scholarly journals Glutamate dehydrogenase 1 mediated glutaminolysis sustains HCC cells proliferation and survival under glucose deprivation

2020 ◽  
Author(s):  
Yujiao Zhou ◽  
Yujiao Zhou ◽  
Haibo Yu ◽  
Haibo Yu ◽  
Shengtao Cheng ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
High Glucose ◽  
Glucose Deprivation ◽  
Glutamine Metabolism ◽  
Metabolic Flexibility ◽  
Glucose Medium ◽  
Glucose Levels ◽  
Low Glucose ◽  
Glucose Condition ◽  
Hcc Cells

Abstract Background: It is generally believed that tumor cells could sustain its proliferation and survival under different nutrient status according to a so-called metabolic flexibility. How the metabolic flexibility of glutamine metabolism of HCC cells behaves under different glucose conditions has not yet been fully elucidated. In this study, we investigated how the glutamine metabolism modulate the proliferation and survival of HCC cells in response to different glucose conditions and explored the underlying molecular mechanism.Methods: Two cell lines SK-Hep-1 and PLC/PRF/5 were used to evaluate the glutamine addiction of HCC cells. Then, the cells were cultivated in high glucose medium (25mM glucose) and low glucose medium (1.0 mM glucose), respectively, to investigate whether glutaminolysis changed in response to different glucose levels. And, the underlying mechanism of glutamate dehydrogenase 1 (GDH1) sustaining HCC cells survival under glucose deprivation was explored. Additionally, the underlying correlation of GDH1 and glutamate–oxaloacetate transaminase 1 (GOT1) in glucose -poor HCC tissue was investigated.Results: HCC cells were addicted to glutamine. The glutaminolysis of HCC cells was different in response to different glucose conditions. That is, glutamate transaminases GOT1 involved glutamine metabolism played a dominant role in regulating cell growth when glucose was sufficient, while deaminase GDH1 mediated glutaminolysis became dominant when glucose was limited. Mechanically, low-glucose treated HCC cells could induce an elevated expression of GDH1 to supplement the TCA cycles in respond to glucose deprivation. Additionally, we further uncovered an underlying negative association between GDH1 and GOT1 in HCC tissues with decreased glucose levelsConclusions: GDH1 mediated pathway played a leading role in maintaining cell proliferation and survival under low glucose condition. By contrast, GOT1 mediated pathway was activated under high glucose condition. Mechanically, highly expressed GDH1 could drive the TCA cycle in response to glucose deprivation. Besides, there was a potential negative correlation between GDH1 and GOT1 in glucose-poor HCC tissues.

scholarly journals High glucose levels reduce fatty acid oxidation and increase triglyceride accumulation in human placenta

2013 ◽  
Vol 305 (2) ◽  
pp. E205-E212 ◽  
Author(s):  
Francisco Visiedo ◽  
Fernando Bugatto ◽  
Viviana Sánchez ◽  
Irene Cózar-Castellano ◽  
Jose L. Bartha ◽  
...  
Keyword(s):  
Fatty Acid ◽  
High Glucose ◽  
De Novo ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Glucose Levels ◽  
Triglyceride Accumulation ◽  
Triglyceride Content ◽  
Low Glucose ◽  
Cpt I

Placentas of women with gestational diabetes mellitus (GDM) exhibit an altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid metabolism remains obscure. We hypothesized that high glucose levels reduce mitochondrial fatty acid oxidation (FAO) and increase triglyceride accumulation in human placenta. To test this hypothesis, we measured FAO, fatty acid esterification, de novo fatty acid synthesis, triglyceride levels, and carnitine palmitoyltransferase activities (CPT) in placental explants of women with GDM or no pregnancy complication. In women with GDM, FAO was reduced by ∼30% without change in mitochondrial content, and triglyceride content was threefold higher than in the control group. Likewise, in placental explants of women with no complications, high glucose levels reduced FAO by ∼20%, and esterification increased linearly with increasing fatty acid concentrations. However, de novo fatty acid synthesis remained unchanged between high and low glucose levels. In addition, high glucose levels increased triglyceride content approximately twofold compared with low glucose levels. Furthermore, etomoxir-mediated inhibition of FAO enhanced esterification capacity by ∼40% and elevated triglyceride content 1.5-fold in placental explants of women, with no complications. Finally, high glucose levels reduced CPT I activity by ∼70% and phosphorylation levels of acetyl-CoA carboxylase by ∼25% in placental explants of women, with no complications. We reveal an unrecognized regulatory mechanism on placental fatty acid metabolism by which high glucose levels reduce mitochondrial FAO through inhibition of CPT I, shifting flux of fatty acids away from oxidation toward the esterification pathway, leading to accumulation of placental triglycerides.

