Perioperative neurocognitive disorders (PNDs) are common neurological complications after anesthesia in the elderly. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) regulates signal transducer and activator of transcription protein 3 (STAT3) signaling to control inflammation in certain organs, but its role in PNDs remains unknown. Herein, we constructed a PND model in 18-month-old rats by treating them with sevoflurane. PND rats developed neuroinflammation, along with a significant decrease in PTPN2 expression and a rise in STAT3 phosphorylation in the hippocampus. Ptpn2 overexpression alleviated the behavioral disorders of PND rats, ameliorated neuronal injury, inhibited neuroinflammation, inflammasome activation, microglial activation, and microglial phenotype switching. Similar results were observed in sevoflurane-treated HMC3 microglia with PTPN2 overexpression, while PTPN2 silencing showed the opposite results. Additionally, PTPN2 seems to be a target of T-box transcription factor 2 (TBX2). These results contribute to the evidence supporting the idea that PTPN2 is a regulatory factor in PND progression.
Liansheng Fan,Suchen Qu,Jing Qian,Gaoyu Shi,Qiqing Huang,Yanni Song,Yu Ji,Quli Fan,Xin Han
Immune checkpoint blockade (ICB) has shown significant progress in treating triple negative breast cancer (TNBC). However, the standalone effectiveness of ICB is modest, offering patients only slight benefits. In this report, we utilize a hypoxia-responsive duplex genome editing strategy to target tumor cell programmed cell death ligand 1 (PD-L1) and protein tyrosine phosphatase non-receptor type 2 (PTPN2), which is synergized with photothermal therapy (PTT) to amplify the therapeutic effect of TNBC. In our approach, the melanin nanoparticles (MNP) serve as the delivery platform for transporting the CRISPR-Cas PTPN2/PD-L1 (Cas-TD) system, which is cross-linked by a hypoxic-sensitive Azo linker and then further modified with tumor homing phenylboronic acid (PBA), resulting in a stimuli-responsive multifunctionality nanotheranostic platform (MPA@Cas-TD@PP). Aided by the guidance of PBA, nanoparticles selectively accumulate at tumor and then disintegrate with enhanced intracellular penetration. Importantly, PTT initiates the immunogenic cell death (ICD), turning the “cold” tumor into a “hot” one, laying the foundation for subsequent ICB. Inhibiting PTPN2 and PD-L1 can synergistically sensitize tumors to immunotherapy, which exhibit magnified immunotherapy effects by increasing activated cytotoxic CD8 + T cells and enhancing interferon-γ (IFN-γ)-mediated effects. In summary, this multifunctional nanotherapeutic platform provides a promising treatment approach for synergistic phototherapy and immunotherapy in TNBC.
Here, we investigated the role of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in psoriasis pathogenesis, focusing on its regulation of the stimulator of interferon genes–signal transducer and activator of transcription 3 (STING–STAT3)-autophagy axis. Using cellular and imiquimod-induced mouse models, we assessed PTPN2 expression and function using multiple techniques, including immunofluorescence, co-immunoprecipitation, and Western blotting. A significant downregulation of PTPN2 expression was observed in psoriatic tissues. We established that PTPN2 directly interacts with STING and regulates its phosphorylation, with direct evidence from catalytic-dead PTPN2 mutant experiments showing that PTPN2's dephosphorylation of STING is activity-dependent. PTPN2 overexpression curbed keratinocyte proliferation, stimulated apoptosis and autophagy, and reduced the secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin (IL) 23 subunit alpha (A), and IL-17A. The application of a STING agonist mitigated these effects, whereas STAT3 inhibition restored them. PTPN2 overexpression attenuated psoriatic pathology, and this therapeutic benefit was further enhanced by co-administering the autophagy inducer rapamycin. Collectively, our results delineate a novel mechanism by which PTPN2 alleviates psoriasis-like pathology in keratinocytes by targeting the STING–STAT3 pathway and promoting autophagy and apoptosis. These findings indicate that PTPN2 is a potential therapeutic target, with in vivo validation supporting its translational relevance.
危险品化学品经营许可证（带存储）