James Balschi - Profile on Academia.edu (original) (raw)
Papers by James Balschi
Abstract 9199: A Novel Small Molecule Troponin Activator Increases Cardiac Contractile Function Without Negative Impact on Energetics or Diastolic Function
Circulation, Nov 16, 2021
Biophysical Journal, Feb 1, 2009
Obesity has become a major public health concern and represents a predisposition factor for the d... more Obesity has become a major public health concern and represents a predisposition factor for the development of cardiovascular-related diseases and noninsulin dependent diabetes mellitus. Therefore, deciphering the molecular mechanisms of fatty acid (FA) uptake will provide new insights for dietary and other therapeutic interventions for managing diseases associated with obesity. FA uptake into cells occurs by multiple mechanisms, including transport and metabolism, beginning at the plasma membrane. Understanding the contri
NMR in Biomedicine, 1993
Triethylenetetraminehexaacetate complexes of Dy(III) or Tm (III) (DyTTHA 3m and TmTTHA3-, introdu... more Triethylenetetraminehexaacetate complexes of Dy(III) or Tm (III) (DyTTHA 3m and TmTTHA3-, introduced as NMR shift reagents for alkali metal cations, Chu et al., J. Magn. Reson. 56, 33 (1984)) bind to the four major biological inorganic cations: Na+, K+, Mg*+, and Ca*+. New 23Na and 39K NMR shift displacement data, obtained over wide and different ranges of concentration, were combined with the previous results (including some 25Mg data) for computer analysis. With a proper treatment of the relevant activity coefficients using Pitzer's formulas, it is established that only mono complexes of the shift reagent and1 a cation need be considered. The cations bind competitively, with nearly identical limiting shifts of 159 and 155 ppm for Na+ and K+; the shift for "Mg is 3/5 as large. The thermodynamic formation constants for M-LnTTHA are 11 and 18 M-' with Na+ and lK+ (enthalpy * Presented, in part, at the Joint Meeting,
Chemischer Informationsdienst, Sep 7, 1982
ChemInform Abstract Die Messungen an Na215N202-Lösungen zeigen für das Hyponitrit-Anion N203' ein... more ChemInform Abstract Die Messungen an Na215N202-Lösungen zeigen für das Hyponitrit-Anion N203' eine lsN-NMR-Resonanz bei 429 ppm. Diprotonierung unter Bildung von HgNgOg verursacht eine Verschiebung von ca. 8 ppm pro Proton. Die Daten sprechen für eine-Protonierung von NzOä ' im Gegensatz zur N-Protonierung von N203'. Die thermische Zersetzung von HN2O; und HN2O3 wird analysiert.
Magnetic Resonance in Medicine, May 1, 1996
Although Caz+ transport regulation at subcellular organelles is of great interest, only limited m... more Although Caz+ transport regulation at subcellular organelles is of great interest, only limited methodology has been available for measuring organellar [Ca2'] levels. The present study employs the ''F NMR resonance frequency of 4F-BAPTA to measure free [Ca"]. In 4F-BAPTA loaded perfused rabbit hearts, two ' ' F NMR resonances were clearly observed. The frequency of one was consistent with cytosolic [Ca2+] levels. Responses to agents that alter sarcoplasmic reticulum function identified the other resonance as originating from that organelle. The experiments demonstrate the utility of NMR shift indicator methodology in obtaining simultaneous multi-Compartment intracellular [Ca2+] measurements and in enabling organellar [Ca2+] measurements to be made from within intact living tissue.
Biophysical Journal, Nov 1, 1988
A limitation of magnetization transfer techniques for studying enzyme kinetics in vivo has been t... more A limitation of magnetization transfer techniques for studying enzyme kinetics in vivo has been the difficulty of treating systems with more than two exchanging species. This problem was addressed in the original papers describing saturation transfer. Since then, a number of approaches have been devised to study these complex situations. Here, we present a method based on the transient saturation transfer experiment in which spin-lattice relaxation time constants and reaction rates are obtained from the same magnetization transfer data. This technique is particularly suitable for biological samples. We apply the method to evaluate flux balance in the three-site linear exchange network composed of ATP, creatine phosphate, and inorganic phosphate in the isolated, perfused rat heart and show that the method yields reasonable values for the reaction velocities of ATP synthesis and degradation.
