpl13a snoRNAs, the master regulators of ROS levels and oxidative stress response, regulate human and murine RBC C3a deposition and prothrombic activation in aging by modulating Nox1 mRNA expression. In vivo Rpl13a snoRNA knockout in aged mice decreased thrombi size by blunting RBC C3a deposition, and RBCs-triggering prothrombin activation. These findings point out to a novel role of RBC Rpl13a snoRNAs in dysregulating RBC ROS-induced C3a deposition promoting venous thrombosis in aging.

Objective: Erectile dysfunction (ED) is considered an early manifestation of cardiovascular disease (CVD), endothelial dysfunction being the link between CVD and vasculogenic ED. Mitochondrial reactive oxygen species (mtROS) have been involved in the vascular complications of metabolic disorders. The aim of this study was to assess the impact of obesity on endothelial function, redox metabolism and mitochondrial bioenergetics of penile erectile tissue.

Methods: Wistar rats were fed a high-fat diet (HFD) or standard diet (STD), and penile vascular function was assessed in microvascular myographs. mtROS levels were measured by mitoSOX (O₂^.-) and Amplex Red (H₂O₂) fluorimetry, and the effect of the mitochondrial antioxidant mitoTempo on endothelium-dependent relaxations was tested. Mitochondrial respiration of intact microarteries was assessed with an Agilent Seahorse XF Pro analyzer, and the expression of mitochondria regulators and endoplasmic reticulum (ER) stress markers was analyzed by Western blot.

Results: Endothelium-dependent relaxations to acetylcholine (ACh) and to the mitoK_ATP channel activator BMS191095 were reduced in penile arteries from HFD. mtROS levels were significantly increased and associated with upregulation of the endothelial NADPH oxidase 4 (Nox4) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in HFD erectile tissue. MitoTempo inhibited endothelial relaxations in control and HFD penile arteries. The bioenergetic profile was significantly reduced in HFD penile arteries. Protein expression of ER stress markers was enhanced in erectile tissue of obese rats.

Conclusions: Mitochondrial dysfunction with impaired bioenergetics and reduced mitoK_ATP channel-mediated relaxation underlie endothelial and vascular dysfunction of erectile tissue in obesity, despite a compensatory mechanism that enhances Nox4-derived endothelial vasodilator mtROS. Therapeutic strategies aimed to stabilize mitochondria could restore redox balance and improve mitochondrial bioenergetics thus preventing oxidative stress and vascular dysfunction underlying metabolic disease associated ED.

Nitric oxide (*NO) is a key signalling molecule, produced enzymatically via *NO synthases (NOS) or following the stepwise reduction of nitrate to nitrite via oral bacteria. Exercise training upregulates NOS expression and improves systemic health, but its effect on oral health, and more particularly the oral microbiome, has not been investigated. We used an exercise training study design to investigate changes in the tongue dorsum microbiome, and in nitrate and nitrite levels in the saliva, plasma and muscle, before, during and after an exercise training period. Eleven untrained males (age 25 ± 5 years, mass 64.0 ± 11.2 kg, stature 171 ± 6 cm, O_2peak 2.25 ± 0.42 l·min^-1) underwent 8-weeks of high-intensity interval training (HIIT), followed by 12-weeks of detraining. The tongue dorsum microbiome was examined using Pac-Bio long-read 16S rRNA sequencing. Nitrate and nitrite levels were quantified with high-performance liquid chromatography. Grouped nitrite-producing species did not change between any timepoints. However, HIIT led to changes in the microbiome composition, increasing the relative abundance of some, but not all, nitrite-producing species. These changes included a decrease in the relative abundance of nitrite-producing Rothia and a decrease in Neisseria, alongside changes in 6 other bacteria at the genus level (all p≤0.05). At the species level, the abundance of 9 bacteria increased post-training (all p≤0.05), 5 of which have nitrite-producing capacity, including Rothia mucilaginosa and Streptococcus salivarius. Post-detraining, 6 nitrite-producing species remained elevated relative to baseline. Nitrate increased in plasma (p=0.03) following training. Nitrite increased in the saliva after training (p=0.02) but decreased in plasma (p=0.03) and muscle (p=0.002). High-intensity exercise training increased the abundance of several nitrite-producing bacteria and altered nitrate and nitrite levels in saliva, plasma, and muscle. Post-detraining, several nitrite-producing bacteria remained elevated relative to baseline, but no significant differences were detected in nitrate or nitrite levels. Switching from a sedentary to an active lifestyle alters both the microbiome of the tongue and the bioavailability of nitrate and nitrite, with potential implications for oral and systemic health.