scholarly journals Consumption of Biscuits with a Beverage of Mulberry or Barley Leaves in the Afternoon Prevents Dinner-Induced High, but Not Low, Increases in Blood Glucose among Young Adults

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1580 ◽  
Author(s):  
Mai Kuwahara ◽  
Hyeon-Ki Kim ◽  
Mamiho Ozaki ◽  
Takuya Nanba ◽  
Hanako Chijiki ◽  
...  
Keyword(s):  
Young Adults ◽  
High Glucose ◽  
Standardized Test ◽  
Postprandial Glucose ◽  
Glucose Levels ◽  
Body Weights ◽  
Barley Leaves ◽  
Low Glucose ◽  
Double Blinded ◽  
The Impact

We examined the impact of consuming biscuits with a beverage of powdered mulberry or barley leaves in the afternoon on postprandial glucose levels at dinnertime among young adults. A total of 18 young adults participated in a partially double-blinded, randomized crossover trial over 2 weeks, consuming either: (1) no biscuits; (2) a biscuit; (3) a biscuit with a beverage of powdered mulberry leaves; or (4) a biscuit with a beverage of powdered barley leaves, as an afternoon snack followed by a standardized test dinner. Glucose levels were recorded after each meal. Results showed intake of biscuits with a beverage of mulberry and barley leaves significantly reduced postprandial rises in glucose after their immediate consumption and dinner, though there was no direct relationship between the glucose levels at the two meals. Compared to those with low glucose levels, participants with high glucose levels at dinner showed a stronger second meal effect, that was attributed to the mulberry or barley leaves, and were also more likely to have lean body weights and prefer evenings. Our findings indicate that eating snacks alongside mulberry or barley leaves is an effective way to suppress postprandial glucose levels in young adults with high glucose levels who prefer evenings.

scholarly journals Glucose-deprivation increases thyroid cancer cells sensitivity to metformin

2015 ◽  
Vol 22 (6) ◽  
pp. 919-932 ◽  
Author(s):  
Athanasios Bikas ◽  
Kirk Jensen ◽  
Aneeta Patel ◽  
John Costello ◽  
Dennis McDaniel ◽  
...  
Keyword(s):  
Cell Death ◽  
Thyroid Cancer ◽  
Cancer Cell ◽  
High Glucose ◽  
Glucose Medium ◽  
Thyroid Cancer Cell ◽  
High Glucose Medium ◽  
Anti Cancer ◽  
Low Glucose ◽  
Thyroid Cancer Cells

Metformin inhibits thyroid cancer cell growth. We sought to determine if variable glucose concentrations in medium alter the anti-cancer efficacy of metformin. Thyroid cancer cells (FTC133 and BCPAP) were cultured in high-glucose (20 mM) and low-glucose (5 mM) medium before treatment with metformin. Cell viability and apoptosis assays were performed. Expression of glycolytic genes was examined by real-time PCR, western blot, and immunostaining. Metformin inhibited cellular proliferation in high-glucose medium and induced cell death in low-glucose medium. In low-, but not in high-glucose medium, metformin induced endoplasmic reticulum stress, autophagy, and oncosis. At micromolar concentrations, metformin induced phosphorylation of AMP-activated protein kinase and blocked p-pS6 in low-glucose medium. Metformin increased the rate of glucose consumption from the medium and prompted medium acidification. Medium supplementation with glucose reversed metformin-inducible morphological changes. Treatment with an inhibitor of glycolysis (2-deoxy-d-glucose (2-DG)) increased thyroid cancer cell sensitivity to metformin. The combination of 2-DG with metformin led to cell death. Thyroid cancer cell lines were characterized by over-expression of glycolytic genes, and metformin decreased the protein level of pyruvate kinase muscle 2 (PKM2). PKM2 expression was detected in recurrent thyroid cancer tissue samples. In conclusion, we have demonstrated that the glucose concentration in the cellular milieu is a factor modulating metformin's anti-cancer activity. These data suggest that the combination of metformin with inhibitors of glycolysis could represent a new strategy for the treatment of thyroid cancer.

