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Steven J. Beaupre - One of the best experts on this subject based on the ideXlab platform.
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bioenergetic components of reproductive effort in viviparous snakes costs of vitellogenesis exceed costs of pregnancy
Comparative Biochemistry and Physiology A-molecular & Integrative Physiology, 2011Co-Authors: James U. Van Dyke, Steven J. BeaupreAbstract:article i nfo Reproductive effort has been defined as the proportion of an organism's energy budget that is allocated to re- production over a biologically meaningful time period. Historically, studies of reproductive Bioenergetics considered energy content of gametes, but not costs of gamete production. Although metabolic costs of vitel- logenesis (MCV) fundamentally reflect the primary bioenergetic cost of reproductive allocation in female reptiles, the few investigations that have considered costs of reproductive allocation have focused on meta- bolic costs of pregnancy (MCP) in viviparous species. We define MCP as energetic costs incurred by pregnant females, including all costs of maintaining gestation conditions necessary for embryogenesis. MCP by our def- inition do not include fetal costs of embryogenesis. We measured metabolic rates in five species of viviparous snakes (Agkistrodon contortrix, Boa constrictor, Eryx colubrinus, Nerodia sipedon, and Thamnophis sirtalis) dur- ing vitellogenesis and pregnancy in order to estimate MCV and MCP. Across all species, MCV were responsible for 30% increases in maternal metabolism. Phylogenetically-independent contrasts showed that MCV were significantly greater in B. constrictor than in other species, likely because B. constrictor yolk energy content was greater than that of other species. Estimates of MCP were not significantly different from zero in any spe- cies. In viviparous snakes, MCV appear to represent significant bioenergetic expenditures, while MCP do not. We suggest that MCV, together with yolk energy content, represent the most significant component of rep- tilian reproductive effort, and therefore deserve greater attention than MCP in studies of reptilian reproduc- tive Bioenergetics.
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Bioenergetic components of reproductive effort in viviparous snakes: costs of vitellogenesis exceed costs of pregnancy.
Comparative biochemistry and physiology. Part A Molecular & integrative physiology, 2011Co-Authors: James U. Van Dyke, Steven J. BeaupreAbstract:Reproductive effort has been defined as the proportion of an organism's energy budget that is allocated to reproduction over a biologically meaningful time period. Historically, studies of reproductive Bioenergetics considered energy content of gametes, but not costs of gamete production. Although metabolic costs of vitellogenesis (MCV) fundamentally reflect the primary bioenergetic cost of reproductive allocation in female reptiles, the few investigations that have considered costs of reproductive allocation have focused on metabolic costs of pregnancy (MCP) in viviparous species. We define MCP as energetic costs incurred by pregnant females, including all costs of maintaining gestation conditions necessary for embryogenesis. MCP by our definition do not include fetal costs of embryogenesis. We measured metabolic rates in five species of viviparous snakes (Agkistrodon contortrix, Boa constrictor, Eryx colubrinus, Nerodia sipedon, and Thamnophis sirtalis) during vitellogenesis and pregnancy in order to estimate MCV and MCP. Across all species, MCV were responsible for 30% increases in maternal metabolism. Phylogenetically-independent contrasts showed that MCV were significantly greater in B. constrictor than in other species, likely because B. constrictor yolk energy content was greater than that of other species. Estimates of MCP were not significantly different from zero in any species. In viviparous snakes, MCV appear to represent significant bioenergetic expenditures, while MCP do not. We suggest that MCV, together with yolk energy content, represent the most significant component of reptilian reproductive effort, and therefore deserve greater attention than MCP in studies of reptilian reproductive Bioenergetics.
Csaba Szabo - One of the best experts on this subject based on the ideXlab platform.
