Metabolic reprogramming and interventions in angiogenesis.

BACKGROUND: Endothelial cell (EC) metabolism plays a crucial role in the process of angiogenesis. Intrinsic metabolic events such as glycolysis, fatty acid oxidation, and glutamine metabolism, support secure vascular migration and proliferation, energy and biomass production, as well as redox homeostasis maintenance during vessel formation. Nevertheless, perturbation of EC metabolism instigates vascular dysregulation-associated diseases, especially cancer. AIM OF REVIEW: In this review, we aim to discuss the metabolic regulation of angiogenesis by EC metabolites and metabolic enzymes, as well as prospect the possible therapeutic opportunities and strategies targeting EC metabolism. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this work, we discuss various aspects of EC metabolism considering normal and diseased vasculature. Of relevance, we highlight that the implications of EC metabolism-targeted intervention (chiefly by metabolic enzymes or metabolites) could be harnessed in orchestrating a spectrum of pathological angiogenesis-associated diseases.

Mechanism of Iron Ion Homeostasis in Intestinal Immunity and Gut Microbiota Remodeling.

Iron is a vital trace element that plays an important role in humans and other organisms. It plays an active role in the growth, development, and reproduction of bacteria, such as Bifidobacteria. Iron deficiency or excess can negatively affect bacterial hosts. Studies have reported a major role of iron in the human intestine, which is necessary for maintaining body homeostasis and intestinal barrier function. Organisms can maintain their normal activities and regulate some cancer cells in the body by regulating iron excretion and iron-dependent ferroptosis. In addition, iron can modify the interaction between hosts and microorganisms by altering their growth and virulence or by affecting the immune system of the host. Lactic acid bacteria such as Lactobacillus acidophilus (L. acidophilus), Lactobacillus rhamnosus (L. rhamnosus), and Lactobacillus casei (L. casei) were reported to increase trace elements, protect the host intestinal barrier, mitigate intestinal inflammation, and regulate immune function. This review article focuses on the two aspects of the iron and gut and generally summarizes the mechanistic role of iron ions in intestinal immunity and the remodeling of gut microbiota.

Carbon metabolism in the regulation of macrophage functions.

Carbon metabolism, including one-carbon (1C) metabolism and central carbon metabolism (CCM), provides energy for the cell and generates metabolites with signaling activities. The regulation of macrophage polarization involves complex signals and includes an epigenetic level. Epigenetic modifications through changes in carbon metabolism allow macrophages to respond in a timely manner to their environment and adapt to metabolic demands during macrophage polarization. Here we summarize the current understanding of the crosstalk between carbon metabolism and epigenetic modifications in macrophages under physiological conditions and in the tumor microenvironment (TME) and provide targets and further directions for macrophage-associated diseases.

Echinacea purpurea-derived homogeneous polysaccharide exerts anti-tumor efficacy via facilitating M1 macrophage polarization.

Echinacea purpurea modulates tumor progression, but the underlying mechanism is poorly defined. We isolated and purified a novel homogeneous polysaccharide from E. purpurea (EPPA), which was shown to be an arabinogalactan with a mean molecular mass (Mr) of 3.8 × 104 Da and with α- (1 → 5) -L-Arabinan as the backbone and α-L-Araf-(1→, →6)-ß-D-Galp-(1→, and →4)-α-D-GalpA-(1→ as the side chains. Interestingly, oral administration of EPPA suppresses tumor progression in vivo and shapes the immune cell profile (e.g., facilitating M1 macrophages) in tumor microenvironment by single-cell RNA sequencing (scRNA-seq) analysis. More importantly, EPPA activates the inflammasome through a phagocytosis-dependent mechanism and rewires transcriptomic and metabolic profile, thereby potentiating M1 macrophage polarization. Collectively, we propose that EPPA supplementation could function as an adjuvant therapeutic strategy for tumor suppression.

GABA regulates IL-1ß production in macrophages.

Neurotransmitters have been well documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrate that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1ß production from inflammatory macrophages. Mechanistically, GABA enhances succinate-flavin adenine dinucleotide (FAD)-lysine specific demethylase1 (LSD1) signaling to regulate histone demethylation of Bcl2l11 and Dusp2, reducing formation of the NLRP3-ASC-Caspase-1 complex. The GABA-succinate axis reduces succinylation of mitochondrial proteins to promote oxidative phosphorylation (OXPHOS). We also find that GABA alleviates lipopolysaccharides (LPS)-induced sepsis as well as high-fat-diet-induced obesity in mice. Our study shows that GABA regulates pro-inflammatory macrophage responses associated with metabolic reprogramming and protein succinylation, suggesting a strategy for treating macrophage-related inflammatory diseases.

