| 1. |
- Xie, Sisi, et al.
(författare)
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Dietary ketone body-escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia
- 2022
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 14:673
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Tidskriftsartikel (refereegranskat)abstract
- Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating beta-hydroxybutyrate (beta-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-beta-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked beta-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a non-toxic, low-cost dietary intervention for combating CIT.
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| 2. |
- Luo, Biying, et al.
(författare)
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Bioactive phytochemicals and their potential roles in modulating gut microbiota
- 2023
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Ingår i: JOURNAL OF AGRICULTURE AND FOOD RESEARCH. - : Elsevier. - 2666-1543. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Dietary phytochemicals, including polyphenols, sulfur-containing compounds, terpenoids, polysaccharides, saponins, pigments, and phytohaemagglutinins, have antioxidant, anti-inflammatory, antiviral, and cancerpreventive or therapeutic properties. Upon entering the body, these compounds pass through the stomach, liver, small intestine, and colon in that order. Bacteria play an important role in the absorption and processing of dietary phytochemicals in the small intestine and in the large intestine. However, the specific processes by which dietary phytochemicals are absorbed and metabolized in the host colon have not been elucidated. This paper describes the metabolism of phytochemicals (including polyphenols, terpenoids, and plant organosulfides) in the colon and describes the roles played by these dietary phytochemicals in the colon, with emphasis on their effects on the gut microbiota. Upon entry into the host, phytochemicals are absorbed and metabolized mainly in the colon, and the differences in their absorption and metabolism are largely due to differences in the colonic microbiota. Moreover, phytochemicals can be absorbed in the intestine by acting on them through enzymes produced by intestinal cells and stem cells, or by interacting with the intestinal flora, thus ameliorating the associated diseases.
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| 3. |
- Wu, Biying, et al.
(författare)
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Megakaryocytes Mediate Hyperglycemia-Induced Tumor Metastasis
- 2021
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 81:21, s. 5506-5522
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Tidskriftsartikel (refereegranskat)abstract
- High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKC alpha pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a plateletadoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKC alpha pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. Significance: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75.
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