Free Radical Biology and Medicine最新文献

Ischemic stroke represents a predominant cause of morbidity and mortality globally, resulting from abrupt vascular occlusion or rupture, which precipitates considerable neuronal damage. This study aims to shed more light on the specific neuroprotective mechanisms of Kirenol, a bioactive diterpene derived from traditional herbal medicine, with a particular focus on its regulation of mitochondrial dynamics via the CK2/AKT signalling pathway and its impact on the mitochondrial fusion protein Optic atrophy 1 (Opa1). The effects of Kirenol on neuronal viability, mitochondrial function, and pertinent signalling pathways were evaluated by employing a middle cerebral artery occlusion (MCAO) model in rats and subjecting HT22 neuronal cells to oxidative stress. Treatment with Kirenol significantly improved neurological outcomes, augmented Opa1 expression, and restored apoptotic-related protein markers, antioxidative factors, mitochondrial membrane potential, and adenosine triphosphate (ATP) levels (P < 0.01). Mechanistically, Kirenol elevated CK2 levels and phosphorylated AKT while inhibiting CK2/AKT signalling attenuated Kirenol's protective effects on Opa1 expression. Furthermore, silencing Opa1 using siRNA diminished the neuroprotective effects of Kirenol on oxidative stress and apoptosis-related markers, underscoring the critical role of Opa1. In vitro assessments demonstrated that Kirenol effectively mitigated oxidative stress-induced neuronal damage, restoring cell morphology and viability. Kirenol exhibited dose-dependent neuroprotective effects in the MCAO model (P < 0.01). These findings elucidate the neuroprotective role of Kirenol in ischemic stroke through Opa1-mediated mitochondrial fusion and highlight the CK2/AKT pathway as a promising therapeutic target.

Heart failure (HF) occurs when the heart fails to meet the body's demands. Differentiating and managing HF with Preserved Ejection Fraction (HFpEF) versus Reduced Ejection Fraction (HFrEF) remains challenging, as therapeutic strategies for HFpEF have largely been ineffective. Exercise intolerance is a hallmark of HFpEF, making the identification of biological pathways underlying exercise-related impairments particularly important. In this study, we integrated cardiopulmonary exercise testing with exercise stress echocardiography (CPET-ESE) and MS-based targeted lipid and epilipid profiling to investigate metabolic and immune dysregulation across different stages of HF. Due to the technical challenges and patient discomfort associated with venous blood collection during exercise, we employed a less invasive Dried Blood Spot (DBS) approach. For the first time, we successfully validated a method for targeted profiling of 52 oxylipins and 4 PUFAs in DBS samples, covering the entire inflammatory cascade. We established reliable DBS handling and storage procedures, with the addition of an internal standard mixture on filter paper ensuring high analyte recovery (93-107%) and precision (RSD ≤12%). Data from HF patients revealed significant differences in AA and anti-inflammatory omega-3 PUFA levels at rest. Furthermore, measuring AA and its epoxide metabolite, 8,9-EET, during exercise enabled clear differentiation between HFpEF, HFrEF, and stage A-B patients, potentially supporting earlier and more accurate diagnosis. Profiling alterations in free fatty acids and oxylipins could serve as a valuable tool for the in-depth pathophysiological characterization of HF patients.

Auranofin (AF) is a gold-based compound and it has been used in the treatment of rheumatoid arthritis for over four decades. Recently, it has been demonstrated to show significant antitumor activity across various cancer types and is being repurposed as an anticancer drug. However, the precise mechanisms underlying its antitumor effects, particularly its binding targets, remain poorly understood. Here, we demonstrate that Auranofin (AF) exerts cytotoxic effects in 786-O renal cancer cells via inducing apoptosis. Mechanistic studies reveal that AF induces reactive oxygen species (ROS) accumulation, which is a key factor in mediating AF-induced stress and subsequently apoptosis. Notably, both ROS and ER stress induce autophagy, and inhibition of autophagy further enhances AF-induced cytotoxicity. Interestingly, activity-based protein profiling (ABPP) analysis identifies two key antioxidant enzymes, peroxiredoxin 1 (PRDX1) and peroxiredoxin 2 (PRDX2), as direct binding targets of AF. Importantly, overexpression of PRDX1 or PRDX2 inhibits AF-induced ROS accumulation and subsequent apoptosis. Overall, our findings demonstrate that AF induces apoptosis by covalently binding to PRDX1/2 to inhibit its activity, leading to ROS accumulation, which triggers ER stress and apoptosis. At the same time, ER stress triggers a cytoprotective autophagic response. These findings provide novel insights into the mechanism of AF-induced cytotoxicity and suggest PRDX1/2 as critical targets for the development of anti-renal cancer therapies.

Saturated fatty acids (SFAs) are the primary contributors to hepatic lipotoxic injuries accompanied by the accumulation of hepatic insoluble protein inclusions that are composed of ubiquitinated proteins and p62, but the role of these inclusions in the SFA-induced hepatic lipotoxic injuries and their regulatory mechanisms are incompletely understood. In this study, we demonstrated that palmitic acid (PA), a dietary SFA, induced aberrant accumulation of hepatic insoluble protein inclusions, leading to hepatic lipotoxic injuries in zebrafish. Mechanistically, the accumulation of hepatic insoluble protein inclusions and the subsequent lipotoxic injuries induced by PA were attributed to reduced autophagy activity and increased endoplasmic reticulum (ER) stress. In addition, the upregulation of p62 by the ER stress response factor XBP1s and ATF4 further exacerbated PA-induced accumulation of hepatic insoluble protein inclusions and subsequent lipotoxic injuries. Importantly, the ω-6 PUFA linoleic acid (LA) attenuated PA-induced accumulation of hepatic insoluble protein inclusions and subsequent lipotoxic injuries by improving defective autophagy and reducing ER stress induced by PA. Overall, the present study provides new mechanisms by which SFAs and ω-6 PUFA influence hepatic lipotoxic injuries. These findings advance the understanding of hepatic lipotoxic injuries induced by SFAs and provide new insights for optimizing the rational substitution of fish oil by vegetable oils in aquaculture and the balance of fatty acid intake in human diets.