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1.
Revisiting preeclampsia: a metabolic disorder of the placenta.
Hu, M, Li, J, Baker, PN, Tong, C
The FEBS journal. 2022;(2):336-354
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Abstract
Preeclampsia (PE) is a leading cause of maternal and neonatal mortality and morbidity worldwide, impacting the long-term health of both mother and offspring. PE has long been characterized by deficient trophoblast invasion into the uterus and consequent placental hypoperfusion, yet the upstream causative factors and effective interventional targets for PE remain unknown. Alterations in the metabolism of preeclamptic placentas are thought to result from placental ischemia, while disturbances of the metabolism and of metabolites in PE pathogenesis are largely ignored. In fact, as one of the largest fetal organs at birth, the placenta consumes a considerable amount of glucose and fatty acid. Increasing evidence suggests glucose and fatty acid exist as energy substrates and regulate placental development through bioactive derivates. Moreover, recent findings have revealed that the placental metabolism adapts readily to environmental changes, altering its response to nutrients and endocrine signals; this adaptability optimizes pregnancy outcomes by diversifying available carbon sources for energy production, hormone synthesis, angiogenesis, immune activation, and tolerance, and fetoplacental growth. These observations raise the possibility that carbohydrate and lipid metabolism abnormalities play a role in both the etiology and clinical progression of PE, sparking a renewed interest in the interrelationship between PE and metabolic dysregulation. This review will focus on key metabolic substrates and regulatory molecules in the placenta and aim to provide novel insights with respect to the metabolism's role in modulating placental development and functions. Further investigations from this perspective are poised to decipher the etiology of PE and suggest potential therapies.
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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.
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Targeting immune cell metabolism in kidney diseases.
Basso, PJ, Andrade-Oliveira, V, Câmara, NOS
Nature reviews. Nephrology. 2021;(7):465-480
Abstract
Insights into the relationship between immunometabolism and inflammation have enabled the targeting of several immunity-mediated inflammatory processes that underlie infectious diseases and cancer or drive transplant rejection, but this field remains largely unexplored in kidney diseases. The kidneys comprise heterogeneous cell populations, contain distinct microenvironments such as areas of hypoxia and hypersalinity, and are responsible for a functional triad of filtration, reabsorption and secretion. These distinctive features create myriad potential metabolic therapeutic targets in the kidney. Immune cells have crucial roles in the maintenance of kidney homeostasis and in the response to kidney injury, and their function is intricately connected to their metabolic properties. Changes in nutrient availability and biomolecules, such as cytokines, growth factors and hormones, initiate cellular signalling events that involve energy-sensing molecules and other metabolism-related proteins to coordinate immune cell differentiation, activation and function. Disruption of homeostasis promptly triggers the metabolic reorganization of kidney immune and non-immune cells, which can promote inflammation and tissue damage. The metabolic differences between kidney and immune cells offer an opportunity to specifically target immunometabolism in the kidney.
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Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy.
Rangel Rivera, GO, Knochelmann, HM, Dwyer, CJ, Smith, AS, Wyatt, MM, Rivera-Reyes, AM, Thaxton, JE, Paulos, CM
Frontiers in immunology. 2021;:645242
Abstract
Emerging reports show that metabolic pathways can be targeted to enhance T cell-mediated immunity to tumors. Yet, tumors consume key metabolites in the host to survive, thus robbing T cells of these nutrients to function and thrive. T cells are often deprived of basic building blocks for energy in the tumor, including glucose and amino acids needed to proliferate or produce cytotoxic molecules against tumors. Immunosuppressive molecules in the host further compromise the lytic capacity of T cells. Moreover, checkpoint receptors inhibit T cell responses by impairing their bioenergetic potential within tumors. In this review, we discuss the fundamental metabolic pathways involved in T cell activation, differentiation and response against tumors. We then address ways to target metabolic pathways to improve the next generation of immunotherapies for cancer patients.
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Mechanistic Targets and Nutritionally Relevant Intervention Strategies to Break Obesity-Breast Cancer Links.
Bustamante-Marin, XM, Merlino, JL, Devericks, E, Carson, MS, Hursting, SD, Stewart, DA
Frontiers in endocrinology. 2021;:632284
Abstract
The worldwide prevalence of overweight and obesity has tripled since 1975. In the United States, the percentage of adults who are obese exceeds 42.5%. Individuals with obesity often display multiple metabolic perturbations, such as insulin resistance and persistent inflammation, which can suppress the immune system. These alterations in homeostatic mechanisms underlie the clinical parameters of metabolic syndrome, an established risk factor for many cancers, including breast cancer. Within the growth-promoting, proinflammatory milieu of the obese state, crosstalk between adipocytes, immune cells and breast epithelial cells occurs via obesity-associated hormones, angiogenic factors, cytokines, and other mediators that can enhance breast cancer risk and/or progression. This review synthesizes evidence on the biological mechanisms underlying obesity-breast cancer links, with emphasis on emerging mechanism-based interventions in the context of nutrition, using modifiable elements of diet alone or paired with physical activity, to reduce the burden of obesity on breast cancer.