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role of 3 mercaptopyruvate sulfurtransferase in the regulation of proliferation migration and Bioenergetics in murine colon cancer cells
Biomolecules, 2020Co-Authors: Fiona Augsburger, Elisa B Randi, Mathieu Jendly, Kelly Ascencao, Nahzli Dilek, Csaba SzaboAbstract:3-mercaptopyruvate sulfurtransferase (3-MST) has emerged as one of the significant sources of biologically active sulfur species in various mammalian cells. The current study was designed to investigate the functional role of 3-MST's catalytic activity in the murine colon cancer cell line CT26. The novel pharmacological 3-MST inhibitor HMPSNE was used to assess cancer cell proliferation, migration and Bioenergetics in vitro. Methods included measurements of cell viability (MTT and LDH assays), cell proliferation and in vitro wound healing (IncuCyte) and cellular Bioenergetics (Seahorse extracellular flux analysis). 3-MST expression was detected by Western blotting; H2S production was measured by the fluorescent dye AzMC. The results show that CT26 cells express 3-MST protein and mRNA, as well as several enzymes involved in H2S degradation (TST, ETHE1). Pharmacological inhibition of 3-MST concentration-dependently suppressed H2S production and, at 100 and 300 µM, attenuated CT26 proliferation and migration. HMPSNE exerted a bell-shaped effect on several cellular bioenergetic parameters related to oxidative phosphorylation, while other bioenergetic parameters were either unaffected or inhibited at the highest concentration of the inhibitor tested (300 µM). In contrast to 3-MST, the expression of CBS (another H2S producing enzyme which has been previously implicated in the regulation of various biological parameters in other tumor cells) was not detectable in CT26 cells and pharmacological inhibition of CBS exerted no significant effects on CT26 proliferation or Bioenergetics. In summary, 3-MST catalytic activity significantly contributes to the regulation of cellular proliferation, migration and Bioenergetics in CT26 murine colon cancer cells. The current studies identify 3-MST as the principal source of biologically active H2S in this cell line.
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3 mercaptopyruvate sulfurtransferase supports endothelial cell angiogenesis and Bioenergetics
British Journal of Pharmacology, 2020Co-Authors: Armita Abdollahi Govar, Gabor Torő, Peter Szaniszlo, Athanasia Pavlidou, Sofia Iris Bibli, Ketan Thanki, Vicente A Resto, Celia Chao, Mark R Hellmich, Csaba SzaboAbstract:BACKGROUND AND PURPOSE During angiogenesis, quiescent endothelial cells (ECs) are activated by various stimuli to form new blood vessels from pre-existing ones in physiological and pathological conditions. Many research groups have shown that hydrogen sulfide (H2 S), the newest member of the gasotransmitter family, acts as a proangiogenic factor. To date, very little is known about the regulatory role of 3-mercaptopyruvate sulfurtransferase (3-MST), an important H2 S-producing enzyme in ECs. The aim of our study was to explore the potential role of 3-MST in human EC Bioenergetics, metabolism, and angiogenesis. EXPERIMENTAL APPROACH To assess in vitro angiogenic responses, we used EA.hy926 human vascular ECs subjected to shRNA-mediated 3-MST attenuation and pharmacological inhibition of proliferation, migration, and tube-like network formation. To evaluate bioenergetic parameters, cell respiration, glycolysis, glucose uptake, and mitochondrial/glycolytic ATP production were measured. Finally, global metabolomic profiling was performed to determine the level of 669 metabolic compounds. KEY RESULTS 3-MST-attenuated ECs subjected to shRNA or pharmacological inhibition of 3-MST significantly reduced EC proliferation, migration, and tube-like network formation. 3-MST silencing also suppressed VEGF-induced EC migration. From bioenergetic and metabolic standpoints, 3-MST attenuation decreased mitochondrial respiration and mitochondrial ATP production, increased glucose uptake, and perturbed the entire EC metabolome. CONCLUSION AND IMPLICATIONS 3-MST regulates Bioenergetics and morphological angiogenic functions in human ECs. The data presented in the current report support the view that 3-MST pathway may be a potential candidate for therapeutic modulation of angiogenesis. LINKED ARTICLES This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
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regulation of vascular tone angiogenesis and cellular Bioenergetics by the 3 mercaptopyruvate sulfurtransferase h2s pathway functional impairment by hyperglycemia and restoration by dl α lipoic acid
Molecular Medicine, 2015Co-Authors: Ciro Coletta, Katalin Modis, Andreas Papapetropoulos, Bartosz Szczesny, Attila Brunyánszki, Gábor Oláh, Kazunori Yanagi, Akbar Ahmad, Ester Rios, Csaba SzaboAbstract:Hydrogen sulfide (H2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and μmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3–1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H2S production depended on enzymatic activity, although at higher concentrations (1–3 mmol/L) there was also evidence for an additional nonenzymatic H2S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants dl-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular Bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and Bioenergetics in hyperglycemia.