Resveratrol in Intestinal Health and Disease: Focusing on Intestinal Barrier.

The integrity of intestinal barrier determines intestinal homeostasis, which could be affected by various factors, like physical, chemical, and biological stimuli. Therefore, it is of considerable interest and importance to maintain intestinal barrier function. Fortunately, many plant polyphenols, including resveratrol, could affect the health of intestinal barrier. Resveratrol has many biological functions, such as antioxidant, anti-inflammation, anti-tumor, and anti-cardiovascular diseases. Accumulating studies have shown that resveratrol affects intestinal tight junction, microbial composition, and inflammation. In this review, we summarize the effects of resveratrol on intestinal barriers as well as the potential mechanisms (e.g., inhibiting the growth of pathogenic bacteria and fungi, regulating the expression of tight junction proteins, and increasing anti-inflammatory T cells while reducing pro-inflammatory T cells), and highlight the applications of resveratrol in ameliorating various intestinal diseases.

Effects of Lactococcus lactis on the Intestinal Functions in Weaning Piglets.

Post-weaning diarrhea of piglets is associated with gut microbiota dysbiosis and intestinal pathogen infection. Recent studies have shown that Lactococcus lactis (L.lactis) could help suppress pathogen infection. This study aimed to investigate the effects of L.lactis on various factors related to growth and immunity in weaning piglets. The results showed that L.lactis improved the growth performance, regulated the amino acid profile (for example, increasing serum tryptophan and ileal mucosal cystine) and the intestinal GABAergic system (including inhibiting ileal gene expression of SLC6A13, GABAAρ1, π, θ, and γ1, and promoting ileal GABAAα5 expression). L.lactis also modulated intestinal immunity by promoting jejunal interleukin 17, 18, 22, ileal toll-like receptor 2, 5, 6, and myeloid differentiation primary response protein 88 gene expression while inhibiting jejunal interferon-γ and ileal interleukin 22 expressions. L.lactis highly affected the intestinal microbiota by improving the beta diversity of gut microbiota and the relative abundance of Halomonas and Shewanella. In conclusion, L.lactis improved the growth performance and regulated amino acid profiles, intestinal immunity and microbiota in weaning piglets.

Ironing Out the Details: How Iron Orchestrates Macrophage Polarization.

Iron fine-tunes innate immune responses, including macrophage inflammation. In this review, we summarize the current understanding about the iron in dictating macrophage polarization. Mechanistically, iron orchestrates macrophage polarization through several aspects, including cellular signaling, cellular metabolism, and epigenetic regulation. Therefore, iron modulates the development and progression of multiple macrophage-associated diseases, such as cancer, atherosclerosis, and liver diseases. Collectively, this review highlights the crucial role of iron for macrophage polarization, and indicates the potential application of iron supplementation as an adjuvant therapy in different inflammatory disorders relative to the balance of macrophage polarization.

GABA transporter sustains IL-1ß production in macrophages.

Accumulating evidence shows that nervous system governs host immune responses; however, how γ-aminobutyric acid (GABA)ergic system shapes the function of innate immune cells is poorly defined. Here, we demonstrate that GABA transporter (GAT2) modulates the macrophage function. GAT2 deficiency lowers the production of interleukin-1ß (IL-1ß) in proinflammatory macrophages. Mechanistically, GAT2 deficiency boosts the betaine/S-adenosylmethionine (SAM)/hypoxanthine metabolic pathway to inhibit transcription factor KID3 expression through the increased DNA methylation in its promoter region. KID3 regulates oxidative phosphorylation (OXPHOS) via targeting the expression of OXPHOS-related genes and is also critical for NLRP3-ASC-caspase-1 complex formation. Likewise, GAT2 deficiency attenuates macrophage-mediated inflammatory responses in vivo, including lipopolysaccharide-induced sepsis, infection-induced pneumonia, and high-fat diet-induced obesity. Together, we propose that targeting GABAergic system (e.g., GABA transporter) could provide previously unidentified therapeutic opportunities for the macrophage-associated diseases.

