Synthesis and molecular docking studies of new aryl imeglimin derivatives as a potent antidiabetic agent in a diabetic zebrafish model.

Diabetes mellitus (DM) is a persistent, progressive, and multifaceted disease characterized by elevated blood glucose levels. Type 2 diabetes mellitus is associated with a relative deficit in insulin mainly due to beta cell dysfunction and peripheral insulin resistance. Metformin has been widely prescribed as a primary treatment option to address this condition. On the other hand, an emerging glucose-reducing agent known as imeglimin has garnered attention due to its similarity to metformin in terms of chemical structure. In this study, an innovative series of imeglimin derivatives, labeled 3(a-j), were synthesized through a one-step reaction involving an aldehyde and metformin. The chemical structures of these derivatives were thoroughly characterized using ESI-MS, 1H, and 13C NMR spectroscopy. In vivo tests on a zebrafish diabetic model were used to evaluate the efficacy of the synthesized compounds. All compounds 3(a-j) showed significant antidiabetic effects. It is worth mentioning that compounds 3b (FBS = 72.3 ± 7.2 mg/dL) and 3g (FBS = 72.7 ± 4.3 mg/dL) have antidiabetic effects comparable to those of the standard drugs metformin (FBS = 74.0 ± 5.1 mg/dL) and imeglimin (82.3 ± 5.2 mg/dL). In addition, a docking study was performed to predict the possible interactions between the synthesized compounds and both SIRT1 and GSK-3ß targets. The docking results were in good agreement with the experimental assay results.

Preclinical studies of chimeric antigen receptor-modified natural killer cells in cancer immunotherapy: a review.

INTRODUCTION: As one of the most efficacious methods of cancer immunotherapy, chimeric antigen receptor-modified immune cells have recently drawn enormous attention. After the great success achieved with CAR-T-cells in cancer treatment both in preclinical setting and in the clinic, other types of immune cells, including natural killer (NK)-cells and macrophages, have been evaluated for their anti-cancer effects along with their potential superiority against CAR-T-cells, especially in terms of safety. First introduced by Tran et al. almost 26 years ago, CAR-NK-cells are now being considered as efficient immunotherapeutic modalities in various types of cancers, not only in preclinical setting but also in numerous phase I and II clinical studies. AREAS COVERED: In this review, we aim to provide a comprehensive survey of the preclinical studies on CAR-NK-cells' development, with an evolutional approach on CAR structures and their associated signaling moieties. Current NK-cell sources and modes of gene transfer are also reviewed. EXPERT OPINION: CAR-NK-cells have appeared as safe and effective immunotherapeutic tools in preclinical settings; however, designing CAR structures with an eye on their specific biology, along with choosing the optimal cell source and gene transfer method require further investigation to support clinical studies.