Biophysical Journal, Feb 1, 2009
SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy
Biomedicine & Pharmacotherapy, Apr 1, 2023
InTech eBooks, Nov 14, 2018
Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are... more Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are highly effective antidiabetic drugs that are widely used to treat type 2 diabetes mellitus (T2DM) due to their unique beneficial actions, such as a renoprotective effect, amelioration of glucose homeostasis, and blood pressure lowering, that other antidiabetic drugs do not have. Those beneficial actions, however, are shadowed by the increased risks of cardiovascular adverse events, including mitochondrial dysfunction, oxidative stress and myocardial energy deficiency, fluid retention, congestive heart failure, and myocardial infarction. Except PPARγ, TZDs also have affinity to numerous non-PPARγ targets in mitochondria, cytosol, and cytoplasm, including MitoNEET, mitochondrial pyruvate carrier, dehydrogenases involved in tricarboxylic acid cycle and electron transport, cytoplasmic ion channels, Na-K-pump, and other unknown enzymes. By binding to these targets, TZDs produce off-target effects and potentially increase cardiotoxicity. In this chapter, we review recent studies, both experimental and clinical, on the myocardial adverse effects associated with TZDs and their underlying mechanisms. We focus our review in large part on the relationship between these myocardial adverse effects and PPARγ.
Inorganic Chemistry, Aug 1, 1983
Triethylenetetraminehexaacetate complexes of Dy(III) or Tm (III) (DyTTHA 3m and TmTTHA3-, introdu... more Triethylenetetraminehexaacetate complexes of Dy(III) or Tm (III) (DyTTHA 3m and TmTTHA3-, introduced as NMR shift reagents for alkali metal cations, Chu et al., J. Magn. Reson. 56, 33 (1984)) bind to the four major biological inorganic cations: Na+, K+, Mg*+, and Ca*+. New 23Na and 39K NMR shift displacement data, obtained over wide and different ranges of concentration, were combined with the previous results (including some 25Mg data) for computer analysis. With a proper treatment of the relevant activity coefficients using Pitzer's formulas, it is established that only mono complexes of the shift reagent and1 a cation need be considered. The cations bind competitively, with nearly identical limiting shifts of 159 and 155 ppm for Na+ and K+; the shift for "Mg is 3/5 as large. The thermodynamic formation constants for M-LnTTHA are 11 and 18 M-' with Na+ and lK+ (enthalpy * Presented, in part, at the Joint Meeting,
Neuroscience Research Communications, Jul 1, 1999
The molecular conformations of dermorphin, Tyr'-D-Ala2-Phe3-Gly4-Tyr5-Pro6-Ser7-NH2, are derived ... more The molecular conformations of dermorphin, Tyr'-D-Ala2-Phe3-Gly4-Tyr5-Pro6-Ser7-NH2, are derived from FT-IR, Raman, CD, and 2D NMR spectroscopic studies in aqueous solution. Segawa et al. (1994,1995) have recently reported NMR studies of dermorphin in aqueous solution from which a folded conformation has been postulated. The folded conformation of dermorphin suggested by this study is characterized by a stacking of the aromatic side chains of Tyr' and Phe3. This appears to be critical to the pharmacological profile of dermorphin. The experimentally derived conformation bears partial resemblance to the low energy conformations predicted by molecular mechanics calculations. The proposed conformational model and its possible relevance to the p-agonist activity of dermorphin are discussed.
Intracellular Na+ Accumulation in Hypoxic vs Ischemic Rat-Heart - Evidence for Na+-H+ Exchange
Circulation, 1987
Accumulation of major organic osmolytes in rat renal inner medulla in dehydration
American Journal of Physiology-Renal Physiology, 1988
Osmotically active organic solutes, osmolytes, exist at high concentrations in the renal inner me... more Osmotically active organic solutes, osmolytes, exist at high concentrations in the renal inner medulla; however, their modulation during antidiuresis remains largely undefined. Renal osmolyte levels were measured by nuclear magnetic resonance spectroscopy and biochemical assays in perchloric acid extracts from normal and dehydrated (3 days) rats. Dehydration increased urine osmolality from 1,503 to 3,748 mosmol/kg and inner medullary urea content from 2,036 to 4,405 nmol/mg protein. In addition, inner medullary trimethylamines [glycerophosphorylcholine (GPC) and betaine] and polyhydric alcohols (inositol and sorbitol) significantly increased by 95 and 78%, respectively. Ninhydrin-positive substances (amino acids), although abundant, were unchanged. Renal cortex also contained GPC, betaine, and inositol but only inositol increased with dehydration. Analysis of correlations among inner medullary osmolytes showed that only GPC was consistently elevated by dehydration and was not direct...