High ambient glucose is effect neutral on cell death and proliferation in human proximal tubular epithelial cells

2005 ◽  
Vol 289 (2) ◽  
pp. F401-F409 ◽  
Author(s):  
Christudas Morais ◽  
Justin Westhuyzen ◽  
Betty Pat ◽  
Glenda Gobe ◽  
Helen Healy
Keyword(s):  
Epithelial Cells ◽  
High Glucose ◽  
Culture Media ◽  
Primary Cultures ◽  
Cellular Growth ◽  
Glucose Medium ◽  
Tubular Epithelial Cells ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Low Glucose

In vitro models of diabetic nephropathy that assess the role of hyperglycemia on proximal tubular cell turnover commonly compare cells in a high-glucose medium (25 or 30 mM) with a low-glucose medium (5 to 6.1 mM). Any cellular growth changes observed are usually attributed to the effect of high glucose. We hypothesize that in such experiments, glucose concentrations in the low-glucose medium may decline during the course of the experiments to levels that inhibit cell growth leading to the comparative conclusion that high glucose induces hyperplasia and/or hypertrophy. In this study, primary cultures of human proximal tubular epithelial cells (PTEC) and immortalized HK-2 cells were exposed to low (5 mM) or high (17, 30, or 47 mM) glucose for up to 6 days (PTEC) and 48 h (HK-2). When culture media were not replenished, low glucose induced a significant increase in necrosis and release of lactate dehydrogenase and a decrease in proliferation, metabolic activity, and protein content without any changes in apoptosis. High-glucose media failed to induce any of these changes. Glucose was undetectable in the low-glucose culture medium after 72 h. No significant differences were observed between any of the treatment groups when culture media were replenished daily. We conclude that regular replenishment of culture media is necessary to prevent the emergence of artifactual and misleading differences between high- and low-glucose groups. The current knowledge of the pathophysiology of high glucose based on cell culture systems may need to be reevaluated.

Hyperglycemia exacerbates cadmium-induced glomerular nephrosis

2021 ◽  
pp. 074823372110378
Author(s):  
Mengyang Li ◽  
Xiuxiu Liu ◽  
Zengli Zhang
Keyword(s):  
High Glucose ◽  
Saline Control ◽  
In Vivo Models ◽  
Nitrogen Levels ◽  
Glucose Levels ◽  
Elevated Glucose ◽  
Low Glucose ◽  
Cd Exposure

Current research suggests that cadmium (Cd) exposure may be associated with the progression of diabetic nephropathy; however, the details of this relationship are insufficiently understood. The present study investigated the effects of elevated glucose on Cd-induced toxicity to glomerular cells using in vitro and in vivo models, and it demonstrated that Cd exposure and the hyperglycemia of diabetes acting together increased the risk of developing glomerular nephrosis . In vitro, human podocytes were exposed to a DMEM low-glucose media without (control), or with Cd (as CdCl2), or a high-glucose media plus Cd. The CCK-8, ROS, apoptosis, and mitochondrial transmembrane potential (ΔΨm) assays showed that human podocytes exposed to Cd in a high-glucose media had greater degrees of injury compared with cells treated with Cd at low (euglycemic)-glucose levels. In vivo, diabetic hyperglycemia was induced by streptozotocin in 8-week-old male C57BL/6 mice to which either CdCl2 or saline (control) was intraperitoneally injected twice weekly for 24 weeks. Compared with euglycemic saline-treated controls, the diabetic mice exposed to Cd demonstrated decreased body weight and increased blood urea nitrogen levels along with histopathological renal architecture changes including collagen fiber accumulation. The results of this study supported the hypothesis that hyperglycemia plus Cd exposure increases the risk of damage to glomerular podocytes compared with Cd exposure in euglycemia.

