Notch stimulates growth by direct regulation of genes involved in the control of glycolysis and the tricarboxylic acid cycle

Glycolytic shift is a characteristic feature of rapidly proliferating cells, such as cells during development and during immune response or cancer cells, as well as of stem cells. It results in increased glycolysis uncoupled from mitochondrial respiration, also known as the Warburg effect. Notch signalling is active in contexts where cells undergo glycolytic shift. We decided to test whether metabolic genes are direct transcriptional targets of Notch signalling and whether upregulation of metabolic genes can help Notch to induce tissue growth under physiological conditions and in conditions of Notch-induced hyperplasia. We show that genes mediating cellular metabolic changes towards the Warburg effect are direct transcriptional targets of Notch signalling. They include genes encoding proteins involved in glucose uptake, glycolysis, lactate to pyruvate conversion and repression of the tricarboxylic acid cycle. The direct transcriptional upregulation of metabolic genes is PI3K/Akt independent and occurs not only in cells with overactivated Notch but also in cells with endogenous levels of Notch signalling and in vivo . Even a short pulse of Notch activity is able to elicit long-lasting metabolic changes resembling the Warburg effect. Loss of Notch signalling in Drosophila wing discs as well as in human microvascular cells leads to downregulation of glycolytic genes. Notch-driven tissue overgrowth can be rescued by downregulation of genes for glucose metabolism. Notch activity is able to support growth of wing during nutrient-deprivation conditions, independent of the growth of the rest of the body. Notch is active in situations that involve metabolic reprogramming, and the direct regulation of metabolic genes may be a common mechanism that helps Notch to exert its effects in target tissues.

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Effects of sevoflurane anesthesia and abdominal surgery on the systemic metabolome: a prospective observational study

BMC Anesthesiology ◽

10.1186/s12871-021-01301-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yiyong Wei ◽

Donghang Zhang ◽

Jin Liu ◽

Mengchan Ou ◽

Peng Liang ◽

...

Keyword(s):

Abdominal Surgery ◽

General Anesthesia ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Metabolic Changes ◽

Sevoflurane Anesthesia ◽

Glutamate Metabolism ◽

Acid Cycle ◽

Link Type ◽

The Mean

Abstract Background Metabolic status can be impacted by general anesthesia and surgery. However, the exact effects of general anesthesia and surgery on systemic metabolome remain unclear, which might contribute to postoperative outcomes. Methods Five hundred patients who underwent abdominal surgery were included. General anesthesia was mainly maintained with sevoflurane. The end-tidal sevoflurane concentration (ETsevo) was adjusted to maintain BIS (Bispectral index) value between 40 and 60. The mean ETsevo from 20 min after endotracheal intubation to 2 h after the beginning of surgery was calculated for each patient. The patients were further divided into low ETsevo group (mean − SD) and high ETsevo group (mean + SD) to investigate the possible metabolic changes relevant to the amount of sevoflurane exposure. Results The mean ETsevo of the 500 patients was 1.60% ± 0.34%. Patients with low ETsevo (n = 55) and high ETsevo (n = 59) were selected for metabolomic analysis (1.06% ± 0.13% vs. 2.17% ± 0.16%, P < 0.001). Sevoflurane and abdominal surgery disturbed the tricarboxylic acid cycle as identified by increased citrate and cis-aconitate levels and impacted glycometabolism as identified by increased sucrose and D-glucose levels in these 114 patients. Glutamate metabolism was also impacted by sevoflurane and abdominal surgery in all the patients. In the patients with high ETsevo, levels of L-glutamine, pyroglutamic acid, sphinganine and L-selenocysteine after sevoflurane anesthesia and abdominal surgery were significantly higher than those of the patients with low ETsevo, suggesting that these metabolic changes might be relevant to the amount of sevoflurane exposure. Conclusions Sevoflurane anesthesia and abdominal surgery can impact principal metabolic pathways in clinical patients including tricarboxylic acid cycle, glycometabolism and glutamate metabolism. This study may provide a resource data for future studies about metabolism relevant to general anaesthesia and surgeries. Trial registration www.chictr.org.cn. identifier: ChiCTR1800014327.

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Inhibition of cancer metabolism: a patent landscape

Pharmaceutical Patent Analyst ◽

10.4155/ppa-2019-0012 ◽

2019 ◽

Vol 8 (4) ◽

pp. 117-138 ◽

Cited By ~ 3

Author(s):

William P Katt ◽

Richard A Cerione

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Small Molecule ◽

Cancer Metabolism ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Metabolic Changes ◽

Pharmacological Intervention ◽

Acid Cycle ◽

Patent Landscape

Cancer metabolism is currently a hot topic. Since it was first realized that cancer cells rely upon an altered metabolic program to sustain their rapid proliferation, the enzymes that support those metabolic changes have appeared to be good targets for pharmacological intervention. Here, we discuss efforts pertaining to targets in cancer metabolism, focusing upon the tricarboxylic acid cycle and the mechanisms which feed nutrients into it. We describe a broad landscape of small-molecule inhibitors, targeting a dozen different proteins, each implicated in cancer progression. We hope that this will serve as a reference both to the areas being most highly examined today and, relatedly, the areas that are still ripe for novel intervention.

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1H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin

AJP Renal Physiology ◽

10.1152/ajprenal.00551.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. F947-F956 ◽

Cited By ~ 39

Author(s):

Liangcai Zhao ◽

Hongchang Gao ◽

Fulin Lian ◽

Xia Liu ◽

Yongxiang Zhao ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Metabolic Profiling ◽

Ketone Body ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Metabolic Changes ◽

Control Group ◽

Acid Cycle ◽

Pattern Recognition Analysis ◽

Pathogenic Process

Elucidation of the metabolic profiling in diabetic nephropathy (DN) rats is of great assistance for understanding the pathogenesis of DN. In this study, 1H-nuclear magnetic resonance (NMR)-based metabonomics combined with HPLC measurements was used to quantitatively analyze the metabolic changes in urine and kidney extracts from diabetic 2-wk and 8-wk rats induced by streptozotocin (STZ). Pattern recognition analysis of either urine or kidney extracts indicated that the two diabetic groups were separated obviously from the control group, suggesting that the metabolic profiles of the diabetic groups were markedly different from the control. The diabetic 8-wk rats showed lower levels of creatine, dimethylamine, and higher levels of ascorbate, succinate, lactate, citrate, allantoin, 2-ketoglutarate, and 3-hydrobutyrate (3-HB) in the urine samples. Moreover, the diabetic 8-wk rats displayed lower levels of succinate, creatine, myo-inositol, alanine, lactate, and ATP, and higher levels of 3-HB and glucose in the kidney extracts. The observed metabolic changes imply the enhanced pathways of either lipid or ketone body synthesis and decreased pathways of either tricarboxylic acid cycle or glycolysis in DN rats compared with the control. Our results suggest that the energy metabolic changes are associated with the pathogenic process of DN.

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