Organic osmolytes in inner medulla of Brattleboro rat: effects of ADH and dehydration
American Journal of Physiology-Renal Physiology, 1989
Inner medullary methylamine [glycerophosphorylcholine (GPC) and glycine betaine (betaine)] and po... more Inner medullary methylamine [glycerophosphorylcholine (GPC) and glycine betaine (betaine)] and polyol [sorbitol and myo-inositol (inositol)] osmolytes were measured in water-restricted and antidiuretic hormone (ADH)-infused Brattleboro (DI) rats. Compared with DI rats allowed water ad libitum, rats dehydrated for 3 days had higher urinary osmolality (Uosmol) (812 vs. 239 mosmol/kgH2O) and plasma osmolality (Posmol) (333 vs. 296 mosmol/kgH2O). Dehydration reduced betaine content (36 vs. 66 nmol/mg protein) but had no significant effect on GPC, sorbitol, or inositol. In separate protocols, DI rats, allowed water ad libitum, were infused for either 3 or 12 days with either ADH in saline (+ADH) or saline alone (-ADH). Compared with -ADH controls, 3- or 12-day ADH-infused rats were antidiuretic (Uosmol, 1,000–1,300 mosmol/kgH2O) but not dehydrated (Posmol, 297-300 mosmol/kgH2O). Three days of ADH infusion caused an increase in GPC (340%), betaine (80%), and sorbitol (248%) but not in ino...
Neuroscience Research Communications, 1999
The molecular conformations of dermorphin, Tyr'-D-Ala2-Phe3-Gly4-Tyr5-Pro6-Ser7-NH2, are derived ... more The molecular conformations of dermorphin, Tyr'-D-Ala2-Phe3-Gly4-Tyr5-Pro6-Ser7-NH2, are derived from FT-IR, Raman, CD, and 2D NMR spectroscopic studies in aqueous solution. Segawa et al. (1994,1995) have recently reported NMR studies of dermorphin in aqueous solution from which a folded conformation has been postulated. The folded conformation of dermorphin suggested by this study is characterized by a stacking of the aromatic side chains of Tyr' and Phe3. This appears to be critical to the pharmacological profile of dermorphin. The experimentally derived conformation bears partial resemblance to the low energy conformations predicted by molecular mechanics calculations. The proposed conformational model and its possible relevance to the p-agonist activity of dermorphin are discussed.
Chemischer Informationsdienst, Nov 22, 1983
ChemInform Abstract A comparison of the paramagnetic shifts caused on the 7Li+ NMR resonance by t... more ChemInform Abstract A comparison of the paramagnetic shifts caused on the 7Li+ NMR resonance by the shift reagents (I)-(IV) is carried out under the same ionic conditions. Shift reagents are tested for their specificity for Li+ over the alkali and alkaline-earth metal cations. The shift reagents (Ia), (Ib), and (IIa) induce, in decreasing order, the largest Li+ shifts. Application of these three shift reagents to the study of Li+ transport in human red blood cells by 7Li+ NMR spectroscopy is briefly discussed.
