EGCG suppresses PD-1 expression of T cells via inhibiting NF-κB phosphorylation and nuclear translocation.

Epigallocatechin-3-gallate (EGCG) is an important tea polyphenol with anti-tumor potential. Our previous studies revealed that EGCG was a promising immune checkpoint inhibitor (ICI) as it could downregulate expression of programmed cell death 1 ligand 1 (PD-L1) in tumor cells, thereby resulting tumor killing effect. In particular, EGCG can effectively avoid the inflammatory storm caused by anti-tumor therapy, which is a healthy green capacity absent from many ICIs. However, the relationship between EGCG and programmed cell death 1 (PD-1) of T cells remains unclear. In this work, we explored the effect of EGCG on T cells and found that EGCG suppressed PD-1 via inhibiting NF-κB phosphorylation and nuclear translocation. Furtherly, the capability of EGCG was confirmed in tumor-bearing mice to inhibit PD-1 expression in T cells and enhance apoptosis in tumor cells. These results implied that EGCG could inhibit the expression of PD-1 in T cells, thereby promoting anti-tumor effects of T cells. EGCG will be a promising candidate in anti-tumor therapy.

The divergent effects of astrocyte ceruloplasmin on learning and memory function in young and old mice.

Ceruloplasmin (CP) plays an important role in maintaining iron homeostasis. Cp gene knockout (Cp-/-) mice develop a neurodegenerative disease with aging and show iron accumulation in the brain. However, iron deficiency has also been observed in 3 M Cp-/- mice. The use of systemic Cp gene knockout is insufficient to reveal specific functions for CP in the central nervous system. Considering recent discoveries that astrocytes synthetize the majority of brain CP, we generated astrocyte conditional Cp knockout (CpGfapcKO) mice, and found that iron contents decreased in the cerebral cortex and hippocampus of young (6 M) and old (18 M) CpGfapcKO mice. Further experiments revealed that 6 M CpGfapcKO mice exhibited impaired learning and memory function, while 18 M CpGfapcKO mice exhibited improved learning and memory function. Our study demonstrates that astrocytic Cp deletion blocks brain iron influx through the blood-brain-barrier, with concomitantly increased iron levels in brain microvascular endothelial cells, resulting in brain iron deficiency and down-regulation of ferritin levels in neurons, astrocytes, microglia and oligodendrocytes. At the young age, the synapse density, synapse-related protein levels, 5-hydroxytryptamine and norepinephrine, hippocampal neurogenesis and myelin formation were all decreased in CpGfapcKO mice. These changes affected learning and memory impairment in young CpGfapcKO mice. In old CpGfapcKO mice, iron accumulation with aging was attenuated, and was accompanied by the alleviation of the ROS-MAPK-apoptosis pathway, Tau phosphorylation and ß-amyloid aggregation, thus delaying age-related memory decline. Overall, our results demonstrate that astrocytic Cp deletion has divergent effects on learning and memory function via different regulatory mechanisms induced by decreased iron contents in the brain of mice, which may present strategies for the prevention and treatment of dementia.

Caffeine Decreases Hepcidin Expression to Alleviate Aberrant Iron Metabolism under Inflammation by Regulating the IL-6/STAT3 Pathway.

Caffeine is well-known as a psychostimulant, and it can also be beneficial in numerous diseases such as diabetes and different types of cancer. Previous studies have shown that caffeine can have a protective role in bacterial infection-induced inflammation and hyperoxia-mediated pulmonary inflammation. Hepcidin, which is regulated by the IL-6/STAT3 inflammation pathway, is a peptide hormone that maintains systemic iron homeostasis. We hypothesized that caffeine's effects on inflammation may also influence hepcidin production and therefore systemic iron metabolism. To this end, we treated 2-month-old mice with caffeine by daily intragastric administration for 7 days, administering intraperitoneal LPS after the final caffeine treatment. Twelve hours after LPS treatment the mice were euthanized, and tissues were collected. We found that caffeine decreased hepatic hepcidin expression and attenuated LPS-induced hepatic hepcidin overexpression. IL-6 expression and STAT3 phosphorylation were also reduced upon caffeine administration. Additionally, hepatic and splenic FPN1 levels increased after caffeine treatment, leading to lower iron levels in liver and spleen tissues and higher iron levels in serum. Caffeine also prevented the increase in spleen weight and decrease in body weight after LPS treatment. Together, our findings suggest that caffeine decreases hepcidin expression via inhibiting inflammation and the activation of the IL-6/STAT3 pathway, thus presenting an attractive, potential therapeutic for the treatment of anemia of inflammation.