Redox Report最新文献

Objectives: Doxorubicin (DOX) induces dose-dependent cardiotoxicity, primarily through oxidative stress and metabolic dysregulation. Although NAD⁺ deficiency has been implicated in cardiovascular pathology, its role in DOX-induced cardiotoxicity (DIC) remains poorly understood. This study investigated NAD⁺ metabolism dysregulation as a redox-sensitive mechanism in DIC pathogenesis.

Methods: Human cardiomyocytes (AC16), mouse atrial myocytes (HL-1), and C57BL/6 mice were used to establish the DIC model. The role and mechanism of NAD⁺ in DIC were investigated using a range of methods.

Results: Using integrated in vitro and in vivo models, we demonstrated that DOX induces myocardial oxidative damage accompanied by NAD⁺ depletion. Exogenous NAD⁺ supplementation mitigated the DOX-induced cardiomyocyte death and redox imbalance. Mechanistically, pharmacological CD38 inhibition with 78C or genetic silencing failed to restore the NAD⁺ pool, whereas nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) overexpression, combined with nicotinamide mononucleotide (NMN) administration, effectively rescued NAD⁺ levels and attenuated oxidative stress. Computational and functional analyses identified FOXO1 as a transcriptional repressor of NMNAT3 following DOX exposure.

Conclusion: This study establishes the dysregulation of the FOXO1-NMNAT3 axis as a key mechanism underlying NAD⁺ depletion in DIC. Targeting this axis through NAD⁺ replenishment, particularly by activating NMNAT3, offers a novel redox-based therapeutic strategy against DIC.

Background: Inflammation and immune responses play key roles in osteoporosis (OP) pathogenesis. Osteoimmunology highlights immune dysregulation as a significant contributor to OP, but the specific biological mechanisms linking immune dysfunction to bone loss remain unclear. Understanding these mechanisms is essential for targeted therapies.

Methods: We established a rat OP model via bilateral ovariectomy. Transcriptomic sequencing (RNA-seq) identified differentially expressed genes (DEGs), and summary data-based Mendelian randomization (SMR) analysis validated their causal associations with OP. Primary neutrophils isolated from bone marrow and differentiated HL-60 neutrophil-like cells were induced to form neutrophil extracellular traps (NETs), and siRNA was employed to knock down the NCF2 gene. Conditioned media from these neutrophils were subsequently applied to primary osteoblasts to evaluate effects on osteogenic differentiation.

Results: RNA-seq identified 4,497 DEGs (1,606 upregulated, 2,891 downregulated) in OP rats, significantly enriched in immune response and NETs formation pathways. NETs markers (NE, MPO, CitH3) were markedly elevated in OP bone tissue and stimulated neutrophils. SMR analysis identified VDAC1, PLCG2, and NCF2 as key genes significantly associated with OP risk, experimentally validated at the tissue and cellular levels. Knockdown of NCF2 reduced NETs formation in neutrophil-like cells and alleviated NETs-induced osteoblast differentiation impairment. Drug prediction and molecular docking analyses demonstrated high affinity and pharmacological potential targeting these genes.

Conclusions: This study unveils the link between NETs formation and OP, highlighting NCF2 as crucial players. These findings provide new insights into immune inflammation's role in bone metabolism and pave the way for targeted OP therapies.

Objectives: Reactive oxygen species (ROS) are short-lived and act in a site-specific manner, underscoring the importance of identifying the subcellular localization of their sources. ROS-generating NADPH oxidases (NOX) regulate pancreatic beta cell (dys)function. However, their subcellular localization and cytokine-mediated regulation in these cells remain largely unknown. We characterized the expression, subcellular localization and time-dependent cytokine-induced regulation of NOX isoforms in beta cells.

Methods: Isoforms were studied via RT-qPCR, immunoblotting and immunofluorescence in rat islets and beta cell lines.

Results: Beta cells express DUOX1 and DUOX2 proteins and Duoxa2 transcripts; lacking Duoxa1 expression. In INS-1E cells, NOX1 and DUOX1 localize in the endoplasmic reticulum (ER); DUOX2 in insulin vesicles; and NOX2 and NOX4 in vesicles, ER and plasma membrane. In INS-1E, cytokines increased expression of Nox1 and Duox1 at 4-8 h (returning to baseline at 16 h) and Nox2 and p47phox at 8 h (persisting until 24 h). Duox(a)2, p67phox and p40phox were downregulated and DUOX1 upregulated at 16-24 h.