Abstract 10678: Butyrate Improves Energetics, Diastolic Function and Contractile Reserve in Hearts from Mice with Hypertrophic Cardiomyopathy Due to Myosin R403Q Mutation
Circulation, 2021
Background: It is well established that hearts with hypertrophic cardiomyopathy (HCM) are energy ... more Background: It is well established that hearts with hypertrophic cardiomyopathy (HCM) are energy starved as reflected by a decreased phosphocreatine to ATP ratio that corresponds to increased ADP and decreased free energy of ATP hydrolysis (ΔG ~ATP ). Notably, worsened energetics precedes hypertrophy in development of HCM and mitochondrial mutations impeding ATP synthesis frequently lead to a hypertrophic phenotype similar to HCM. It remains unclear whether targeted strategies to boost mitochondrial ATP synthesis may improve chronically depressed diastolic function and contractile reserve. Here we hypothesize that saturating mitochondria with an accessible substrate, butyrate, acutely improves energetics and function in HCM. Methods and Results: Isolated hearts from 6 months old mice with HCM due to R403Q myosin mutation (R403Q) vs. the wild type littermates (WT) were studied using 31 P NMR spectroscopy to measure ATP synthesis, ADP and ΔG ~ATP at low (LW) and high workload (HW) and...
Méthode et appareil utilisant l'imagerie par résonance magnétique pour la détermination du phénotype et la surveillance de tissus
La presente invention concerne une technique d'imagerie par resonance magnetique (IRM) et eve... more La presente invention concerne une technique d'imagerie par resonance magnetique (IRM) et eventuellement un logiciel, collectivement designes sous le nom de modele de « vitesse d'obturation », permettant d'analyser des donnees d'image de patients atteints de cancer. Dans certains modes de realisation, l'invention porte sur une approche minimalement invasive, et neanmoins extremement precise, permettant de determiner si des tumeurs sont malignes ou benignes par distinction des caracteristiques de l'activite de reactif de contraste dans des tumeurs benignes et malignes. Des modes de realisation donnes a titre d'exemple portent sur des biomarqueurs mesures par IRM pour la determination et la surveillance de la malignite d'une tumeur, l'elimination efficace ou la limitation des faux positifs qui affectent les techniques d'IRM existantes, tout en ameliorant la determination du phenotype de tissus et la surveillance et la prevision d'interventio...
NMR in Biomedicine, 2020
Metabolic heart disease (MHD), which is strongly associated with heart failure with preserved eje... more Metabolic heart disease (MHD), which is strongly associated with heart failure with preserved ejection fraction (HFpEF), is characterized by reduced mitochondrial energy production and contractile performance. In this study, we tested the hypothesis that an acute increase in ATP synthesis, via short chain fatty acid (butyrate) perfusion, restores contractile function in MHD. Isolated hearts of mice with MHD due to consumption of a high fat high sucrose (HFHS) or on control diet (CD) for 4 months were studied using 31 P NMR spectroscopy to measure high energy phosphates and ATP synthesis rates during increased work demand. At baseline, HFHS hearts had increased ADP and decreased free energy of ATP hydrolysis (ΔG ~ATP ), though contractile function was similar between the two groups. At high work demand, the ATP synthesis rate in HFHS hearts was reduced by over 50%. Unlike CD hearts, HFHS hearts did not increase contractile function at high work demand, indicating a lack of contractile reserve. However, acutely supplementing HFHS hearts with 4mM butyrate normalized ATP synthesis, ADP, ΔG ~ATP , and contractile reserve. Thus, acute reversal of depressed mitochondrial ATP production improves contractile dysfunction in MHD. These findings suggest that energy starvation may be a reversible cause of myocardial dysfunction in MHD, and opens new therapeutic opportunities.
