scholarly journals Cancer Stem Cell Enrichment and Metabolic Substrate Adaptability are Driven by Hydrogen Sulfide Suppression in Glioblastoma

2020 ◽  
Author(s):  
Daniel J. Silver ◽  
Gustavo A. Roversi ◽  
Nazmin Bithi ◽  
Chase K. A. Neumann ◽  
Katie M. Troike ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hydrogen Sulfide ◽  
Cancer Stem Cell ◽  
High Fat Diet ◽  
Control Diet ◽  
Chemotherapy Resistance ◽  
Cellular Metabolism ◽  
Protein S ◽  
High Fat ◽  
The Impact

AbstractGlioblastoma (GBM) remains among the deadliest of human malignancies. The emergence of the cancer stem cell (CSC) phenotype represents a major challenge to disease management and durable treatment response. The extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. The CSC state endows cells with a fluid metabolic profile, enabling the utilization of multiple nutrient sources. Therefore, to test the impact of diet on CSC enrichment, we evaluated disease progression in tumor-bearing mice fed an obesity-inducing high-fat diet (HFD) versus an energy-balanced, low-fat control diet. HFD consumption resulted in hyper-aggressive disease that was accompanied by CSC enrichment and shortened survival. HFD consumption also drove intracerebral accumulation of saturated fats, which in turn inhibited the production and signaling of the gasotransmitter hydrogen sulfide (H2S). H2S is an endogenously produced bio-active metabolite derived from sulfur amino acid catabolism. It functions principally through protein S-sulfhydration and regulates a variety of programs including mitochondrial bioenergetics and cellular metabolism. Inhibition of H2S synthesis resulted in increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to cytotoxicity and death of cultured GBM cells. Compared to non-cancerous controls, patient GBM specimens were reduced in overall protein S-sulfhydration, which was primarily lost from proteins regulating cellular metabolism. These findings support the hypothesis that diet-regulated H2S signaling serves to suppress GBM by restricting metabolic adaptability, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.One Sentence SummaryConsumption of a high-fat diet (HFD) accelerates glioblastoma (GBM) by inhibiting the production and signaling of the tumor-suppressive metabolite hydrogen sulfide (H2S).

scholarly journals TAMI-12. CANCER STEM CELL ENRICHMENT AND METABOLIC SUBSTRATE ADAPTABILITY ARE DRIVEN BY HYDROGEN SULFIDE SUPPRESSION IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii215-ii215
Author(s):  
Daniel Silver ◽  
Gustavo Roversi ◽  
Nazmin Bithi ◽  
Chase K Neumann ◽  
Katie Troike ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hydrogen Sulfide ◽  
Cancer Stem Cell ◽  
Control Diet ◽  
Chemotherapy Resistance ◽  
Cellular Metabolism ◽  
Protein S ◽  
Standard Of Care ◽  
Nutrient Sources ◽  
The Impact

Abstract Glioblastoma (GBM) remains among the deadliest of human malignancies. The emergence of the cancer stem cell (CSC) phenotype represents a major challenge to disease management and durable treatment response. The extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. The CSC state endows cells with a fluid metabolic profile, enabling the utilization of multiple nutrient sources. Therefore, to test the impact of diet on CSC enrichment, we evaluated disease progression in tumor-bearing mice fed an obesity-inducing high-fat diet (HFD) versus an energy-balanced, low-fat control diet. HFD consumption resulted in hyper-aggressive disease that was accompanied by CSC enrichment and shortened survival. HFD consumption also drove intracerebral accumulation of saturated fats, which in turn inhibited the production and signaling of the gasotransmitter hydrogen sulfide (H2S). H2S is an endogenously produced bio-active metabolite derived from sulfur amino acid catabolism. It functions principally through protein S-sulfhydration and regulates a variety of programs including mitochondrial bioenergetics and cellular metabolism. Inhibition of H2S synthesis resulted in increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to cytotoxicity and death of cultured GBM cells. Compared to non-cancerous controls, patient GBM specimens were reduced in overall protein S-sulfhydration, which was primarily lost from proteins regulating cellular metabolism. These findings support the hypothesis that diet-regulated H2S signaling serves to suppress GBM by restricting metabolic adaptability, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.

