Monoclonal antibody (MAb)-based radioimmunoassay (RIA) and immunopurification procedures were used to probe the immunochemical relatedness of cytochromes P-450 in tissues from different species. RIAs based on MAb 1-7-1 and MAb 1-31-2, both to the major 3-methylcholanthrene (MC)-induced rat liver microsomal cytochrome P-450, detected antigenically related forms of cytochrome P-450 in liver microsomes from MC-induced rats, C57BL/6 and DBA/2 mice, hamsters, and guinea pigs, and in lung and kidney microsomes of MC-induced rats. Individual cytochromes P-450 were also isolated from these microsomes by MAb-directed immunopurification. When bound to Sepharose, MAb 1-7-1 adsorbed two species of Mr 56,000 and 57,000 from liver microsomes from rats and C57BL/6 mice, while MAb 1-31-2 adsorbed only the Mr 57,000 polypeptide. These results reveal that livers from both rats and C57BL/6 mice contain a cytochrome P-450 (Mr 56,000) with the epitope for 1-7-1 and a cytochrome P-450 (Mr 57,000) with epitopes for both 1-31-2 and 1-7-1. Additional immunochemical relatedness between the cytochromes P-450 in different tissues was demonstrated by MAb-directed immunopurification of cytochromes P-450 from DBA/2 mouse liver (Mr 56,000), guinea pig liver (Mr 53,000), hamster liver (Mr 57,000), and rat lung (Mr 57,000). These results demonstrate the efficacy of MAb-based RIA and immunopurification procedures for simple and rapid detection and purification of cytochromes P-450 from a variety of tissues.
Chimeric antigen receptor T cell therapy has demonstrated antileukemia efficacy. However, this therapeutic approach is hampered by severe cytokine release syndrome, which is a major impediment to its widespread application in the clinic. The safety of this approach can be improved by engineering a rapid and reversible "off" or "on" safety switch for CAR-T cells. Cutting-edge investigations combining the advantages of genetic engineering and chemical technology have led to the invention of small-molecule-based safety switches for CAR-T cells. Small molecules such as FITC, folate, rimiducid, rapamycin, proteolysis-targeting chimera (PROTAC) compounds, and dasatinib are being investigated to design such safety switches. Optimized CAR-T cells may have enhanced therapeutic efficiency with fewer adverse effects. Herein we summarize and classify current novel small-molecule-based safety switches for CAR-T cells that aim to provide pharmacological control over the activities and toxicities associated with CAR-T cell-based cancer immunotherapies.
Radiation-induced thrombocytopenia (RIT) faces a perplexing challenge in the clinical treatment of cancer patients, and current therapeutic approaches are inadequate in the clinical settings. In this researsh, oxymatrine, a new molecule capable of healing RIT was screened out, and the underlying regulatory mechanism associated with magakaryocyte (MK) differentiation and thrombopoiesis was demonstrated. The capacity of oxymatrine to induce MK differentiation was verified in K-562 and Meg-01 cells in vitro. The ability to induce thrombopoiesis was subsequently demonstrated in Tg (cd41:eGFP) zebrafish and RIT model mice. In addition, we carried out network pharmacological prediction, drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) analyses to explore the potential targets of oxymatrine. Moreover, the pathway underlying the effects of oxymatrine was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blot, and immunofluorescence. Oxymatrine markedly promoted MK differentiation and maturation in vitro. Moreover, oxymatrine induced thrombopoiesis in Tg (cd41:eGFP) zebrafish and accelerated thrombopoiesis and platelet function recovery in RIT model mice. Mechanistically, oxymatrine directly binds to toll-like receptor 2 (TLR2) and further regulates the downstream pathway stimulator of interferon genes (STING)/nuclear factor-kappaB (NF-κB), which can be blocked by C29 and C-176, which are specific inhibitors of TLR2 and STING, respectively. Taken together, we demonstrated that oxymatrine , a novel TLR2 agonist, plays a critical role in accelerating MK differentiation and thrombopoiesis via the STING/NF-κB axis, suggesting that oxymatrine is a promising candidate for RIT therapy.
The invading microbial pathogens are controlled by the rapid and effective innate immune responses sequentially formation of the long-lasting adaptive memories. Toll-like receptors (TLRs) play a vital role in innate and adaptive immune response by function as a bridge to modulate the immune response. Further, genetic studies in human or animals showed that regulation of TLR signaling contributes to the antibacterial efficacy, and developing novel reagent to modulate TLR related immune response becomes an interesting therapy method to against bacterial infections. Herein we review the recent developments of this area, focusing on the reagent of synthetic molecules, natural products and peptides (or proteins), as TLR-related antibacterial drugs.
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