scholarly journals In Vitro Increase in Intracellular Calcium Concentrations Induced by Low or High Extracellular Glucose Levels in Ependymocytes and Serotonergic Neurons of the Rat Lower Brainstem

Endocrinology ◽  
2004 ◽  
Vol 145 (5) ◽  
pp. 2507-2515 ◽  
Author(s):  
Ryutaro Moriyama ◽  
Hiroko Tsukamura ◽  
Mika Kinoshita ◽  
Hirokatsu Okazaki ◽  
Yukio Kato ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
High Glucose ◽  
Male Rats ◽  
Dependent Manner ◽  
Isolated Cells ◽  
Serotonergic Neurons ◽  
Glucose Levels ◽  
Extracellular Glucose ◽  
Low Glucose

Abstract Pancreatic glucokinase (GK)-like immunoreactivities are located in ependymocytes and serotonergic neurons of the rat brain. The present study investigated in vitro changes in intracellular calcium concentrations ([Ca2+]i) in response to low (2 mm) or high (20 mm) extracellular glucose concentrations in isolated cells from the wall of the central canal (CC), raphe obscurus nucleus (ROb), ventromedial hypothalamus (VMH), and lateral hypothalamic area (LHA) in male rats. An increase in [Ca2+]i was found in cells from the CC (21.1% or 9.8% of ependymocytes), ROb (10.9% or 14.5% of serotonergic neurons), VMH (7.8% and 25.2% of neurons), and LHA (20% or 15.7% of neurons), when extracellular glucose levels were changed from 10 to either 2 or 20 mm, respectively. Most of the ependymocytes and serotonergic neurons responding to the glucose changes were immunoreactive to the anti-GK in the CC (96.8% for low glucose and 100% for high glucose) and ROb (100% for low and high glucose). The [Ca2+]i increase was blocked with calcium-free medium or L-type calcium channel blocker. Cells with an increase in [Ca2+]i in response to low glucose did not respond to high glucose and vice versa. Inhibition of GK activity with acute alloxan treatment blocked low or high glucose-induced [Ca2+]i increases in most GK-immunoreactive cells from the CC or ROb. The glucose-sensitive [Ca2+]i increase in neurons of the VMH and LHA was also alloxan-sensitive, but no cells taken from the VMH and LHA were immunoreactive to the antibody used. The present study further indicates that ependymocytes of the CC and serotonergic neurons in the ROb are also sensitive to the changes in extracellular glucose in a GK-dependent manner, but that the subtype of GK in these cells could be different from that in the VMH and LHA.

scholarly journals Corosolic acid inhibits cancer progression by decreasing the level of CDK19-mediated O-GlcNAcylation in liver cancer cells

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Congcong Zhang ◽  
Yongjie Niu ◽  
Zhixian Wang ◽  
Xin Xu ◽  
Yan Li ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Progression ◽  
High Glucose ◽  
Antitumor Effects ◽  
Glucose Levels ◽  
Liver Cancer Cells ◽  
Corosolic Acid ◽  
Hcc Cells