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Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H_2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid
Molecular Medicine, 2015Co-Authors: Ciro Coletta, Katalin Modis, Andreas Papapetropoulos, Bartosz Szczesny, Attila Brunyánszki, Gábor Oláh, Ester C. S. Rios, Kazunori Yanagi, Akbar Ahmad, Csaba SzaboAbstract:Hydrogen sulfide (H_2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H_2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H_2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H_2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H_2S levels in rats. 3-MP (10 µmol/L to 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3–1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H_2S production depended on enzymatic activity, although at higher concentrations (1–3 mmol/L) there was also evidence for an additional nonenzymatic H_2S production by 3-MP. In vivo , 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants DL -α-lipoic acid (LA) in vivo , or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular Bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H_2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H_2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and Bioenergetics in hyperglycemia.
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p17 modulatory effect of s adenyl methionine an allosteric activator of cystathionine beta synthase on the proliferation and Bioenergetics of colon cancer cells mechanism of action
Nitric Oxide, 2014Co-Authors: Ciro Coletta, Katalin Modis, Andreas Papapetropoulos, Bartosz Szczesny, Celia Chao, Mark R Hellmich, Antonia Asimakopoulou, Csaba SzaboAbstract:Previous studies reported that S-adenosyl- l -methionine (SAM), an allosteric activator of cystathionine-beta-synthase (CBS) increases the production of hydrogen sulfide (H2S) in isolated enzyme preparations. Given the multiple pharmacological effects of SAM, the goal of our study was to probe the specific role of CBS in the effects of SAM in HCT116 colon cancer cells. SAM (0.1 μM–3 mM) concentration-dependently increased CBS-mediated H2S production. The effect of SAM on cell proliferation (assessed real time for up to 24 h by xCELLigence) was time-dependent. SAM (0.1–3 mM) enhanced HCT116 cell proliferation at all concentrations tested in the first 12 h following treatment, but induced cell death/inhibition of proliferation thereafter (12–24 h). The short-term stimulatory effects of SAM were attenuated by stable CBS silencing. In contrast, the anti-proliferative effects of SAM were maintained in cells with CBS silencing. Short-term exposure of HCT116 cells to SAM (0.1–1 mM, 1 h) concentration-dependently increased the oxygen consumption and bioenergetic function of HCT116 cells, while longer-term exposures resulted in a suppression of these parameters at all concentrations of SAM tested. While the stimulatory effect of SAM on proliferation and Bioenergetics were attenuated in cells with stable CBS silencing, the inhibitory effects of SAM were largely unaffected by it. Thus, CBS in colon cancer cells produces H2S in a regulated fashion. H2S, when produced at low-to-intermediate levels, serves as an endogenous cancer cell growth and bioenergetic factor. While the short-term inhibition of cell proliferation by high concentrations of SAM may be partially related to “over-stimulation” of CBS, the long-term inhibitory effects of SAM on cell proliferation and Bioenergetics are mainly CBS-independent.
James U. Van Dyke - One of the best experts on this subject based on the ideXlab platform.