Antioxidants & Redox Signaling, 2019
Aims: Metabolic syndrome is associated with metabolic heart disease (MHD) that is characterized b... more Aims: Metabolic syndrome is associated with metabolic heart disease (MHD) that is characterized by left ventricular (LV) hypertrophy, interstitial fibrosis, contractile dysfunction, and mitochondrial dysfunction. Overexpression of catalase in mitochondria (transgenic expression of catalase targeted to the mitochondria [mCAT]) prevents the structural and functional features of MHD caused by a high-fat, high-sucrose (HFHS) diet for ‡4 months. However, it is unclear whether the effect of mCAT is due to prevention of reactive oxygen species (ROS)-mediated cardiac remodeling, a direct effect on mitochondrial function, or both. To address this question, we measured myocardial function and energetics in mice, with or without mCAT, after 1 month of HFHS, before the development of cardiac structural remodeling. Results: HFHS diet for 1 month had no effect on body weight, heart weight, LV structure, myocyte size, or interstitial fibrosis. Isolated cardiac mitochondria from HFHS-fed mice produced 2.2-to 3.8-fold more H 2 O 2 , and 16%-29% less adenosine triphosphate (ATP). In isolated beating hearts from HFHS-fed mice, [phosphocreatine (PCr)] and the free energy available for ATP hydrolysis (DG *ATP ) were decreased, and they failed to increase with work demands. Overexpression of mCAT normalized ROS and ATP production in isolated mitochondria, and it corrected myocardial [PCr] and DG *ATP in the beating heart. Innovation: This is the first demonstration that in MHD, mitochondrial ROS mediate energetic dysfunction that is sufficient to impair contractile function. Conclusion: ROS produced and acting in the mitochondria impair myocardial energetics, leading to slowed relaxation and decreased contractile reserve. These effects precede structural remodeling and are corrected by mCAT, indicating that ROS-mediated energetic impairment, per se, is sufficient to cause contractile dysfunction in MHD. Antioxid. Redox Signal. 31,[539][540][541][542][543][544][545][546][547][548][549]
Abstract 9199: A Novel Small Molecule Troponin Activator Increases Cardiac Contractile Function Without Negative Impact on Energetics or Diastolic Function
Circulation, Nov 16, 2021
Biophysical Journal, Feb 1, 2009
Obesity has become a major public health concern and represents a predisposition factor for the d... more Obesity has become a major public health concern and represents a predisposition factor for the development of cardiovascular-related diseases and noninsulin dependent diabetes mellitus. Therefore, deciphering the molecular mechanisms of fatty acid (FA) uptake will provide new insights for dietary and other therapeutic interventions for managing diseases associated with obesity. FA uptake into cells occurs by multiple mechanisms, including transport and metabolism, beginning at the plasma membrane. Understanding the contri
NMR in Biomedicine, 1993
Triethylenetetraminehexaacetate complexes of Dy(III) or Tm (III) (DyTTHA 3m and TmTTHA3-, introdu... more Triethylenetetraminehexaacetate complexes of Dy(III) or Tm (III) (DyTTHA 3m and TmTTHA3-, introduced as NMR shift reagents for alkali metal cations, Chu et al., J. Magn. Reson. 56, 33 (1984)) bind to the four major biological inorganic cations: Na+, K+, Mg*+, and Ca*+. New 23Na and 39K NMR shift displacement data, obtained over wide and different ranges of concentration, were combined with the previous results (including some 25Mg data) for computer analysis. With a proper treatment of the relevant activity coefficients using Pitzer's formulas, it is established that only mono complexes of the shift reagent and1 a cation need be considered. The cations bind competitively, with nearly identical limiting shifts of 159 and 155 ppm for Na+ and K+; the shift for "Mg is 3/5 as large. The thermodynamic formation constants for M-LnTTHA are 11 and 18 M-' with Na+ and lK+ (enthalpy * Presented, in part, at the Joint Meeting,
Chemischer Informationsdienst, Sep 7, 1982
ChemInform Abstract Die Messungen an Na215N202-Lösungen zeigen für das Hyponitrit-Anion N203' ein... more ChemInform Abstract Die Messungen an Na215N202-Lösungen zeigen für das Hyponitrit-Anion N203' eine lsN-NMR-Resonanz bei 429 ppm. Diprotonierung unter Bildung von HgNgOg verursacht eine Verschiebung von ca. 8 ppm pro Proton. Die Daten sprechen für eine-Protonierung von NzOä ' im Gegensatz zur N-Protonierung von N203'. Die thermische Zersetzung von HN2O; und HN2O3 wird analysiert.
Magnetic Resonance in Medicine, May 1, 1996
Although Caz+ transport regulation at subcellular organelles is of great interest, only limited m... more Although Caz+ transport regulation at subcellular organelles is of great interest, only limited methodology has been available for measuring organellar [Ca2'] levels. The present study employs the ''F NMR resonance frequency of 4F-BAPTA to measure free [Ca"]. In 4F-BAPTA loaded perfused rabbit hearts, two ' ' F NMR resonances were clearly observed. The frequency of one was consistent with cytosolic [Ca2+] levels. Responses to agents that alter sarcoplasmic reticulum function identified the other resonance as originating from that organelle. The experiments demonstrate the utility of NMR shift indicator methodology in obtaining simultaneous multi-Compartment intracellular [Ca2+] measurements and in enabling organellar [Ca2+] measurements to be made from within intact living tissue.