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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.
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7.
SCFA: mechanisms and functional importance in the gut.
Martin-Gallausiaux, C, Marinelli, L, Blottière, HM, Larraufie, P, Lapaque, N
The Proceedings of the Nutrition Society. 2021;(1):37-49
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Abstract
In recent years, the importance of the gut microbiota in human health has been revealed and many publications have highlighted its role as a key component of human physiology. Owing to the use of modern sequencing approaches, the characterisation of the microbiome in healthy individuals and in disease has demonstrated a disturbance of the microbiota, or dysbiosis, associated with pathological conditions. The microbiota establishes a symbiotic crosstalk with their host: commensal microbes benefit from the nutrient-rich environment provided by the gut and the microbiota produces hundreds of proteins and metabolites that modulate key functions of the host, including nutrient processing, maintenance of energy homoeostasis and immune system development. Many bacteria-derived metabolites originate from dietary sources. Among them, an important role has been attributed to the metabolites derived from the bacterial fermentation of dietary fibres, namely SCFA linking host nutrition to intestinal homoeostasis maintenance. SCFA are important fuels for intestinal epithelial cells (IEC) and regulate IEC functions through different mechanisms to modulate their proliferation, differentiation as well as functions of subpopulations such as enteroendocrine cells, to impact gut motility and to strengthen the gut barrier functions as well as host metabolism. Recent findings show that SCFA, and in particular butyrate, also have important intestinal and immuno-modulatory functions. In this review, we discuss the mechanisms and the impact of SCFA on gut functions and host immunity and consequently on human health.
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Dietary Regulation of Immunity.
Lee, AH, Dixit, VD
Immunity. 2020;(3):510-523
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Abstract
Integrated immunometabolic responses link dietary intake, energy utilization, and storage to immune regulation of tissue function and is therefore essential for the maintenance and restoration of homeostasis. Adipose-resident leukocytes have non-traditional immunological functions that regulate organismal metabolism by controlling insulin action, lipolysis, and mitochondrial respiration to control the usage of substrates for production of heat versus ATP. Energetically expensive vital functions such as immunological responses might have thus evolved to respond accordingly to dietary surplus and deficit of macronutrient intake. Here, we review the interaction of dietary intake of macronutrients and their metabolism with the immune system. We discuss immunometabolic checkpoints that promote healthspan and highlight how dietary fate and regulation of glucose, fat, and protein metabolism might affect immunity.
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Competition for nutrients and its role in controlling immune responses.
Kedia-Mehta, N, Finlay, DK
Nature communications. 2019;(1):2123
Abstract
Changes in cellular metabolism are associated with the activation of diverse immune subsets. These changes are fuelled by nutrients including glucose, amino acids and fatty acids, and are closely linked to immune cell fate and function. An emerging concept is that nutrients are not equally available to all immune cells, suggesting that the regulation of nutrient utility through competitive uptake and use is important for controlling immune responses. This review considers immune microenvironments where nutrients become limiting, the signalling alterations caused by insufficient nutrients, and the importance of nutrient availability in the regulation of immune responses.
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10.
Immunomodulatory and Metabolic Changes after Gnetin-C Supplementation in Humans.
Nakagami, Y, Suzuki, S, Espinoza, JL, Vu Quang, L, Enomoto, M, Takasugi, S, Nakamura, A, Nakayama, T, Tani, H, Hanamura, I, et al
Nutrients. 2019;(6)
Abstract
Gnetin-C is a naturally occurring stilbene derived from the seeds of Gnetum gnemon L., an edible plant native to Southeast Asia that is called melinjo. Although the biological properties and safety of G. gnemon extract, which contains nearly 3% Gnetin-C, have been confirmed in various human studies, whether or not pure Gnetin-C is safe for humans is unclear at present. We conducted a randomized, double-blind, placebo-controlled trial. Healthy subjects were randomly divided into two groups. The interventional group (n = 6) was given Gnetin-C, and the control group (n = 6) was provided a placebo, for 14 days. Lipid profiles, biomarkers of oxidative stress and circulating blood cells were assessed before and after the intervention. All subjects completed the study, with no side effects reported across the study duration. Gnetin-C supplementation demonstrated a statistically significant increase in the absolute number of circulating natural killer (NK) cells expressing the activating receptors NKG2D and NKp46. NK cells derived from subjects who received Gnetin-C for two weeks showed higher cytotoxicity against K562 target cells than those before receiving Gnetin-C. In addition, Gnetin-C also resulted in a significant decrease in the absolute neutrophil count in the blood compared with the placebo. Furthermore, Gnetin-C significantly reduced the levels of uric acid, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total adiponectin, and high-molecular-weight adiponectin. These data indicate that Gnetin-C has biological effects of enhancing the NK activity on circulating human immune cells. The immunomodulatory effects are consistent with a putative improvement in cancer immunosurveillance via the upregulation of the NKG2D receptor. The study was registered with UMIN-CTR, number 000030364, on 12 December 2017.