From bench to bedside: elucidating VEGF(R) inhibitor-related heart failure in cancer treatmentPeng, Cai, Kuang
et alJ Transl Med (2025) 23 (1), 109
Abstract: Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors play a pivotal role in treating various tumors; however, the clinical characteristics and molecular mechanisms of their associated heart failure (HF) remain incompletely understood.We investigated the epidemiological characteristics of VEGF or VEGFR inhibitors [VEGF(R)i]-related heart failure (VirHF) using the global pharmacovigilance database Vigibase. The phenotypic features and molecular mechanisms of VirHF were characterized using VEGF(R)i-treated mouse models through a combination of echocardiography, histopathological analysis, and transcriptome sequencing. Furthermore, we performed a retrospective analysis of cardiac function parameters in patients undergoing VEGF(R)i treatment at local hospitals.In the analysis of 1871 VirHF cases, elderly patients (≥ 65 years) and female subjects demonstrated an elevated risk of occurrence. Experimental studies in mice revealed that both acute and chronic VEGF(R)i administration resulted in reduced left ventricular EF, cardiomyocyte hypertrophy, and myocardial fibrosis. Transcriptomic analysis identified significant dysregulation of multiple key signaling pathways, including DNA repair (R = 0.46), mitochondrial ATP synthesis (R = 0.39), glycogen metabolism regulation (R = 0.45), and proteasome-mediated protein degradation (R = 0.45). Moreover, significant upregulation was observed in inflammatory pathways, specifically those involving IL-1, IL-6, TNF-α, and IRF3/IRF7-mediated immune responses. Clinical cohort analyses demonstrated significant elevations in both cardiac injury biomarkers (NT-proBNP, CK-MB, cTnT) and inflammatory mediators (CRP) following VEGF(R)i administration.Our findings present the first comprehensive characterization of VirHF clinical features and elucidate its underlying molecular mechanisms, thereby providing a theoretical framework for optimizing the clinical safety of VEGF(R)i therapy.© 2025. The Author(s).
Anti-inflammatory and antioxidant properties of oleuropein in human keratinocytes characterized by bottom-up proteomicsLi, Deng, Yang
et alFront Pharmacol (2024) 15, 1496078
Abstract: Oleuropein is a phenolic compound commonly found in cosmetic ingredients including olive leaves and jasmine flowers with various skin-beneficial effects. Here, we evaluated oleuropein's anti-inflammatory and antioxidant activities in human skin cells. In a cell-based inflammasome model with human monocytes (THP-1 cells), oleuropein (12-200 µM) reduced proinflammatory cytokine interleukin (IL)-6 by 38.8%-45.5%, respectively. Oleuropein (50 and 100 µM) also alleviated oxidative stress in keratinocytes (HaCaT cells) by reducing H2O2-induced cell death by 6.4% and 9.2%, respectively. Additionally, biological evaluations revealed that oleuropein's antioxidant effects were attributed to its mitigation of reactive oxygen species in HaCaT cells. Furthermore, a multiplexed gene assay identified IL-1β and thioredoxin-interacting proteins as potential molecular targets involved in oleuropein's protective effects in HaCaT cells. This was supported by findings from several cellular assays showing that oleuropein reduced the level of IL-1β and inhibited the activity of caspase-1/IL-1 converting enzyme, as well as ameliorated pyroptosis in HaCaT cells. Moreover, a bottom-up proteomics study was conducted to explore potential molecular targets and signaling pathways involved in oleuropein's antioxidant activities. Taken together, findings from this study expand the understanding of oleuropein's skin protective effects against oxidative and inflammatory stresses, which support that oleuropein is a promising natural cosmeceutical for skincare applications.Copyright © 2025 Li, Deng, Yang, Zhao, Jin, Cai, Seeram, Ma, Li, Yang and Liu.
Comparative efficacy and safety of colchicine and interleukin-1 antagonists in recurrent pericarditis: a network meta-analysisDesai, Maheta, Agrawal
et alPanminerva Med (2024)
Abstract: Despite advancement of therapeutic approaches to recurrent pericarditis, it poses notable challenges to its' management. As per the current guidelines, colchicine is the first line therapy, although, non-conventional treatments like interleukin-1 (IL-1) antagonists (rilonacept, anakinra, goflikicept) are progressively utilized for refractory cases.A comprehensive electronic search identified relevant literature across multiple databases, focusing on recurrence rates and adverse effects associated with each treatment regimen.Eleven studies (6 on colchicine, 5 on IL-1 antagonists) involving 1053 patients were included. Colchicine significantly reduced recurrence risk by 63% (OR 0.37, 95% CI 0.27-0.52). IL-1 antagonists demonstrated superior efficacy: anakinra reduced recurrence by 98% (OR 0.02, 95% CI 0.01-0.07), rilonacept by 98% (OR 0.02, 95% CI 0.01-0.07), and goflikicept by 99% (OR 0.01, 95% CI 0.00-0.05). Adverse effects were comparable between colchicine and IL-1 antagonists except for rilonacept, which showed a higher risk (OR 5.70, 95% CI 2.13-15.27).IL-1 antagonists significantly reduce recurrent pericarditis episodes compared to colchicine, with anakinra, rilonacept, and goflikicept demonstrating high efficacy and acceptable safety profiles. These findings support their consideration as alternative therapies in colchicine-refractory cases of recurrent pericarditis. Further studies are warranted to refine treatment guidelines and optimize patient outcomes.
The IL-2 SYNTHORIN molecule promotes functionally adapted Tregs in a preclinical model of type 1 diabetesAlvarez, Acuff, La Muraglia
et alJCI Insight (2024) 9 (24)
Abstract: Deficits in IL-2 signaling can precipitate autoimmunity by altering the function and survival of FoxP3+ regulatory T cells (Tregs) while high concentrations of IL-2 fuel inflammatory responses. Recently, we showed that the non-beta IL-2 SYNTHORIN molecule SAR444336 (SAR'336) can bypass the induction of autoimmune and inflammatory responses by increasing its reliance on IL-2 receptor α chain subunit (CD25) to provide a bona fide IL-2 signal selectively to Tregs, making it an attractive approach for the control of autoimmunity. In this report, we further demonstrate that SAR'336 can support non-beta IL-2 signaling in murine Tregs and limit NK and CD8+ T cells' proliferation and function. Using a murine model of spontaneous type 1 diabetes, we showed that the administration of SAR'336 slows the development of disease in mice by decreasing the degree of insulitis through the expansion of antigen-specific Tregs over Th1 cells in pancreatic islets. Specifically, SAR'336 promoted the differentiation of IL-33-responsive (ST2+), IL-10-producing GATA3+ Tregs over other Treg subsets in the pancreas, demonstrating the ability of this molecule to further orchestrate Treg adaptation. These results offer insight into the capacity of SAR'336 to generate highly specialized, tissue-localized Tregs that promote restoration of homeostasis during ongoing autoimmune disease.
膜杰作
Star Staining
+添加评论