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bioenergetic components of reproductive effort in viviparous snakes costs of vitellogenesis exceed costs of pregnancy
Comparative Biochemistry and Physiology A-molecular & Integrative Physiology, 2011Co-Authors: James U. Van Dyke, Steven J. BeaupreAbstract:article i nfo Reproductive effort has been defined as the proportion of an organism's energy budget that is allocated to re- production over a biologically meaningful time period. Historically, studies of reproductive Bioenergetics considered energy content of gametes, but not costs of gamete production. Although metabolic costs of vitel- logenesis (MCV) fundamentally reflect the primary bioenergetic cost of reproductive allocation in female reptiles, the few investigations that have considered costs of reproductive allocation have focused on meta- bolic costs of pregnancy (MCP) in viviparous species. We define MCP as energetic costs incurred by pregnant females, including all costs of maintaining gestation conditions necessary for embryogenesis. MCP by our def- inition do not include fetal costs of embryogenesis. We measured metabolic rates in five species of viviparous snakes (Agkistrodon contortrix, Boa constrictor, Eryx colubrinus, Nerodia sipedon, and Thamnophis sirtalis) dur- ing vitellogenesis and pregnancy in order to estimate MCV and MCP. Across all species, MCV were responsible for 30% increases in maternal metabolism. Phylogenetically-independent contrasts showed that MCV were significantly greater in B. constrictor than in other species, likely because B. constrictor yolk energy content was greater than that of other species. Estimates of MCP were not significantly different from zero in any spe- cies. In viviparous snakes, MCV appear to represent significant bioenergetic expenditures, while MCP do not. We suggest that MCV, together with yolk energy content, represent the most significant component of rep- tilian reproductive effort, and therefore deserve greater attention than MCP in studies of reptilian reproduc- tive Bioenergetics.
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Bioenergetic components of reproductive effort in viviparous snakes: costs of vitellogenesis exceed costs of pregnancy.
Comparative biochemistry and physiology. Part A Molecular & integrative physiology, 2011Co-Authors: James U. Van Dyke, Steven J. BeaupreAbstract:Reproductive effort has been defined as the proportion of an organism's energy budget that is allocated to reproduction over a biologically meaningful time period. Historically, studies of reproductive Bioenergetics considered energy content of gametes, but not costs of gamete production. Although metabolic costs of vitellogenesis (MCV) fundamentally reflect the primary bioenergetic cost of reproductive allocation in female reptiles, the few investigations that have considered costs of reproductive allocation have focused on metabolic costs of pregnancy (MCP) in viviparous species. We define MCP as energetic costs incurred by pregnant females, including all costs of maintaining gestation conditions necessary for embryogenesis. MCP by our definition do not include fetal costs of embryogenesis. We measured metabolic rates in five species of viviparous snakes (Agkistrodon contortrix, Boa constrictor, Eryx colubrinus, Nerodia sipedon, and Thamnophis sirtalis) during vitellogenesis and pregnancy in order to estimate MCV and MCP. Across all species, MCV were responsible for 30% increases in maternal metabolism. Phylogenetically-independent contrasts showed that MCV were significantly greater in B. constrictor than in other species, likely because B. constrictor yolk energy content was greater than that of other species. Estimates of MCP were not significantly different from zero in any species. In viviparous snakes, MCV appear to represent significant bioenergetic expenditures, while MCP do not. We suggest that MCV, together with yolk energy content, represent the most significant component of reptilian reproductive effort, and therefore deserve greater attention than MCP in studies of reptilian reproductive Bioenergetics.
Dost Ongur - One of the best experts on this subject based on the ideXlab platform.
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in vivo evidence for cerebral bioenergetic abnormalities in schizophrenia measured using 31p magnetization transfer spectroscopy
JAMA Psychiatry, 2014Co-Authors: Alissa J Cooper, Bruce M Cohen, Scott E Lukas, Dost Ongur, Thida Thida, Selma Sehovic, Xiaoliang ZhangAbstract:Importance Abnormalities in neural activity and cerebral Bioenergetics have been observed in schizophrenia (SZ). Further defining energy metabolism anomalies would provide crucial information about molecular mechanisms underlying SZ and may be valuable for developing novel treatment strategies. Objective To investigate cerebral Bioenergetics in SZ via measurement of creatine kinase activity using in vivo 31 P magnetization transfer spectroscopy. Design, Setting, and Participants Cross-sectional case-control study in the setting of clinical services and a brain imaging center of an academic psychiatric hospital. Twenty-six participants with chronic SZ (including a subgroup diagnosed as having schizoaffective disorder) and 26 age-matched and sex-matched healthy control subjects (25 usable magnetic resonance spectroscopy data sets from the