Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients' T cell ferroptosis.

BACKGROUND: Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death. Therefore, ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after trans-plantation. AIM: To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP. METHODS: A rat LT model of acute rejection was established, and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT. In vitro, primary CD3+ T cells were sorted from rat spleens and human peripheral blood, and co-cultured with or without 5-fluorouracil (5-FU) (active agent of CAP). The levels of ferroptosis-related proteins, ferrous ion concentration, and oxidative stress-related indicators were observed. The changes in mito-chondrial structure were observed using electron microscopy. RESULTS: With no significant myelotoxicity, metronomic CAP alleviated graft injury (Banff score 9 vs 7.333, P < 0.001), prolonged the survival time of the recipient rats (11.5 d vs 16 d, P < 0.01), and reduced the infiltration rate of CD3+ T cells in peripheral blood (6.859 vs 3.735, P < 0.001), liver graft (7.459 vs 3.432, P < 0.001), and spleen (26.92 vs 12.9, P < 0.001), thereby inhibiting acute rejection after LT. In vitro, 5-FU, an end product of CAP metabolism, induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4, which caused the accumulation of ferrous ions. It also inhibited nuclear erythroid 2 p45-related factor 2, heme oxygenase-1, and glutathione peroxidase 4, eventually leading to oxidative damage and ferroptosis of T cells. CONCLUSION: Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.

Triplexed Tracking Labile Sulfur-Containing Species on a Single-Molecule "Nezha" Sensor.

Sulfur-containing species (SCS), especially sulfur dioxide-relevant species, play an essential role in ecological balance. Owing to the intrinsically labile and mobile characteristics of SCS, it is still considered to be an insurmountable challenge for multiplexed tracking dynamics of SCS with distinct molecular structure, valence state, and condensed state. To address this key problem, we proposed herein alternative versatile single-molecule sensors (VSMs) that intramolecularly integrate high affinity target-guided multiple recognition units into a single sensory molecule, clarified as molecular Nezha available in triplexed responses to gaseous sulfur dioxide, liquid sulfur trioxide, and aqueous bisulfite through ubiquitous charge transfer and nucleophilic addition. High-performance molecular Nezha remarkably facilitated promising applications in a quantitative visualization of SCS on lab-on-paper and tracking the dynamics transformation of SCS as well comprehensive evaluation of multiphase adsorption science of SCS on an advanced Zeolitic imidazolate framework-8 (ZIF-8).

A glucose-activatable trimodal glucometer self-assembled from glucose oxidase and MnO2 nanosheets for diabetes monitoring.

Daily monitoring of blood glucose is of great importance for the treatment of diabetes mellitus. Herein, we present an ensemble glucometer with a sandwich structure formed by the spontaneous entrapment of glucose oxidase (GOD) onto manganese dioxide nanosheets (MnO2 NSs) via the hydrophobic effect and hydrogen bond interaction. Within the hybrid glucometer, the ultrathin MnO2 NSs act as an enzyme nanosupport and target-activated signal transducer. Trimodal self-indication by fluorescence (FL) and UV-absorbance (UV) and magnetic resonance signal (MRS) activation with glucose-specificity provides multiple response signals to glucose. Taking account of its operational simplicity and convenience, even being observable by the naked eye, a detection limit as low as 0.1 µM was obtained by using the ensemble glucometer in a colorimetric assay, whilst the precision for 11 replicated detections of 10 µM glucose was 3.5% (relative standard deviation, RSD). Notably, the value of the Michaelis-Menton constant of GOD involved the presented glucometer is estimated to be 0.051 mM, showing an exceptional enhanced enzymatic activity of free GOD measured by far. The designed glucometer, with its high sensitivity and simplicity highlighted, was capable of routine blood glucose monitoring for type-I diabetes mellitus in rats. Furthermore, the fully integrated platform can be readily generalized in principle for a number of biomarkers for point of care diagnostics in the future.