Conclusion: The absence of Duoxa1 in beta cells might lead to DUOX1 mismatching, impairing its trafficking and activity. NOXs in beta cells are diverse in subcellular localization and cytokine-induced regulation, suggesting their isoform-specific involvement in beta cell function, stress and apoptosis.

Uric acid (UA), the final product of purine metabolism in humans, exhibits a dual role as an anti or pro-oxidant, depending on the microenvironment. The two-electron oxidation of UA by biological oxidants can neutralize such harmful molecules. Additionally, UA chelates metals and can activate adaptive response against oxidation. However, some products of the reaction between UA and oxidants are not inert and, therefore, do not confer the anticipated antioxidant protection. A direct pro-oxidant effect is favoured in the one-electron oxidation of UA by heme-peroxidases yielding free radical intermediates that can initiate or propagate a radical-chain reaction. Additionally, an indirect pro-oxidant effect has been proposed by eliciting the expression or activation of enzymes that catalyse oxidant production, e.g. NADPH oxidase (NOX). This review brings together fundamental concepts and the molecular mechanisms of the redox reactions involving UA. The signature metabolites from these reactions are discussed to give valuable insights on whether these intermediates are being formed and what role they may play in disease pathogenesis. It proposes that, through identifying specific products, it may be possible to elucidate whether a harmful or protective action is linked to downstream bioactivities.

This study sought to ascertain if zinc nanoparticles (ZnNPs) could lessen the toxicity of azoxystrobin (AZ). This naturally occurring methoxyacrylate is one of the most often used fungicides in agriculture in male albino rats. Six sets of 60 mature male albino rats were randomly assigned: control (distilled water), Azoxystrobin formulation (AZOF), Azoxystrobin nano-formula (AZON), ZnNPs, AZOF + ZnNPs, and AZON + ZnNPs. Blood and tissues were obtained for further immunohistochemical, pathological, and biochemical examination. The results showed that exposure to AZOF and AZON significantly increased the levels of the oxidative stress indicators glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA). Additionally, AZOF significantly impacts liver function bioindicators, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. AZOF and AZON induced damage to the liver and kidney by disrupting vascular dilatation and causing hemorrhages, apoptosis, inflammatory lymphocytes, and necrosis. Furthermore, co-administration of ZnNPs with fungicides (AZOF and AZON) can gently enhance the alterations of oxidative stress and liver function bioindicators levels. These findings showed that ZnNPs could help male rats receiving AZ treat their histologically abnormal liver and kidney.

Background: Lung cancer is one of the leading causes of cancer-related deaths worldwide with limited treatment options available. The anti-tumor effects of the TrxR inhibitor Butaselen (BS/BS1801) on lung cancer and its underlying mechanisms remain unknown.

Methods: This study utilized lung cancer cell lines, LLC1-bearing mice models, and organoids to detect the inhibitory effects of BS on lung cancer. The ROS-induction and apoptotic role of BS on lung cancer cells and molecular mechanisms were assessed with flow cytometry, western blot, Co-IP, real-time PCR, ChIP, reporter gene assay, ELISA, and bisulfite pyrosequencing.

Results: BS can effectively inhibit lung cancer both in vitro and in vivo, by triggering ROS-induced apoptosis. The inactivation of NF-κB and MAPK signaling pathways, along with the activation of PI3K-Akt and HBP1 signaling pathways, are involved in BS's suppression of lung cancer. HBP1 is a novel downstream target of the Trx system. The activation of HBP1 by BS is dependent on ROS accumulation and further leads to the transcriptional inhibition of DNMT1 and the demethylation of the whole genome, as well as the promoters of p21 and HOXA9.

Conclusion: The TrxR/Trx inhibitor butaselen suppresses lung cancer by triggering ROS-induced apoptosis. This study provides a novel and effective regimen for treating lung cancer.

