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Nature Communications Aug 2022Metabolite alteration has been associated with the pathogenesis of inflammatory bowel disease (IBD), including colitis. Mannose, a natural bioactive monosaccharide that...
Metabolite alteration has been associated with the pathogenesis of inflammatory bowel disease (IBD), including colitis. Mannose, a natural bioactive monosaccharide that is involved in metabolism and synthesis of glycoproteins, exhibits anti-inflammatory and anti-oxidative activities. We show here that the circulating level of mannose is increased in patients with IBD and mice with experimental colitis. Mannose treatment attenuates intestinal barrier damage in two mouse colitis models, dextran sodium sulfate (DSS)-induced colitis and spontaneous colitis in IL-10-deficient mice. We demonstrate that mannose treatment enhanced lysosomal integrity and limited the release of cathepsin B, preventing mitochondrial dysfunction and myosin light chain kinase (MLCK)-induced tight junction disruption in the context of intestinal epithelial damage. Mannose exerts a synergistic therapeutic effect with mesalamine on mouse colitis. Cumulatively, the results indicate that mannose supplementation may be an optional approach to the treatment of colitis and other diseases associated with intestinal barrier dysfunction.
Topics: Animals; Caco-2 Cells; Colitis; Dextran Sulfate; Disease Models, Animal; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Mannose; Mice; Mice, Inbred C57BL; Tight Junctions
PubMed: 35974017
DOI: 10.1038/s41467-022-32505-8 -
Nature Nov 2018It is now well established that tumours undergo changes in cellular metabolism. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced...
It is now well established that tumours undergo changes in cellular metabolism. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.
Topics: Administration, Oral; Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Body Weight; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Synergism; Female; Glucose; Glycolysis; Humans; Mannose; Mannose-6-Phosphate Isomerase; Mannosephosphates; Mice; Mice, Inbred C57BL; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; RNA Interference; bcl-X Protein
PubMed: 30464341
DOI: 10.1038/s41586-018-0729-3 -
Nutrition Journal Mar 2022Urinary tract infections (UTIs) are one of the most prevalent bacterial diseases worldwide. Despite the efficacy of antibiotics targeted against UTI, the recurrence... (Review)
Review
Urinary tract infections (UTIs) are one of the most prevalent bacterial diseases worldwide. Despite the efficacy of antibiotics targeted against UTI, the recurrence rates remain significant among the patients. Furthermore, the development of antibiotic resistance is a major concern and creates a demand for alternative treatment options. D-mannose, a monosaccharide naturally found in fruits, is commonly marketed as a dietary supplement for reducing the risk for UTIs. Research suggests that supplemented D-mannose could be a promising alternative or complementary remedy especially as a prophylaxis for recurrent UTIs. When excreted in urine, D-mannose potentially inhibits Escherichia coli, the main causative organism of UTIs, from attaching to urothelium and causing infection. In this review, we provide an overview of UTIs, E. coli pathogenesis and D-mannose and outline the existing clinical evidence of D-mannose in reducing the risk of UTI and its recurrence. Furthermore, we discuss the potential effect mechanisms of D-mannose against uropathogenic E.coli.
Topics: Anti-Bacterial Agents; Escherichia coli Infections; Humans; Mannose; Urinary Tract Infections; Uropathogenic Escherichia coli
PubMed: 35313893
DOI: 10.1186/s12937-022-00769-x -
Cell Research Dec 2023Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear....
Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDME or GSDME knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.
Topics: Humans; Animals; Mice; Pyroptosis; Mannose; AMP-Activated Protein Kinases; Gasdermins
PubMed: 37460805
DOI: 10.1038/s41422-023-00848-6 -
Cell Proliferation Nov 2021Chondrocyte ferroptosis contributes to osteoarthritis (OA) progression, and D-mannose shows therapeutic value in many inflammatory conditions. Here, we investigated...
OBJECTIVES
Chondrocyte ferroptosis contributes to osteoarthritis (OA) progression, and D-mannose shows therapeutic value in many inflammatory conditions. Here, we investigated whether D-mannose interferes in chondrocyte ferroptotic cell death during osteoarthritic cartilage degeneration.
MATERIALS AND METHODS
In vivo anterior cruciate ligament transection (ACLT)-induced OA mouse model and an in vitro study of chondrocytes in an OA microenvironment induced by interleukin-1β (IL-1β) exposure were employed. Combined with Epas1 gene gain- and loss-of-function, histology, immunofluorescence, quantitative RT-PCR, Western blot, cell viability and flow cytometry experiments were performed to evaluate the chondroprotective effects of D-mannose in OA progression and the role of hypoxia-inducible factor 2 alpha (HIF-2 α) in D-mannose-induced ferroptosis resistance of chondrocytes.
RESULTS
D-mannose exerted a chondroprotective effect by attenuating the sensitivity of chondrocytes to ferroptosis and alleviated OA progression. HIF-2α was identified as a central mediator in D-mannose-induced ferroptosis resistance of chondrocytes. Furthermore, overexpression of HIF-2α in chondrocytes by Ad-Epas1 intra-articular injection abolished the chondroprotective effect of D-mannose during OA progression and eliminated the role of D-mannose as a ferroptosis suppressor.
CONCLUSIONS
D-mannose alleviates osteoarthritis progression by suppressing HIF-2α-mediated chondrocyte sensitivity to ferroptosis, indicating D-mannose to be a potential therapeutic strategy for ferroptosis-related diseases.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cartilage, Articular; Chondrocytes; Ferroptosis; Mannose; Mice, Inbred C57BL; Osteoarthritis; Mice
PubMed: 34561933
DOI: 10.1111/cpr.13134 -
Cellular & Molecular Immunology Feb 2023Mannose is a naturally occurring sugar widely consumed in the daily diet; however, mechanistic insights into how mannose metabolism affects intestinal inflammation...