scholarly journals ETMM-01. CANCER STEM CELL ENRICHMENT AND METABOLIC SUBSTRATE ADAPTABILITY ARE DRIVEN BY HYDROGEN SULFIDE SUPPRESSION IN GLIOBLASTOMA

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i14-i14
Author(s):  
Daniel J Silver ◽  
Gustavo A Roversi ◽  
Nazmin Bithi ◽  
Chase K A Neumann ◽  
Katie M Troike ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hydrogen Sulfide ◽  
Cancer Stem Cell ◽  
Control Diet ◽  
Chemotherapy Resistance ◽  
Cellular Metabolism ◽  
Protein S ◽  
Standard Of Care ◽  
Nutrient Sources ◽  
The Impact

Abstract Glioblastoma (GBM) remains among the deadliest of human malignancies. The emergence of the cancer stem cell (CSC) phenotype represents a major challenge to disease management and durable treatment response. The extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. The CSC state endows cells with a fluid metabolic profile, enabling the utilization of multiple nutrient sources. Therefore, to test the impact of diet on CSC enrichment, we evaluated disease progression in tumor-bearing mice fed an obesity-inducing high-fat diet (HFD) versus an energy-balanced, low-fat control diet. HFD consumption resulted in hyper-aggressive disease that was accompanied by CSC enrichment and shortened survival. HFD consumption also drove intracerebral accumulation of saturated fats, which in turn inhibited the production and signaling of the gasotransmitter hydrogen sulfide (H2S). H2S is an endogenously produced bio-active metabolite derived from sulfur amino acid catabolism. It functions principally through protein S-sulfhydration and regulates a variety of programs including mitochondrial bioenergetics and cellular metabolism. Inhibition of H2S synthesis resulted in increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to cytotoxicity and death of cultured GBM cells. Compared to non-cancerous controls, patient GBM specimens were reduced in overall protein S-sulfhydration, which was primarily lost from proteins regulating cellular metabolism. These findings support the hypothesis that diet-regulated H2S signaling serves to suppress GBM by restricting metabolic adaptability, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.

scholarly journals STEM-03. CONSUMPTION OF A HIGH-FAT DIET INHIBITS THE TUMOR SUPPRESSIVE ACTIVITY OF HYDROGEN SULFIDE, DRIVING CANCER STEM CELL ENRICHMENT AND DISEASE AGGRESSION IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi234-vi234
Author(s):  
Daniel Silver ◽  
Gustavo Roversi ◽  
Nazmin Bithi ◽  
Katie Troike ◽  
Chase Neumann ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hydrogen Sulfide ◽  
Cancer Stem Cell ◽  
Tumor Cell ◽  
High Fat Diet ◽  
Protein S ◽  
High Fat ◽  
Organ Systems ◽  
Human Gbm ◽  
The Impact

Abstract Glioblastoma (GBM) remains among the deadliest of human malignancies. Effective disease management is lacking due in part to the emergence of the cancer stem cell (CSC) phenotype. The tumor cell extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. Alongside other pathological features, the CSC state endows populations of tumor cells with a fluid metabolic profile that enables utilization of multiple nutrition sources. Therefore, to test the impact of diet on CSC enrichment, we interrogated disease progression in tumor-bearing mice fed either a high-fat diet (HFD), similar to the Western Pattern diet or a control low-fat diet. Compared to controls, HFD-consumption resulted in the presentation of a hyper-aggressive disease phenotype with truncated survival and tumors markedly enriched in tumor-initiating SOX2+ CSCs. To understand the underlying mechanism driving this finding, we examined tumors for the diet-regulated metabolite hydrogen sulfide (H2S). H2S is an endogenously produced bio-active gasotransmitter similar to nitric oxide. It functions principally through protein S-sulfhydration to regulate a variety of cellular programs including mitochondrial function, stress signaling and metabolism. While there is exceedingly limited information on H2S and GBM, its HFD-driven suppression has been reported in other organ systems. We discovered a significant reduction in H2S synthesis resulting from HFD-consumption in the brain of the mouse and a striking decrease in protein S-sulfhydration in human GBM tumor tissue when compared to non-cancerous control brain tissue. We demonstrated that chemical inhibition of H2S synthesis resulted in increased tumor cell viability whereas exposure to chemical H2S donors led to pronounced cell death of cultured mouse and human GBM cells. These data demonstrate for the first time, that H2S serves as a tumor suppressor for GBM. Moreover, the diet-driven suppression of H2S helps explain the hyper-aggressive in vivo phenotype that presents in response to HFD-consumption.