Serine Supports IL-1ß Production in Macrophages Through mTOR Signaling.

Intracellular metabolic programs tightly regulate the functions of macrophages, and previous studies have shown that serine mainly shapes the macrophage function via one-carbon metabolism. However, it is unknown whether serine modulates the macrophage function independent of one-carbon metabolism. Here, we find that serine deprivation lowers interleukin (IL)-1ß production and inflammasome activation, as well as reprograms the transcriptomic and metabolic profile in M1 macrophages. Intriguingly, supplementation of formate, glycine, dNTPs, and glucose cannot rescue the production of IL-1ß from serine-deprived macrophages. Mechanistically, serine deprivation inhibits macrophage IL-1ß production through inhibition of mechanistic target of rapamycin (mTOR) signaling. Of note, the macrophages from mice feeding serine-free diet have lower IL-1ß production, and these mice also show less inflammation after LPS challenge. Collectively, our data highlight a new regulatory mechanism for serine to modulate the macrophage function.

GABA attenuates ETEC-induced intestinal epithelial cell apoptosis involving GABAAR signaling and the AMPK-autophagy pathway.

Enterotoxigenic Escherichia coli (ETEC) triggers diarrhea in humans and livestock. We have previously showed that ETEC promotes intestinal epithelial cell apoptosis and increases gamma-aminobutyric acid (GABA) concentration in the jejunum, suggesting that GABA might mediate ETEC-induced apoptosis. Here, we found that GABA alleviates ETEC-induced intestinal barrier dysfunctions, including ETEC-induced apoptosis both in vivo and in vitro. Interestingly, the alleviation of GABA on ETEC-induced apoptosis largely depends on autophagy. Mechanistically, GABA attenuates ETEC-induced apoptosis via activating GABAAR signaling and the AMPK-autophagy pathway. These findings highlight that maintaining intestinal GABA concentration could alleviate intestinal ETEC infection.

l-Serine Lowers the Inflammatory Responses during Pasteurella multocida Infection.

Pasteurella multocida causes a variety of infectious diseases in various species of mammals and birds, resulting in enormous economic loss to the modern livestock and poultry industry. However, the mechanism of host-pathogen interaction is unclear. Here, we found that l-serine levels were significantly decreased in murine lungs infected with P. multocida Exogenous l-serine supplementation significantly increased the survival rate of mice and decreased the colonization of P. multocida in the lungs of mice. Notably, l-serine decreased the macrophage- and neutrophil-mediated inflammatory responses in mice during P. multocida infection.

Glutamine Metabolism in Macrophages: A Novel Target for Obesity/Type 2 Diabetes.

Obesity is a nutritional disorder resulting from a chronic imbalance between energy intake and expenditure. This disease is characterized by inflammation in multiple cell types, including macrophages. M1 macrophage responses are correlated with the progression of obesity or diabetes; therefore, strategies that induce repolarization of macrophages from an M1 to an M2 phenotype may be promising for the prevention of obesity- or diabetes-associated pathology. Glutamine (the most abundant amino acid in the plasma of humans and many other mammals including rats) is effective in inducing polarization of M2 macrophages through the glutamine-UDP-N-acetylglucosamine pathway and α-ketoglutarate produced via glutaminolysis, whereas succinate synthesized via glutamine-dependent anerplerosis or the γ-aminobutyric acid shunt promotes polarization of M1 macrophages. Interestingly, patients with obesity or diabetes show altered glutamine metabolism, including decreases in glutamine and α-ketoglutarate concentrations in serum but increases in succinate concentrations. Thus, manipulation of macrophage polarization through glutamine metabolism may provide a potential target for prevention of obesity- or diabetes-associated pathology.

Melatonin in macrophage biology: Current understanding and future perspectives.

Melatonin is a ubiquitous hormone found in various organisms and highly affects the function of immune cells. In this review, we summarize the current understanding of the significance of melatonin in macrophage biology and the beneficial effects of melatonin in macrophage-associated diseases. Enzymes associated with synthesis of melatonin, as well as membrane receptors for melatonin, are found in macrophages. Indeed, melatonin influences the phenotype polarization of macrophages. Mechanistically, the roles of melatonin in macrophages are related to several cellular signaling pathways, such as NF-κB, STATs, and NLRP3/caspase-1. Notably, miRNAs (eg, miR-155/-34a/-23a), cellular metabolic pathways (eg, α-KG, HIF-1α, and ROS), and mitochondrial dynamics and mitophagy are also involved. Thus, melatonin modulates the development and progression of various macrophage-associated diseases, such as cancer and rheumatoid arthritis. This review provides a better understanding about the importance of melatonin in macrophage biology and macrophage-associated diseases.

