Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin‐like 4 ( ANGPTL 4) as one of the most significantly upregulated genes. Clinically, ANGPTL 4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL 4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis‐associated pathological outcomes. Conversely, exogenous ANGPTL 4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL 4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI 3K/ AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS ‐activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL 4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL 4 is a potential strategy for the treatment of pancreatitis.
The uniqueness of multivariate metal–organic frameworks (MTV-MOFs) has been widely explored to discover their unknown opportunities. While mesoscopic apportionments have been studied, macroscopic heterogeneity and its spatial effects remain unexplored in MTV-MOFs. In this study, we investigated the effect of macroscopic heterogeneity on MTV-MOFs on their uptake behaviors by comparing three types of MTV-MOFs having the functional groups in inner, outer, or entire parts of crystals. Their adsorption behavior for carbon dioxide (CO2) and water (H2O) brought out that functional groups located in the outer part of the crystals dominantly influence the sorption behavior of MTV-MOFs. These results are also visualized by observing iodine adsorption in the three types of MTV-MOFs using scanning transmission electron microscopy–electron energy loss spectroscopy. We believe that this finding provides new ways to decipher and design MTV-MOFs for their unusual properties.
Kidney diseases pose a tremendous burden to patients and healthcare facilities globally (Luyckx et al., 2018). A recent report indicates that over 700 million individuals are affected by chronic kidney disease (CKD) worldwide (Sundström et al., 2022). According to time frames, acute kidney injury (AKI) and CKD have a substantial impact on mortality and other health-related consequences, including end-stage kidney disease (ESKD) and cardiovascular events (Kellum et al., 2021;Kovesdy, 2022; Matsushita et al., 2022). Despite the recent development of promising therapeutics, such as sodium-glucose co-transporter 2 inhibitors, disease-specific therapies for diverse kidney diseases are still lacking (van Asbeck et al., 2020).Various forms of cell death including apoptosis, necroptosis, autophagy, and ferroptosis are involved in different types of kidney injuries (Priante et al., 2019;Maremonti et al., 2022). Among these cell death processes, non-apoptotic cell death is considered a potential therapeutic target. Regulated necrosis such as ferroptosis and necroptosis is a more immunogenic form of cell death that triggers the innate immune system by 599 According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis. Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.
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