scholarly journals The Impact of DJOS Surgery, a High Fat Diet and a Control Diet on the Enzymes of Glucose Metabolism in the Liver and Muscles of Sprague-Dawley Rats

2019 ◽  
Vol 10 ◽  
Author(s):  
Dominika Stygar ◽  
Dorian Andrare ◽  
Barbara Bażanów ◽  
Elżbieta Chełmecka ◽  
Tomasz Sawczyn ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
High Fat Diet ◽  
Control Diet ◽  
Sprague Dawley ◽  
High Fat ◽  
Sprague Dawley Rats ◽  
The Impact

scholarly journals Effects of Diet-Induced Obesity and Deficient in Vitamin D on Spermatozoa Function and DNA Integrity in Sprague-Dawley Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
O. Merino ◽  
R. Sánchez ◽  
B. M. Gregorio ◽  
F. J. Sampaio ◽  
J. Risopatrón
Keyword(s):  
Vitamin D ◽  
Dna Fragmentation ◽  
High Fat Diet ◽  
Control Diet ◽  
Sperm Function ◽  
Sprague Dawley ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Sprague Dawley Rats ◽  
The Impact

Obesity has adverse effects on male fertility and usually is diagnosed with a prevalence of vitamin D deficiency (VD-). Discussion on the impact of obesity/VD- on sperm function has been limited. This study analyzed the effects of diet-induced obesity/VD- on viability and plasma membrane integrity (PMI), superoxide anion (O2-) level, and DNA fragmentation (DNAfrag) in sperm Sprague-Dawley rats. The males were randomized into four groups and fed for a period of 12 weeks: G1: control diet with vitamin D (C/VD+), G2: control diet without vitamin D (C/VD-), G3: high-fat diet with vitamin D (HF/VD+), and G4: high-fat diet without vitamin D (HF/VD-). Sperm function parameters were analyzed by flow cytometry. PMI percentages and O2- levels were not affected by any of the diets. DNA fragmentation was increasing significantly (p<0.05) in the spermatozoa of animals with diets vitamin D deficient (G2) and diet-induced obesity (G4). Our results allow us to point out that diet-induced obesity and VD- produce greater damage in DNA sperm of rats. The use of nutraceuticals containing vitamin D could be reducing the risk of fragmentation of DNA in spermatozoa.

Beneficial effects of maternal swimming during pregnancy on offspring metabolism when the father is obese

2018 ◽  
Vol 10 (4) ◽  
pp. 502-506 ◽  
Author(s):  
R. Tarevnic ◽  
F. Ornellas ◽  
C. A. Mandarim-de-Lacerda ◽  
M. B. Aguila
Keyword(s):  
Body Size ◽  
Exercise Training ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Control Diet ◽  
High Fat ◽  
Beneficial Effects ◽  
Maternal Exercise ◽  
The Impact ◽  
Old Mice

AbstractWe aimed to evaluate the impact of maternal exercise training on the offspring metabolism and body size caused by father obesity. C57BL/6 male 4-week-old mice were fed a high-fat diet (HF father) or control diet (C father), while equal age female mice were fed only a C diet and were separated into two groups: trained (T mother) and non-trained (NT mother), and at 12 weeks of age mice were mated. A continuous swimming protocol was applied for 10 weeks (before and during gestation), and offspring were followed since weaning until sacrifice (at 12 weeks of age). HF father, compared to C father, showed obesity, elevated total cholesterol (TC) and triglycerides (TG), and glucose intolerance. Both sexes HF/NT offspring showed hyperglycemia, glucose intolerance and high levels of TC and TG, without obesity. However, HF/T offspring showed data close to C/NT, demonstrating the beneficial effect of maternal exercise in the offspring of obese fathers.

scholarly journals Attenuation of High-Fat Diet-Induced Rat Liver Oxidative Stress and Steatosis by Combined Hydroxytyrosol- (HT-) Eicosapentaenoic Acid Supplementation Mainly Relies on HT