AbstractDiabetes is an important risk factor for liver cancer, but its mechanism is unknown. Corosolic acid (CA) has been proven to have both hypoglycemic and antitumor effects, so revealing the function of CA can help us understand the relationship between diabetes and liver cancer. In previous studies, we confirmed that CA can effectively inhibit the expression of YAP, an important oncoprotein in HCC cells, and the proliferation of HCC cells. In addition, we also found that O-GlcNAcylation plays an indispensable role in HCC tumorigenesis. However, it is not clear whether CA can inhibit the effect of O-GlcNAcylation on HCC cells. In this study, the antitumor ability of CA was investigated by inhibiting the O-GlcNAcylation level and its corresponding mechanism. The results showed that HG (high glucose) could promote the proliferation of liver cancer cells, while CA could inhibit cell growth under HG conditions and tumor growth in a xenotransplantation model. CA can inhibit the activation of the HBP pathway and reduce the expression of YAP and OGT under HG conditions. Importantly, we found that CA can reduce YAP expression and O-GlcNAcylation by inhibiting the activity of CDK19. Overexpression of CDK19 partially reversed the CA-induced decrease in YAP and O-GlcNAcylation. This is the first evidence that CA can reduce the proliferative capacity of cells with high glucose levels and further inhibit tumor growth by inactivating the CDK19/YAP/O-GlcNAcylation pathway, suggesting that CA is a candidate drug for the development of treatments against diabetes-associated liver cancer.

scholarly journals Glucose regulates tissue-specific chondro-osteogenic differentiation of human cartilage endplate stem cells via O-GlcNAcylation of Sox9 and Runx2

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Chao Sun ◽  
Weiren Lan ◽  
Bin Li ◽  
Rui Zuo ◽  
Hui Xing ◽  
...  
Keyword(s):  
Western Blot ◽  
Osteogenic Differentiation ◽  
High Glucose ◽  
Immunohistochemical Staining ◽  
Chondrogenic Differentiation ◽  
Glucose Medium ◽  
Cartilage Endplate ◽  
High Glucose Medium ◽  
Differentiation Medium ◽  
Low Glucose

Abstract Background The degenerative disc disease (DDD) is a major cause of low back pain. The physiological low-glucose microenvironment of the cartilage endplate (CEP) is disrupted in DDD. Glucose influences protein O-GlcNAcylation via the hexosamine biosynthetic pathway (HBP), which is the key to stem cell fate. Thiamet-G is an inhibitor of O-GlcNAcase for accumulating O-GlcNAcylated proteins while 6-diazo-5-oxo-l-norleucine (DON) inhibits HBP. Mechanisms of DDD are incompletely understood but include CEP degeneration and calcification. We aimed to identify the molecular mechanisms of glucose in CEP calcification in DDD. Methods We assessed normal and degenerated CEP tissues from patients, and the effects of chondrogenesis and osteogenesis of the CEP were determined by western blot and immunohistochemical staining. Cartilage endplate stem cells (CESCs) were induced with low-, normal-, and high-glucose medium for 21 days, and chondrogenic and osteogenic differentiations were measured by Q-PCR, western blot, and immunohistochemical staining. CESCs were induced with low-glucose and high-glucose medium with or without Thiamet-G or DON for 21 days, and chondrogenic and osteogenic differentiations were measured by Q-PCR, western blot, and immunohistochemical staining. Sox9 and Runx2 O-GlcNAcylation were measured by immunofluorescence. The effects of O-GlcNAcylation on the downstream genes of Sox9 and Runx2 were determined by Q-PCR and western blot. Results Degenerated CEPs from DDD patients lost chondrogenesis, acquired osteogenesis, and had higher protein O-GlcNAcylation level compared to normal CEPs from LVF patients. CESC chondrogenic differentiation gradually decreased while osteogenic differentiation gradually increased from low- to high-glucose differentiation medium. Furthermore, Thiamet-G promoted CESC osteogenic differentiation and inhibited chondrogenic differentiation in low-glucose differentiation medium; however, DON acted opposite role in high-glucose differentiation medium. Interestingly, we found that Sox9 and Runx2 were O-GlcNAcylated in differentiated CESCs. Finally, O-GlcNAcylation of Sox9 and Runx2 decreased chondrogenesis and increased osteogenesis in CESCs. Conclusions Our findings demonstrate the effect of glucose concentration on regulating the chondrogenic and osteogenic differentiation potential of CESCs and provide insight into the mechanism of how glucose concentration regulates Sox9 and Runx2 O-GlcNAcylation to affect the differentiation of CESCs, which may represent a target for CEP degeneration therapy.