Betaine Inhibits Interleukin-1ß Production and Release: Potential Mechanisms.

Betaine is a critical nutrient for mammal health, and has been found to alleviate inflammation by lowering interleukin (IL)-1ß secretion; however, the underlying mechanisms by which betaine inhibits IL-1ß secretion remain to be uncovered. In this review, we summarize the current understanding about the mechanisms of betaine in IL-1ß production and release. For IL-1ß production, betaine affects canonical and non-canonical inflammasome-mediated processing of IL-1ß through signaling pathways, such as NF-κB, NLRP3 and caspase-8/11. For IL-1ß release, betaine inhibits IL-1ß release through blocking the exocytosis of IL-1ß-containing secretory lysosomes, reducing the shedding of IL-1ß-containing plasma membrane microvesicles, suppressing the exocytosis of IL-1ß-containing exosomes, and attenuating the passive efflux of IL-1ß across hyperpermeable plasma membrane during pyroptotic cell death, which are associated with ERK1/2/PLA2 and caspase-8/A-SMase signaling pathways. Collectively, this review highlights the anti-inflammatory property of betaine by inhibiting the production and release of IL-1ß, and indicates the potential application of betaine supplementation as an adjuvant therapy in various inflammatory diseases associating with IL-1ß secretion.

Glutamine supplementation improves intestinal cell proliferation and stem cell differentiation in weanling mice.

BACKGROUND: Intestinal stem cells can be differentiated into absorptive enterocytes and secretory cells, including Paneth cells, goblet cells, and enteroendocrine cells. Glutamine is a primary metabolic fuel of small intestinal enterocytes and is essential for the viability and growth of intestinal cells. OBJECTIVE: Whether glutamine supplementation affects the differentiation of intestinal stem cells is unknown. DESIGN: Three-week-old ICR (Institute of Cancer Research) male mice were divided randomly into two groups: 1) mice receiving a basal diet and normal drinking water and 2) mice receiving a basal diet and drinking water supplemented with glutamine. After 2 weeks, the mice were sacrificed to collect the ileum for analysis. RESULTS: The study found that glutamine supplementation in weanling mice decreases the crypt depth in the ileum, leading to higher ratio of villus to crypt in the ileum, but promotes cell proliferation of intestinal cells and mRNA expression of Lgr5 (leucine-rich repeat-containing g-protein coupled receptor5) in the ileum. Glutamine has no effect on the number of Paneth cells and goblet cells, and the expression of markers for absorptive enterocytes, Paneth cells, goblet cells, and enteroendocrine cells. CONCLUSION: These findings reveal the beneficial effects of dietary glutamine supplementation to improve intestinal morphology in weanling mammals.

Transcriptomic analysis on responses of the liver and kidney of finishing pigs fed cadmium contaminated rice.

BACKGROUND: Cadmium (Cd) is a common harmful substance that has many deleterious effects on the liver and kidney. Most reports about Cd toxic studies focused on its inorganic status, whereas the toxicity of Cd in organic materials is less studied. Here, we performed RNA-seq to explore the influences of Cd contaminated rice on function of the liver and kidney of finishing pigs. RESULTS: The concentration of Cd in liver and kidney of pigs fed Cd contaminated rice increased by 4.00 and 2.94 times, respectively, compared to those in the control group. With transcriptomic analysis, approximately 4-6 × 107 clean reads were acquired. Five differently expressed genes (DEGs) were identified in the liver, and 12 DEGs in the kidney. SPHK2 was commonly down-regulated. No significantly enriched gene ontology (GO) terms were identified. By Kyoto encyclopaedia of genes and genomes (KEGG) enrichments, four pathways were identified in hepatic tissue, and five pathways in nephritic tissue. Intriguingly, two pathways (sphingolipid metabolism and VEGF signalling pathway) were altered both in the liver and kidney. CONCLUSION: Cd contaminated rice may cause liver and kidney damage and inflammation, or even lead to more severe harm to these tissues. © 2017 Society of Chemical Industry.