Redox Report最新文献

Background: Interleukin-6 (IL-6) is a pleiotropic cytokine that participates in multiple metabolic disorders. IL-6 is well recognized to induce hepcidin expression and decreased serum iron through the JAK2/STAT3 pathway under inflammatory conditions. Targeted inhibition of IL-6 represents a potential therapeutic regimen for multiple diseases. The current study aimed to explore the physiological concentration of IL-6 in sustaining systemic iron homeostasis.

Methods: IL-6-knockout mice (IL-6-/-) were established in the current study. Western blot measured the expression of key iron-related proteins in liver, kidney, spleen and duodenum, as well as hepatic hepcidin mRNA expression. Serum iron and hematologic parameters were detected. ELISA and Masson's trichrome staining were performed to detect renal TGF-β1 expression and collagen deposition. Furthermore, bone marrow-derived and peritoneal macrophages were prepared to identify the iron recycling.

Results: Serum iron and tissue iron content were markedly elevated in IL-6-/- mice. Mechanistically, decreased renal erythropoietin (EPO) synthesis contributed to iron utilization, macrophage-mediated recycling of iron was markedly reduced, thereby resulting in systemic iron accumulation. However, IL-6-/- mice displayed increased Hepcidin expression via p-ERK activation and a significant reduction in duodenal iron uptake.

Conclusion: This study highlighted the critical role of IL-6 in iron homeostasis both in physiological and pathological situations.

Background: Fatty acid oxidation (FAO) is implicated in lung diseases, but its role in bronchial asthma is not fully understood. We investigated its effect on airway epithelial barrier integrity.

Methods: Using a house dust mite (HDM)-induced murine asthma model and HDM, IL-4, IL-13, or TNF-α stimulated human primary bronchial epithelial cells (BECs) and bronchial epithelial (Beas-2b) cells, we modulated FAO with L-carnitine (agonist) and Etomoxir (inhibitor). BECs and Beas-2b cells were infected with lentivirus-mediated CPT1A shRNA prior to stimulation. Barrier function, mitochondrial oxidative stress, inflammation, and metabolism were assessed.

Results: FAO level in lungs negatively correlated with increased inflammation and tissue injury in HDM-induced asthmatic mice (all p < 0.05), while positively regulating tight junction protein expression. In BECs and Beas-2b cells, Etomoxir treatment and CPT1A knockdown exacerbated the impairment of FAO caused by various stimulants (all p < 0.05). Furthermore, FAO negatively regulated HDM/cytokine-induced epithelial barrier damage, hyperactive inflammatory response, and mitochondrial dysfunction in Beas-2b cells (all p < 0.05). In contrast, treatment with L-carnitine significantly alleviated these pathophysiological features in both in vivo and in vitro models.

Conclusion: FAO plays a protective role in the occurrence and development of asthma by maintaining airway epithelial cell homeostasis and barrier function.

Objectives: Reperfusion, an essential therapeutic strategy for salvaging ischemic myocardium in ischemic heart disease, paradoxically exacerbates myocardial injury. Ferroptosis is a pivotal mechanism underlying myocardial ischemia-reperfusion injury (MIRI). Nrf2 can regulate ferroptosis, which could undergo SUMOylation at lysine 110 (K110) and was subsequently de-SUMOylated by Senp1. This study aimed to determine whether Nrf2 de-SUMOylation could mitigate MIRI by inhibiting myocardial ferroptosis.

Methods: Nrf2 K110R mice, mimicking Nrf2 de-SUMOylation, were generated. Mice cardiac morphology and function were observed by hematoxylin-eosin staining (HE) and echocardiography under normal and MIRI conditions. Ferroptosis inhibitor liproxstatin-1 (Lip-1) was used to demonstrate ferroptosis participation in Nrf2 de-SUMOylation regulated MIRI. In vitro, SUMO1/sentrin-specific protease 1 Senp1 KO H9C2 cells were subjected to RSL₃-induced ferroptosis to explore underlying mechanism.

Results: Nrf2 K110R mice showed normal cardiac morphology and function at baseline. However, de-SUMOylation of Nrf2 alleviated myocardial ferroptosis, resulting in a reduction of MIRI severity in MIRI mice. The administration of Lip-1 attenuated the differences in MIRI between Nrf2 wild-type and K110R mice. Mechanistically, Nrf2 de-SUMOylation was associated with a reduction in Transferrin receptor (Tfr) expression level, thereby mitigating ferroptosis in cardiomyocytes.

Conclusion: This study highlighted the role of Nrf2 SUMOylation in promoting ferroptosis during MIRI and identified Nrf2 de-SUMOylation as a potential therapeutic target for MIRI.

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.

Objectives: Urolithin A (UA) is a natural polyphenolic compound produced by gut bacteria. Vascular remodeling contributes to hypertension, and vascular smooth muscle cells (VSMCs) proliferation and migration are important processes in vascular remodeling.

Methods: VSMCs were obtained from the thoracic aorta of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Intraperitoneal injections of UA (50 mg/kg, every 2 days for 4 weeks) were performed in SHR.

Results: UA attenuated proliferation and migration, reduced mitochondrial reactive oxygen species (mitoROS) levels, and increased SOD2 activity in VSMCs of SHR, which were prevented by SOD2 knockdown. UA promoted mitochondrial short-length SIRT3 (SL-SIRT3) production and SOD2 deacetylation. SIRT3 inhibitor 3-TYP abolished the effects of UA on SOD2 deacetylation, mitoROS levels and VSMCs proliferation and migration. Repeated intraperitoneal injection of UA every 2 days for 4 weeks attenuated vascular remodeling and hypertension, increased SL-SIRT3 levels and SOD2 activity, and reduced SOD2 acetylation and mitoROS levels in aorta and mesenteric arteries of SHR.

Conclusion: UA attenuates VSMCs proliferation and migration in SHR by increasing mitochondrial SL-SIRT3 level, and subsequent SOD2 deacetylation and mitoROS reduction in SHR. Long-term administration of UA attenuates vascular remodeling, hypertension and oxidative stress in SHR.

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.

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.

Background: Mesenchymal stem cells (MSCs) are a potential therapy for acute respiratory distress syndrome (ARDS), but their mechanisms in repairing mitochondrial damage in ARDS endothelial cells remain unclear.

Methods: We first examined MSCs' mitochondrial transfer ability and mechanisms to mouse pulmonary microvascular endothelial cells (MPMECs) in ARDS. Then, we investigated how MSC-mediated mitochondrial transfer affects the repair of endothelial damage. Finally, we elucidated the mechanisms by which MSC-mediated mitochondrial transfer promotes vascular regeneration.

Results: Compared to mitochondrial-damaged MSCs, normal MSCs showed a significantly higher mitochondrial transfer rate to MPMECs, with increases of 41.68% in vitro (P < 0.0001) and 10.50% in vivo (P = 0.0005). Furthermore, MSC-mediated mitochondrial transfer significantly reduced reactive oxygen species (P < 0.05) and promoted proliferation (P < 0.0001) in MPMECs. Finally, MSC-mediated mitochondrial transfer significantly increased the activity of the tricarboxylic acid (TCA) cycle (MD of CS mRNA: 23.76, P = 0.032), and further enhanced fatty acid synthesis (MD of FAS mRNA: 6.67, P = 0.0001), leading to a 6.7-fold increase in vascular endothelial growth factor release from MPMECs and promoted vascular regeneration in ARDS.

Conclusion: MSC-mediated mitochondrial transfer to MPMECs activates the TCA cycle and fatty acid synthesis, promoting endothelial proliferation and pro-angiogenic factor release, thereby enhancing vascular regeneration in ARDS.