scholarly journals Maintenance of Mitochondrial Morphology by Autophagy and Its Role in High Glucose Effects on Chronological Lifespan ofSaccharomyces cerevisiae

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
May T. Aung-Htut ◽  
Yuen T. Lam ◽  
Yu-Leng Lim ◽  
Mark Rinnerthaler ◽  
Cristy L. Gelling ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
High Glucose ◽  
Carbon Sources ◽  
Yeast Cells ◽  
Mitochondrial Morphology ◽  
Glucose Medium ◽  
Mitochondrial Fragmentation ◽  
Chronological Lifespan ◽  
Low Glucose ◽  
Glucose Effects

InSaccharomyces cerevisiae, mitochondrial morphology changes when cells are shifted between nonfermentative and fermentative carbon sources. Here, we show that cells ofS. cerevisiaegrown in different glucose concentrations display different mitochondrial morphologies. The morphology of mitochondria in the cells growing in 0.5% glucose was similar to that of mitochondria in respiring cells. However, the mitochondria of cells growing in higher glucose concentrations (2% and 4%) became fragmented after growth in these media, due to the production of acetic acid; however, the fragmentation was not due to intracellular acidification. From a screen of mutants involved in sensing and utilizing nutrients, cells lackingTOR1had reduced mitochondrial fragmentation, and autophagy was found to be essential for this reduction. Mitochondrial fragmentation in cells grown in high glucose was reversible by transferring them into conditioned medium from a culture grown on 0.5% glucose. Similarly, the chronological lifespan of cells grown in high glucose medium was reduced, and this phenotype could be reversed when cells were transferred to low glucose conditioned medium. These data indicate that chronological lifespan seems correlated with mitochondrial morphology of yeast cells and that both phenotypes can be influenced by factors from conditioned medium of cultures grown in low glucose medium.

scholarly journals High Glucose Affects Proliferation, Reactive Oxygen Species and Mineralization of Human Dental Pulp Cells

2020 ◽  
Vol 31 (3) ◽  
pp. 298-303
Author(s):  
Sivaporn Horsophonphong ◽  
Nakarin Kitkumthorn ◽  
Hathaitip Sritanaudomchai ◽  
Siriruk Nakornchai ◽  
Rudee Surarit
Keyword(s):  
High Glucose ◽  
Dental Pulp ◽  
Oxygen Species ◽  
Human Dental Pulp Cells ◽  
Odontogenic Differentiation ◽  
High Glucose Condition ◽  
Human Dental Pulp ◽  
Pulp Cells ◽  
Low Glucose ◽  
Glucose Condition

Abstract Diabetes is a group of metabolic disorders that can lead to damage and dysfunction of many organs including the dental pulp. Increased inflammatory response, reduction of dentin formation and impaired healing were reported in diabetic dental pulp. Hyperglycemia, which is a main characteristic of diabetes, was suggested to play a role in many diabetic complications. Therefore our aim was to investigate the effects of high glucose levels on proliferation, reactive oxygen species (ROS) production and odontogenic differentiation of human dental pulp cells (HDPCs). HDPCs were cultured under low glucose (5.5mM Glucose), high glucose (25 mM Glucose) and mannitol (iso-osmolar control) conditions. Cell proliferation was analyzed by MTT assay for 11 days. Glutathione and DCFH-DA assay were used to assess ROS and antioxidant levels after 24 h of glucose exposure. Odontogenic differentiation was evaluated and quantified by alizarin red staining on day 21. Expression of mineralization-associated genes, which were alkaline phosphatase, dentin sialophosphoprotein and osteonectin, was determined by RT-qPCR on day 14. The results showed that high glucose concentration decreased proliferation of HDPCs. Odontogenic differentiation, both by gene expression and mineral matrix deposit, was inhibited by high glucose condition. In addition, high DCF levels and low reduced glutathione levels were observed in high glucose condition. However, no differences were observed between mannitol and low glucose conditions. In conclusion, the results clearly showed the negative effect of high glucose condition on HDPCs proliferation and differentiation. Moreover, it also induced ROS production of HDPCs.

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