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Francisca Echeverría ◽  
Rodrigo Valenzuela ◽  
Andrés Bustamante ◽  
Daniela Álvarez ◽  
Macarena Ortiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Eicosapentaenoic Acid ◽  
High Fat Diet ◽  
Control Diet ◽  
Liver Steatosis ◽  
Pharmacological Therapy ◽  
High Fat ◽  
Total Recovery ◽  
Nonalcoholic Fatty Liver ◽  
The Impact

Pharmacological therapy for nonalcoholic fatty liver disease (NAFLD) is not approved at the present time. For this purpose, the effect of combined eicosapentaenoic acid (EPA; 50 mg/kg/day) modulating hepatic lipid metabolism and hydroxytyrosol (HT; 5 mg/kg/day) exerting antioxidant actions was evaluated on hepatic steatosis and oxidative stress induced by a high-fat diet (HFD; 60% fat, 20% protein, and 20% carbohydrates) compared to a control diet (CD; 10% fat, 20% protein, and 70% carbohydrates) in mice fed for 12 weeks. HFD-induced liver steatosis (i) was reduced by 32% by EPA, without changes in oxidative stress-related parameters and mild recovery of Nrf2 functioning affording antioxidation and (ii) was decreased by 42% by HT, concomitantly with total regain of the glutathione status diminished by HFD, 42% to 59% recovery of lipid peroxidation and protein oxidation enhanced by HFD, and regain of Nrf2 functioning, whereas (iii) combined EPA + HT supplementation elicited 74% reduction in liver steatosis, with total recovery of the antioxidant potential in a similar manner than HT. It is concluded that combined HT + EPA drastically decreases NAFLD development, an effect that shows additivity in HT and EPA effects that mainly relies on HT, strengthening the impact of oxidative stress as a central mechanism underlying liver steatosis in obesity.

scholarly journals Offspring susceptibility to metabolic alterations due to maternal high-fat diet and the impact of inhaled ozone used as a stressor

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Samantha J. Snow ◽  
Katarzyna Broniowska ◽  
Edward D. Karoly ◽  
Andres R. Henriquez ◽  
Pamela M. Phillips ◽  
...  
Keyword(s):  
Fatty Acids ◽  
High Fat Diet ◽  
Metabolic Response ◽  
Control Diet ◽  
Metabolomic Analysis ◽  
High Fat ◽  
Dietary Regimen ◽  
Metabolic Alterations ◽  
Group Sex ◽  
The Impact

Abstract The influence of maternal high-fat diet (HFD) on metabolic response to ozone was examined in Long-Evans rat offspring. F0 females were fed control diet (CD; 10%kcal from fat) or HFD (60%kcal from fat) starting at post-natal day (PND) 30. Rats were bred on PND 72. Dietary regimen was maintained until PND 30 when all offspring were switched to CD. On PND 40, F1 offspring (n = 10/group/sex) were exposed to air or 0.8 ppm ozone for 5 h. Serum samples were collected for global metabolomic analysis (n = 8/group/sex). Offspring from HFD dams had increased body fat and weight relative to CD. Metabolomic analysis revealed significant sex-, diet-, and exposure-related changes. Maternal HFD increased free fatty acids and decreased phospholipids (male > female) in air-exposed rats. Microbiome-associated histidine and tyrosine metabolites were increased in both sexes, while 1,5-anhydroglucitol levels decreased in males indicating susceptibility to insulin resistance. Ozone decreased monohydroxy fatty acids and acyl carnitines and increased pyruvate along with TCA cycle intermediates in females (HFD > CD). Ozone increased various amino acids, polyamines, and metabolites of gut microbiota in HFD female offspring indicating gut microbiome alterations. Collectively, these data suggest that maternal HFD increases offspring susceptibility to metabolic alterations in a sex-specific manner when challenged with environmental stressors.

scholarly journals Paternal Resistance Training Induced Modifications in the Left Ventricle Proteome Independent of Offspring Diet