Mitochondrial health is maintained in a steady state through mitochondrial dynamics and autophagy processes. Recent studies have identified healthy mitochondria as crucial regulators of cellular function and survival. This process involves adenosine triphosphate (ATP) synthesis by mitochondrial oxidative phosphorylation (OXPHOS), regulation of calcium metabolism and inflammatory responses, and intracellular oxidative stress management. In the skeletal system, they participate in the regulation of cellular behaviors and the responses of osteoblasts, osteoclasts, chondrocytes, and osteocytes to external stimuli. Indeed, mitochondrial damage or dysfunction occurs in the development of a few bone diseases. For example, mitochondrial damage may lead to an imbalance in osteoblasts and osteoclasts, resulting in osteoporosis, osteomalacia, or poor bone production, and chondrocyte death and inflammatory infiltration in osteoarthritis are the main causes of cartilage degeneration due to mitochondrial damage. However, the opposite exists for osteosarcoma, where overactive mitochondrial metabolism is able to accelerate the proliferation and migration of osteosarcoma cells, which is a major disease feature. Bone is a dynamic organ and osteocytes play a fundamental role in all regions of bone tissue and are involved in regulating bone integrity. This review examines the impact of mitochondrial physiological function on osteocyte health and summarizes the microscopic molecular mechanisms underlying its effects. It highlights that targeted therapies focusing on osteocyte mitochondria may be beneficial for osteocyte survival, providing a new insight for the diagnosis, prevention, and treatment of diseases associated with osteocyte death.

Objectives: Asthma, a prevalent chronic disease, poses significant health threats and burdens healthcare systems. This study focused on the role of bronchial epithelial cells in asthma pathophysiology.

Methods: Bioinformatics was used to identify key asthmarelated genes. An ovalbumin-sensitized mouse model and an IL-13-stimulated Beas-2B cell model were established for further investigation.

Results: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was identified as a crucial gene in asthma. CEACAM5 expression was elevated in asthmatic mouse lung tissues and IL-13-stimulated Beas-2B cells, primarily in bronchial epithelial cells. CEACAM5 induced reactive oxygen species (ROS), lipid peroxidation, and ferroptosis. Interfering with CEACAM5 reduced ROS, malondialdehyde levels, and enhanced antioxidant capacity, while inhibiting iron accumulation and autophagy. Overexpression of CEACAM5 in IL-13-stimulated cells activated the JAK/STAT6 pathway, which was necessary for CEACAM5-induced autophagy, ROS accumulation, lipid peroxidation, and ferroptosis.

Conclusion: CEACAM5 promotes ferroptosis and autophagy in airway epithelial cells via the JAK/STAT6 pathway, exacerbating asthma symptoms. It represents a potential target for clinical treatment.

Targeting ferroptosis, cell death caused by the iron-dependent accumulation of lipid peroxides, and disruption of the redox balance are promising strategies in cancer therapy owing to the physiological characteristics of cancer cells. However, the detection of ferroptosis using in vivo imaging remains challenging. We previously reported that redox maps showing the reduction power per unit time of implanted tumor tissues via non-invasive redox imaging using a novel, compact, and portable electron paramagnetic resonance imaging (EPRI) device could be compared with tumor tissue sections. This study aimed to apply the EPRI technique to the in vivo detection of ferroptosis. Notably, redox maps reflecting changes in the redox status of tumors induced by the ferroptosis-inducing agent imidazole ketone erastin (IKE) were compared with the immunohistochemical images of 4-hydroxynonenal (4-HNE) in tumor tissue sections. Our comparison revealed a negative correlation between the reducing power of tumor tissue and the number of 4-HNE-positive cells. Furthermore, the control and IKE-treated groups exhibited significantly different distributions on the correlation map. Therefore, redox imaging using EPRI may contribute to the non-invasive detection of ferroptosis in vivo.

Objectives: Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease. The precise molecular mechanism of ferroptosis, an iron-dependent and non-apoptotic form of regulated cell death, remains poorly understood in DKD, as does the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on ferroptosis-mediated DKD.

Methods: This study used bulk RNA sequencing, in vitro and in vivo models, and human kidney samples to explore the molecular mechanisms involved in oxidative stress and ferroptosis in the proximal tubule (PT) of DKD.

Results: High glucose (HG) induced features of ferroptosis in HK-2 cells. Transcriptome analysis of primary PT cells from diabetic patients indicated that glutathione cysteine ligase modifier (GCLM) subunit is involved in ferroptosis. Immunohistochemical staining revealed that db/db mice and diabetic patients had lower glutathione peroxidase 4 and GCLM expression in the PT. Suppression of GCLM enhanced ferroptosis, whereas GCLM overexpression mitigated HG-induced ferroptosis in HK-2 cells. Antioxidants reduced oxidative stress and ferroptosis in both in vitro and in vivo models of DKD. Furthermore, SGLT2i attenuated PT ferroptosis in these models and improved DKD by increasing GCLM expression.

Conclusion: SGLT2i reduced ferroptosis in PT by boosting GCLM expression, thereby slowing DKD progression, revealing that GCLM has the potential against DKD.