The accumulation of senescent cells, characterized by a senescence-associated secretory phenotype (SASP), contributes to chronic inflammation and age-related diseases (ARD). During aging, macrophages can adopt a senescent-like phenotype and an altered function, which promotes senescent cell accumulation. In the context of aging and ARD, controlling the resolution of the inflammatory response and preventing chronic inflammation, especially by targeting macrophages, must be a priority. Aging being a dynamic process, we developed a model of in vitro murine peritoneal macrophage aging. Our results show that macrophages cultured for 7 or 14 days exhibit a senescence-like phenotype: proliferation decrease, the levels of cyclin-dependent kinase inhibitors p16^INK4A and p21^CIP1 and of pro-inflammatory SASP components (MCP-1, IL-6, IL-1β, TNF-α, and MMP-9) increase, phagocytosis capacity decline and glycolytic activity is induced. In our model, chronic treatment with CB3, a thioredoxin-1 mimetic anti-inflammatory peptide, completely prevents p21^CIP1 increase and enables day 14 macrophages to maintain proliferative activity.We describe a new model of macrophage aging with a senescence-like phenotype associated with inflammatory, metabolic and functional perturbations. This model is a valuable tool for characterizing macrophage aging mechanisms and developing innovative strategies with promising therapeutical purpose in limiting inflammaging and ARD.

2024-01-15·The FASEB Journal

Thioredoxin‐1 and its mimetic peptide improve systolic cardiac function and remodeling after myocardial infarction

Article

作者: Medali, Tania ; Ibrahim, Ayman M. ; Couchie, Dominique ; Mihoc, Maria ; Soliman, Saif ; Szweda, Luke I. ; Derks, Wouter ; Yacoub, Magdi ; Wagdy, Kerolos ; Rouis, Mustapha ; Mougenot, Nathalie ; Friguet, Bertrand ; Aguib, Yasmine ; Bergmann, Olaf

AbstractMyocardial infarction (MI) is characterized by a significant loss of cardiomyocytes (CMs), and it is suggested that reactive oxygen species (ROS) are involved in cell cycle arrest, leading to impaired CM renewal. Thioredoxin‐1 (Trx‐1) scavenges ROS and may play a role in restoring CM renewal. However, the truncated form of Trx‐1, Trx‐80, can compromise its efficacy by exerting antagonistic effects. Therefore, a Trx‐1 mimetic peptide called CB3 was tested as an alternative way to restore CMs. This study aimed to investigate the effects of Trx‐1, Trx‐80, and CB3 on mice with experimental MI and study the underlying mechanism of CB3 on CMs. Mouse cardiac parameters were quantified by echocardiography, and infarction size and fibrosis determined using Trichrome and Picro‐Sirius Red staining. The study found that Trx‐1 and CB3 improved mouse cardiac function, reduced the size of cardiac infarct and fibrosis, and decreased the expression of cardiac inflammatory markers. Furthermore, CB3 polarized macrophages into M2 phenotype, reduced apoptosis and oxidative stress after MI, and increased CM proliferation in cell culture and in vivo. CB3 effectively protected against myocardial infarction and could represent a new class of compounds for treating MI.

2024-01-01·Neuroscience

Redox Protein Thioredoxin Mediates Neurite Outgrowth in Primary Cultured Mouse Cerebral Cortical Neurons

Article

作者: Ha, Ryan ; Alejandra Llanes-Cuesta, M ; Hoi, Vanessa ; Imamul Islam, Md ; Tan, Hua ; Wang, Jun-Feng ; Eftekharpour, Eftekhar

Thioredoxin system plays an important role in maintaining the cellular redox balance. Recent evidence suggests that thioredoxin (Trx) system may promote cell survival and neuroprotection. In this study, we explored the role of thioredoxin system in neuronal differentiation using a primary mouse cortical neuronal cell culture. First, Trx and Trx reductase (TrxR) protein levels were analyzed in cultured neurons from 1 to 32 days in vitro (DIV). The result showed that Trx and TrxR protein levels time-dependently increased in the neuron cell culture from 1 to 18 DIV. To establish the role of Trx in neuronal differentiation, Trx gene expression was knockdown in cultured neurons using Trx sgRNA CRISPR/Cas9 technology. Treatment with CRISPR/Cas9/Trx sgRNA decreased Trx protein levels and caused a reduction in dendritic outgrowth and branching of cultured neurons. Then, primary cortical neurons were treated with the Trx inhibitor PX12 to block Trx reducing activity. Treatment with PX12 also reduced dendritic outgrowth and branching. Furthermore, PX12 treatment reduced the ratio of phosphorylated cyclic AMP response element-binding protein (CREB)/total CREB protein levels. To investigate whether CREB phosphorylation is redox regulated, SH-SY5Y cells were treated with H₂O₂, which reduced phosphorylated CREB protein levels and increased CREB thiol oxidation. However, treatment with CB3, a Trx-mimetic tripeptide, rescued H₂O₂-decreased CREB phosphorylation. Our results suggest that Trx regulates neuronal differentiation and maturation of primary mouse cortical neurons by targeting CREB neurotrophic pathway. Trx may regulate CREB activation by maintaining the cellular redox balance.

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适应症	最高研发状态	国家/地区	公司	日期
帕金森病	临床前	美国	Melior Pharmaceuticals I, Inc.	-
帕金森病	临床前	美国	Purdue University	-
帕金森病	临床前	美国	Cantabio Pharmaceuticals, Inc.	-
帕金森病	临床前	匈牙利	Hungarian Academy of Sciences	-