Mannose is a naturally occurring sugar widely consumed in the daily diet; however, mechanistic insights into how mannose metabolism affects intestinal inflammation remain lacking. Herein, we reported that mannose supplementation ameliorated colitis development and promoted colitis recovery. Macrophage-secreted inflammatory cytokines, particularly TNF-α, induced pathological endoplasmic reticulum stress (ERS) in intestinal epithelial cells (IECs), which was prevented by mannose via normalization of protein N-glycosylation. By preserving epithelial integrity, mannose reduced the inflammatory activation of colonic macrophages. On the other hand, mannose directly suppressed macrophage TNF-α production translationally by reducing the glyceraldehyde 3-phosphate level, thus promoting GAPDH binding to TNF-α mRNA. Additionally, we found dysregulated mannose metabolism in the colonic mucosa of patients with inflammatory bowel disease. Finally, we revealed that activating PMM2 activity with epalrestat, a clinically approved drug for the treatment of diabetic neuropathy, elicited further sensitization to the therapeutic effect of mannose. Therefore, mannose metabolism prevents TNF-α-mediated pathogenic crosstalk between IECs and intestinal macrophages, thereby normalizing aberrant immunometabolism in the gut.
Topics: Humans; Animals; Mice; Tumor Necrosis Factor-alpha; Mannose; Colitis; Inflammatory Bowel Diseases; Intestinal Mucosa; Homeostasis; Mice, Inbred C57BL
PubMed: 36471112
DOI: 10.1038/s41423-022-00955-1 -
Current Opinion in Structural Biology Aug 2022A unique glycan-binding protein expressed in macrophages and some types of other immune cells is the mannose receptor (MR, CD206). It is an endocytic, transmembrane... (Review)
Review
A unique glycan-binding protein expressed in macrophages and some types of other immune cells is the mannose receptor (MR, CD206). It is an endocytic, transmembrane protein with multiple glycan-binding domains and different specificities in binding glycans. The mannose receptor is important as it has major roles in diverse biological processes, including regulation of circulating levels of reproductive hormones, homeostasis, innate immunity, and infections. These different functions involve the recognition of a wide range of glycans, and their nature is currently under intense study. But the mannose receptor is just one of many glycan-binding proteins expressed in macrophages, leading to an interest in the potential relationship between the macrophage glycome and how it may regulate cognate glycan-binding protein activities. This review focuses primarily on the mannose receptor and its carbohydrate ligands, as well as macrophages and their glycomes.
Topics: Lectins, C-Type; Ligands; Macrophages; Mannose; Mannose Receptor; Mannose-Binding Lectins; Polysaccharides; Receptors, Cell Surface
PubMed: 35617912
DOI: 10.1016/j.sbi.2022.102394 -
Biomedicine & Pharmacotherapy =... Sep 2020Mannose is a monosaccharide widely distributed in body fluids and tissues, especially in the nerve, skin, testicles, retina, liver and intestines. It is used to... (Review)
Review
Mannose is a monosaccharide widely distributed in body fluids and tissues, especially in the nerve, skin, testicles, retina, liver and intestines. It is used to synthesize glycoproteins and participate in immune regulation. In recent years, mannose has been applied more and more widely in the biomedical context as people have a deeper understanding of its biological effects. This review introduces the use of mannose in treating various diseases (including cancer, urinary tract infections, type 1 diabetes, and diabetic wounds), preventing pancreatic fistula, and improving magnetic resonance imaging for acute pancreatitis. We also demonstrate that mannose has the potential for clinical applications.
Topics: Animals; Anti-Obesity Agents; Antineoplastic Agents; Contrast Media; Drug Carriers; Humans; Hypoglycemic Agents; Magnetic Resonance Imaging; Mannose; Pancreatic Fistula; Pancreatitis; Wound Healing
PubMed: 32563989
DOI: 10.1016/j.biopha.2020.110420 -
Nature Communications Mar 2024Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered...
Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.
Topics: Animals; Mice; Mannose-6-Phosphate Isomerase; Glycosylation; Mannose; Glucose; Antiviral Agents
PubMed: 38459021
DOI: 10.1038/s41467-024-46415-4 -
Biochemical and Biophysical Research... Oct 2014Mannose is a simple sugar with a complex life. It is a welcome therapy for genetic and acquired human diseases, but it kills honeybees and blinds baby mice. It could... (Review)
Review
Mannose is a simple sugar with a complex life. It is a welcome therapy for genetic and acquired human diseases, but it kills honeybees and blinds baby mice. It could cause diabetic complications. Mannose chemistry, metabolism, and metabolomics in cells, tissues and mammals can help explain these multiple systemic effects. Mannose has good, bad or ugly outcomes depending on its steady state levels and metabolic flux. This review describes the role of mannose at cellular level and its impact on organisms.
Topics: Animals; Congenital Disorders of Glycosylation; Dietary Carbohydrates; Disease Models, Animal; Female; Gene Knockdown Techniques; Humans; Mannose; Mannose-6-Phosphate Isomerase; Metabolic Flux Analysis; Metabolic Networks and Pathways; Metabolomics; Mice; Phosphotransferases (Phosphomutases); Polysaccharides; Pregnancy; Zebrafish
PubMed: 24931670
DOI: 10.1016/j.bbrc.2014.06.021