Manganese homeostasis at the host-pathogen interface and in the host immune system.

Manganese serves as an indispensable catalytic center and the structural core of various enzymes that participate in a plethora of biological processes, including oxidative phosphorylation, glycosylation, and signal transduction. In pathogenic microorganisms, manganese is required for survival by maintaining basic biochemical activity and virulence; in contrast, the host utilizes a process known as nutritional immunity to sequester manganese from invading pathogens. Recent epidemiological and animal studies have shown that manganese increases the immune response in a wide range of vertebrates, including humans, rodents, birds, and fish. On the other hand, excess manganese can cause neurotoxicity and other detrimental effects. Here, we review recent data illustrating the essential role of manganese homeostasis at the host-pathogen interface and in the host immune system. We also discuss the accumulating body of evidence that manganese modulates various signaling pathways in immune processes. Finally, we discuss the key molecular players involved in manganese's immune regulatory function, as well as the clinical implications with respect to cancer immunotherapy.

The role of iron homeostasis in remodeling immune function and regulating inflammatory disease.

The essential trace element iron regulates a wide range of biological processes in virtually all living organisms. Because both iron deficiency and iron overload can lead to various pathological conditions, iron homeostasis is tightly regulated, and understanding this complex process will help pave the way to developing new therapeutic strategies for inflammatory disease. In recent years, significant progress has been made with respect to elucidating the roles of iron and iron-related genes in the development and maintenance of the immune system. Here, we review the timing and mechanisms by which systemic and cellular iron metabolism are regulated during the inflammatory response and during infectious disease, processes in which both the host and the pathogen compete for iron. We also discuss the evidence and implications that immune cells such as macrophages, T cells, and B cells require sufficient amounts of iron for their proliferation and for mediating their effector functions, in which iron serves as a co-factor in toll-like receptor 4 (TLR4) signaling, mitochondrial respiration, posttranslational regulation, and epigenetic modification. In addition, we discuss the therapeutic implications of targeting ferroptosis, iron homeostasis and/or iron metabolism with respect to conferring protection against pathogen infection, controlling inflammation, and improving the efficacy of immunotherapy.

Functional characterization of a potent anti-tumor polysaccharide in a mouse model of gastric cancer.

AIMS: Natural polysaccharides are emerging as a new class of immunomodulatory agents due to their potent immunostimulatory effects and suitable biocompatibility. The aim of this study was to identify potent and selective anticancer activity of a bioactive polysaccharide. MATERIALS AND METHODS: In vitro, viability assay was performed to screen 16 of bioactive polysaccharides in a panel of normal and cancer cell lines. Foci formation, soft agar, BrdU incorporation, cell cycle analyses, and ß-galactosidase staining were performed to validate the screening results. In vivo, both murine gastric cancer syngeneic and a human gastric tumor xenografts models were applied. Tumor histology, immunohistochemical staining, cytokine array and flow cytometry analyses were assayed. KEY FINDINGS: BSP (bamboo shaving polysaccharides) was identified as the most selective polysaccharide for inhibiting the growth of six gastric cancer cell lines while having no toxic effect on normal gastric mucosal cells. Similarly, BSP had more potent killing effect on a subset of human stomach cancer cells than liver or lung cancer cells. In vivo, BSP significantly inhibited tumor growth and prolonged the survival of mice bearing a gastric tumor; these effects are mediated by tumor cell apoptosis and remodeling of the tumor microenvironment by boosting both immune cell subpopulations and cytokine production in murine gastric cancer syngeneic model. A significant decrease of F4/80-positive tumor-associated macrophages was also observed. SIGNIFICANCE: The findings of this study suggest that the potent and selective anti-tumor activity of bioactive polysaccharides such as BSP warrants clinical testing for the treatment of gastric cancer.