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Ivo Vieira de Sousa Neto ◽  
Ramires Alsamir Tibana ◽  
Jonato Prestes ◽  
Leonardo Gomes de Oliveira da Silva ◽  
Jeeser Alves Almeida ◽  
...  
Keyword(s):  
Resistance Training ◽  
Left Ventricle ◽  
High Fat Diet ◽  
Control Diet ◽  
Transgenerational Inheritance ◽  
High Fat ◽  
Cell Component ◽  
Molecular Aspects ◽  
The Impact ◽  
Harmful Effects

Ancestral obesogenic exposure is able to trigger harmful effects in the offspring left ventricle (LV) which could lead to cardiovascular diseases. However, the impact of the father’s lifestyle on the offspring LV is largely unexplored. The aim of this study was to investigate the effects of 8 weeks of paternal resistance training (RT) on the offspring left ventricle (LV) proteome exposed to control or high-fat (HF) diet. Wistar rats were randomly divided into two groups: sedentary fathers and trained fathers (8 weeks, 3 times per week with weights secured to the animals’ tails). The offspring were obtained by mating with sedentary females. Upon weaning, male offspring were divided into 4 groups (5 animals per group): offspring from sedentary fathers, exposed to control diet (SFO-C); offspring from trained fathers, exposed to control diet (TFO-C); offspring from sedentary fathers, exposed to high-fat diet (SFO-HF); and offspring from trained fathers, exposed to high-fat diet (TFO-HF). The LC-MS/MS analysis revealed 537 regulated proteins among groups. Offspring exposure to HF diet caused reduction in the abundance levels of proteins related to cell component organization, metabolic processes, and transport. Proteins related to antioxidant activity, transport, and transcription regulation were increased in TFO-C and TFO-HF as compared with the SFO-C and SFO-HF groups. Paternal RT demonstrated to be an important intervention capable of inducing significant effects on the LV proteome regardless of offspring diet due to the increase of proteins involved into LV homeostasis maintenance. This study contributes to a better understanding of the molecular aspects involved in transgenerational inheritance.

scholarly journals A high-fat diet fed during different periods of life impairs steroidogenesis of rat Leydig cells

Reproduction ◽  
2016 ◽  
Vol 152 (6) ◽  
pp. 795-808 ◽  
Author(s):  
Maria Etelvina Pinto-Fochi ◽  
Eloísa Zanin Pytlowanciv ◽  
Vanessa Reame ◽  
Alex Rafacho ◽  
Daniele Lisboa Ribeiro ◽  
...  
Keyword(s):  
Sexual Maturation ◽  
High Fat Diet ◽  
Structural Damage ◽  
Leydig Cells ◽  
Maternal Obesity ◽  
Control Diet ◽  
High Fat ◽  
Unsaturated Fat ◽  
Conventional Diet ◽  
The Impact

This study evaluated the impact of a high-fat diet (HFD) during different stages of rat life, associated or not with maternal obesity, on the content of sex steroid hormones and morphophysiology of Leydig cells. The following periods of development were examined: gestation (O1), gestation and lactation (O2), from weaning to adulthood (O3), from lactation to adulthood (O4), gestation to adulthood (O5), and after sexual maturation (O6). The HFD contained 20% unsaturated fat, whereas the control diet had 4% fat. Maternal obesity was induced by feeding HFD 15 weeks before mating. All HFD groups presented increased body weight, hyperinsulinemia and reduced insulin sensitivity. Except for O1, all HFD groups exhibited a higher adiposity index, hyperleptinemia, reduced testosterone and estradiol testicular levels, and decreased testicular 17β-HSD enzyme . Morphometrical analyses indicated atrophy of Leydig cells in the O2 group. Myelin vesicles were observed in the mitochondrial matrix of Leydig cells in O3, O4, O5 and O6, and autophagosomes containing mitochondria were found in O5 and O6. In conclusion, HFD feeding, before or after sexual maturation, reduces the functional capacity of rat Leydig cells. Maternal obesity associated with HFD during pregnancy/lactation prejudices Leydig cell steroidogenesis and induces its atrophy in adulthood, even if it is replaced by a conventional diet at later stages of life. Regardless of the life period of exposure to HFD, deregulation of leptin is the main factor related to steroidogenic impairment of Leydig cells, and, in groups exposed for longer periods (O3, O4, O5 and O6), this is worsened by structural damage and mitochondrial degeneration of these cells.

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