latter). Intervention 31 P magnetization transfer spectroscopy. Main Outcomes and Measures The primary outcome measure was the forward rate constant ( kf ) of the creatine kinase enzyme in the frontal lobe. We also collected independent measures of brain intracellular pH and steady-state metabolite ratios of high-energy phosphate-containing compounds (phosphocreatine and adenosine triphosphate [ATP]), inorganic phosphate, and the 2 membrane phospholipids phosphodiester and phosphomonoester. Results A substantial (22%) and statistically significant ( P = .003) reduction in creatine kinase kf was observed in SZ. In addition, intracellular pH was significantly reduced (7.00 in the SZ group vs 7.03 in the control group, P = .007) in this condition. The phosphocreatine to ATP ratio, inorganic phosphate to ATP ratio, and phosphomonoester to ATP ratio were not substantially altered in SZ, but a significant ( P = .02) reduction was found in the phosphodiester to ATP ratio. The abnormalities were similar between SZ and schizoaffective disorder. Conclusions and Relevance Using a novel 31 P magnetization transfer magnetic resonance spectroscopy approach, we provide direct and compelling evidence for a specific bioenergetic abnormality in SZ. Reduced kf of the creatine kinase enzyme is consistent with an abnormality in storage and use of brain energy. The intracellular pH reduction suggests a relative increase in the contribution of glycolysis to ATP synthesis, providing convergent evidence for bioenergetic abnormalities in SZ. The similar phosphocreatine to ATP ratios in SZ and healthy controls suggest that the underlying Bioenergetics abnormality is not associated with change in this metabolite ratio.
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creatine kinase and atp synthase reaction rates in human frontal lobe measured by 31p magnetization transfer spectroscopy at 4t
Magnetic Resonance Imaging, 2013Co-Authors: Alissa J Cooper, Bruce M Cohen, Scott E Lukas, Dost OngurAbstract:Abstract The human frontal lobe is critical for cognitive function in the healthy brain. Many psychiatric disorders including schizophrenia and bipolar disorder are associated with apparent mitochondrial dysfunction and bioenergetic abnormalities in the frontal lobe. Therefore, measuring cerebral Bioenergetics associated with creatine kinase and adenosine triphosphate (ATP) synthase reactions could provide crucial information regarding the underlying molecular mechanisms associated with psychiatric disorders. In this study, the unidirectional forward chemical exchange metabolic fluxes of creatine kinase and ATP synthase reactions as well as reverse chemical exchange metabolic flux associated with ATP hydrolysis were determined at 4T by 31P magnetization transfer. The current experiments indicate that the kinetic network of PCr↔ATP↔Pi can be measured reliably in the human frontal lobe at 4T, which will enable detailed in vivo characterization of bioenergetic abnormalities in a variety of neuropsychiatric disorders.
Ciro Coletta - One of the best experts on this subject based on the ideXlab platform.
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regulation of vascular tone angiogenesis and cellular Bioenergetics by the 3 mercaptopyruvate sulfurtransferase h2s pathway functional impairment by hyperglycemia and restoration by dl α lipoic acid
Molecular Medicine, 2015Co-Authors: Ciro Coletta, Katalin Modis, Andreas Papapetropoulos, Bartosz Szczesny, Attila Brunyánszki, Gábor Oláh, Kazunori Yanagi, Akbar Ahmad, Ester Rios, Csaba SzaboAbstract:Hydrogen sulfide (H2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and μmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3–1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H2S production depended on enzymatic activity, although at higher concentrations (1–3 mmol/L) there was also evidence for an additional nonenzymatic H2S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants dl-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular Bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and Bioenergetics in hyperglycemia.
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Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H_2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid
Molecular Medicine, 2015Co-Authors: Ciro Coletta, Katalin Modis, Andreas Papapetropoulos, Bartosz Szczesny, Attila Brunyánszki, Gábor Oláh, Ester C. S. Rios, Kazunori Yanagi, Akbar Ahmad, Csaba SzaboAbstract:Hydrogen sulfide (H_2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H_2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H_2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H_2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H_2S levels in rats. 3-MP (10 µmol/L to 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3–1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H_2S production depended on enzymatic activity, although at higher concentrations (1–3 mmol/L) there was also evidence for an additional nonenzymatic H_2S production by 3-MP. In vivo , 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants DL -α-lipoic acid (LA) in vivo , or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular Bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H_2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H_2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and Bioenergetics in hyperglycemia.
