ABSTRACT
The typical hallmark of tumor evolution is metabolic dysregulation. In addition to secreting immunoregulatory metabolites, tumor cells and various immune cells display different metabolic pathways and plasticity. Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy. We develop a nanoplatform (CLCeMOF) based on cerium metal-organic framework (CeMOF) by lactate oxidase (LOX) modification and glutaminase inhibitor (CB839) loading. The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species "storm" to elicit immune responses. Meanwhile, LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment, preparing the ground for intracellular regulation. Most noticeably, the immunometabolic checkpoint blockade therapy, as a result of glutamine antagonism, is exploited for overall cell mobilization. It is found that CLCeMOF inhibited glutamine metabolism-dependent cells (tumor cells, immunosuppressive cells, etc.), increased infiltration of dendritic cells, and especially reprogrammed CD8+ T lymphocytes with considerable metabolic flexibility toward a highly activated, long-lived, and memory-like phenotype. Such an idea intervenes both metabolite (lactate) and cellular metabolic pathway, which essentially alters overall cell fates toward the desired situation. Collectively, the metabolic intervention strategy is bound to break the evolutionary adaptability of tumors for reinforced immunotherapy.
ABSTRACT
Objective: To observe the effect of nutritional support and metabolic intervention in a patient receiving combined liver and intestinal transplantation. Methods: Glycyl glutamine(Gly Gln)and arginine supplemented total parenteral nutrition(TPN) was administered since postoperative day(POD)1. Glutamine(Gln) and arginine supplemented enteral nutrition(EN) was applied since POD 4. Growth hormone(GH) was delivered intermittently since POD 4.With adaptation and tolerance, enteral feeding was progressively increased while parenteral nutrition reciprocally decreased. Results: Transplanted organs functioned well. Conclusions: Rehabilitation of the allograft function can profit from the application of nutritional support and metabolic intervention.
ABSTRACT
Objectives:To observe the effect of metabolic intervention of anti TNF antibody on the hypermetabolism occurred in intra abdominal infection(IAI) complicated by multiple organ dysfunction syndrome(MODS). Methods:Twenty rabbits were operated on with cecal ligation plus puncture(CLP) inducing IAI and MODS and were randomly divided into two groups, one receiving the anti TNF serum raised against TNF ?(anti TNF group) at 0.5?h after CLP and another receiving the non specific serum (control group). All animals were placed in metabolic cages and maintained with intravenous infusion for the observation period of one week. Serum levels of cytokines(TNF, IL 6), hormones (cortisol, insulin, glucagon), biochemical indexes (glucose, cholesterol, triglyceride, albumin) and daily excretions of urea nitrogen (UN),creatinine (Cr) and 3 methylhistidine (3 MH) were dynamically determined for 7 days. The death of animals was also recorded. Results:Compared with the control group, the levels of serum TNF, IL 6 and cortisol were significantly decreased and the levels of insulin and glucagon were kept normal after the injection of immune serum in anti TNF group, with significant improvements of biochemical indexes and decreased excretions of UN, Cr and 3 MH in urine. The survival rate was significantly increased in the anti TNF group. Conclusions:The anti TNF antibody can attenuate the metabolic abnormalities of IAI and MODS, being of the metabolic intervention on the hypermetabolism.