1.
Emerging roles of non-coding RNAs in the metabolic reprogramming of tumor-associated macrophages.
Li, J, Lu, Z, Zhang, Y, Xia, L, Su, Z
Immunology letters. 2021;:27-34
Abstract
Macrophages are the most common immune cells in the tumor microenvironment, and tumor-associated macrophages play an important role in cancer development. Metabolic reprogramming is important for the functional plasticity of macrophages. Studies investigating the relevance of non-coding RNAs (ncRNAs) in human cancer found that ncRNAs can regulate the metabolism of cancer cells and tumor-associated macrophages. NcRNAs include short ncRNAs, long ncRNAs (lncRNAs), and circular RNAs (circRNAs). The most common short ncRNAs are microRNAs, which regulate glucose, lipid, and amino acid metabolism in macrophages by acting on metabolism-related pathways and targeting metabolism-related enzymes and proteins, and are therefore involved in cancer progression. The role of lncRNAs and circRNAs in the metabolism of tumor-associated macrophages remains unclear. LncRNAs affect the glucose metabolism of macrophages, whereas their role in lipid and amino acid metabolism is not clear. CircRNAs regulate amino acid metabolism in macrophages. The roles of ncRNAs in energy metabolism and the underlying mechanisms need to be investigated further. Here, we summarize recent findings on the involvement of ncRNAs in metabolic reprogramming in tumor-associated macrophages, which affect the tumor microenvironment and play important roles in the development of cancer. Improving our understanding of the effects of ncRNAs on metabolic reprogramming of tumor-associated macrophages may facilitate the development of effective clinical therapies.
2.
Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease.
Ozen, A, Kasap, N, Vujkovic-Cvijin, I, Apps, R, Cheung, F, Karakoc-Aydiner, E, Akkelle, B, Sari, S, Tutar, E, Ozcay, F, et al
Nature immunology. 2021;(2):128-139
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Abstract
Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.
3.
Individual Amino Acid Supplementation Can Improve Energy Metabolism and Decrease ROS Production in Neuronal Cells Overexpressing Alpha-Synuclein.
Delic, V, Griffin, JWD, Zivkovic, S, Zhang, Y, Phan, TA, Gong, H, Chaput, D, Reynes, C, Dinh, VB, Cruz, J, et al
Neuromolecular medicine. 2017;(2-3):322-344
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein accumulation and loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. Increased levels of alpha-synuclein have been shown to result in loss of mitochondrial electron transport chain complex I activity leading to increased reactive oxygen species (ROS) production. WT alpha-synuclein was stably overexpressed in human BE(2)-M17 neuroblastoma cells resulting in increased levels of an alpha-synuclein multimer, but no increase in alpha-synuclein monomer levels. Oxygen consumption was decreased by alpha-synuclein overexpression, but ATP levels did not decrease and ROS levels did not increase. Treatment with ferrous sulfate, a ROS generator, resulted in decreased oxygen consumption in both control and alpha-synuclein overexpressing cells. However, this treatment only decreased ATP levels and increased ROS production in the cells overexpressing alpha-synuclein. Similarly, paraquat, another ROS generator, decreased ATP levels in the alpha-synuclein overexpressing cells, but not in the control cells, further demonstrating how alpha-synuclein sensitized the cells to oxidative insult. Proteomic analysis yielded molecular insights into the cellular adaptations to alpha-synuclein overexpression, such as the increased abundance of many mitochondrial proteins. Many amino acids and citric acid cycle intermediates and their ester forms were individually supplemented to the cells with L-serine, L-proline, L-aspartate, or L-glutamine decreasing ROS production in oxidatively stressed alpha-synuclein overexpressing cells, while diethyl oxaloacetate or L-valine supplementation increased ATP levels. These results suggest that dietary supplementation with individual metabolites could yield bioenergetic improvements in PD patients to delay loss of dopaminergic neurons.