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p17 modulatory effect of s adenyl methionine an allosteric activator of cystathionine beta synthase on the proliferation and Bioenergetics of colon cancer cells mechanism of action
Nitric Oxide, 2014Co-Authors: Ciro Coletta, Katalin Modis, Andreas Papapetropoulos, Bartosz Szczesny, Celia Chao, Mark R Hellmich, Antonia Asimakopoulou, Csaba SzaboAbstract:Previous studies reported that S-adenosyl- l -methionine (SAM), an allosteric activator of cystathionine-beta-synthase (CBS) increases the production of hydrogen sulfide (H2S) in isolated enzyme preparations. Given the multiple pharmacological effects of SAM, the goal of our study was to probe the specific role of CBS in the effects of SAM in HCT116 colon cancer cells. SAM (0.1 μM–3 mM) concentration-dependently increased CBS-mediated H2S production. The effect of SAM on cell proliferation (assessed real time for up to 24 h by xCELLigence) was time-dependent. SAM (0.1–3 mM) enhanced HCT116 cell proliferation at all concentrations tested in the first 12 h following treatment, but induced cell death/inhibition of proliferation thereafter (12–24 h). The short-term stimulatory effects of SAM were attenuated by stable CBS silencing. In contrast, the anti-proliferative effects of SAM were maintained in cells with CBS silencing. Short-term exposure of HCT116 cells to SAM (0.1–1 mM, 1 h) concentration-dependently increased the oxygen consumption and bioenergetic function of HCT116 cells, while longer-term exposures resulted in a suppression of these parameters at all concentrations of SAM tested. While the stimulatory effect of SAM on proliferation and Bioenergetics were attenuated in cells with stable CBS silencing, the inhibitory effects of SAM were largely unaffected by it. Thus, CBS in colon cancer cells produces H2S in a regulated fashion. H2S, when produced at low-to-intermediate levels, serves as an endogenous cancer cell growth and bioenergetic factor. While the short-term inhibition of cell proliferation by high concentrations of SAM may be partially related to “over-stimulation” of CBS, the long-term inhibitory effects of SAM on cell proliferation and Bioenergetics are mainly CBS-independent.
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intramitochondrial hydrogen sulfide production by 3 mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular Bioenergetics
The FASEB Journal, 2013Co-Authors: Katalin Modis, Ciro Coletta, Katalin Erdelyi, Andreas Papapetropoulos, Csaba SzaboAbstract:It is well established that exposure of mammalian cells to hydrogen sulfide (H(2)S) suppresses mitochondrial function by inhibiting cytochrome-c oxidase (CcOX; complex IV). However, recent experimental data show that administration of H(2)S to mammalian cells can serve as an electron donor and inorganic source of energy. The aim of our study was to investigate the role of endogenously produced H(2)S in the regulation of mitochondrial electron transport and oxidative phosphorylation in isolated liver mitochondria and in the cultured murine hepatoma cell line Hepa1c1c7. Low concentrations of H(2)S (0.1-1 μM) elicited a significant increase in mitochondrial function, while higher concentrations of H(2)S (3-30 μM) were inhibitory. The positive bioenergetic effect of H(2)S required a basal activity of the Krebs cycle and was most pronounced at intermediate concentrations of succinate. 3-mercaptopyruvate (3-MP), the substrate of the mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) stimulated mitochondrial H(2)S production and enhanced mitochondrial electron transport and cellular Bioenergetics at low concentrations (10-100 nM), while at higher concentrations, it inhibited cellular Bioenergetics. SiRNA silencing of 3-MST reduced basal bioenergetic parameters and prevented the stimulating effect of 3-MP on mitochondrial Bioenergetics. Silencing of sulfide quinone oxidoreductase (SQR) also reduced basal and 3-MP-stimulated bioenergetic parameters. We conclude that an endogenous intramitochondrial H(2)S-producing pathway, governed by 3-MST, complements and balances the bioenergetic role of Krebs cycle-derived electron donors. This pathway may serve a physiological role in the maintenance of mitochondrial electron transport and cellular Bioenergetics.