Biophysical Journal, Nov 1, 1988
A limitation of magnetization transfer techniques for studying enzyme kinetics in vivo has been t... more A limitation of magnetization transfer techniques for studying enzyme kinetics in vivo has been the difficulty of treating systems with more than two exchanging species. This problem was addressed in the original papers describing saturation transfer. Since then, a number of approaches have been devised to study these complex situations. Here, we present a method based on the transient saturation transfer experiment in which spin-lattice relaxation time constants and reaction rates are obtained from the same magnetization transfer data. This technique is particularly suitable for biological samples. We apply the method to evaluate flux balance in the three-site linear exchange network composed of ATP, creatine phosphate, and inorganic phosphate in the isolated, perfused rat heart and show that the method yields reasonable values for the reaction velocities of ATP synthesis and degradation.
Biophysical Journal, Feb 1, 2009
SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy
Biomedicine & Pharmacotherapy, Apr 1, 2023
InTech eBooks, Nov 14, 2018
Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are... more Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are highly effective antidiabetic drugs that are widely used to treat type 2 diabetes mellitus (T2DM) due to their unique beneficial actions, such as a renoprotective effect, amelioration of glucose homeostasis, and blood pressure lowering, that other antidiabetic drugs do not have. Those beneficial actions, however, are shadowed by the increased risks of cardiovascular adverse events, including mitochondrial dysfunction, oxidative stress and myocardial energy deficiency, fluid retention, congestive heart failure, and myocardial infarction. Except PPARγ, TZDs also have affinity to numerous non-PPARγ targets in mitochondria, cytosol, and cytoplasm, including MitoNEET, mitochondrial pyruvate carrier, dehydrogenases involved in tricarboxylic acid cycle and electron transport, cytoplasmic ion channels, Na-K-pump, and other unknown enzymes. By binding to these targets, TZDs produce off-target effects and potentially increase cardiotoxicity. In this chapter, we review recent studies, both experimental and clinical, on the myocardial adverse effects associated with TZDs and their underlying mechanisms. We focus our review in large part on the relationship between these myocardial adverse effects and PPARγ.
Inorganic Chemistry, Aug 1, 1983
Triethylenetetraminehexaacetate complexes of Dy(III) or Tm (III) (DyTTHA 3m and TmTTHA3-, introdu... more Triethylenetetraminehexaacetate complexes of Dy(III) or Tm (III) (DyTTHA 3m and TmTTHA3-, introduced as NMR shift reagents for alkali metal cations, Chu et al., J. Magn. Reson. 56, 33 (1984)) bind to the four major biological inorganic cations: Na+, K+, Mg*+, and Ca*+. New 23Na and 39K NMR shift displacement data, obtained over wide and different ranges of concentration, were combined with the previous results (including some 25Mg data) for computer analysis. With a proper treatment of the relevant activity coefficients using Pitzer's formulas, it is established that only mono complexes of the shift reagent and1 a cation need be considered. The cations bind competitively, with nearly identical limiting shifts of 159 and 155 ppm for Na+ and K+; the shift for "Mg is 3/5 as large. The thermodynamic formation constants for M-LnTTHA are 11 and 18 M-' with Na+ and lK+ (enthalpy * Presented, in part, at the Joint Meeting,
Neuroscience Research Communications, Jul 1, 1999
The molecular conformations of dermorphin, Tyr'-D-Ala2-Phe3-Gly4-Tyr5-Pro6-Ser7-NH2, are derived ... more The molecular conformations of dermorphin, Tyr'-D-Ala2-Phe3-Gly4-Tyr5-Pro6-Ser7-NH2, are derived from FT-IR, Raman, CD, and 2D NMR spectroscopic studies in aqueous solution. Segawa et al. (1994,1995) have recently reported NMR studies of dermorphin in aqueous solution from which a folded conformation has been postulated. The folded conformation of dermorphin suggested by this study is characterized by a stacking of the aromatic side chains of Tyr' and Phe3. This appears to be critical to the pharmacological profile of dermorphin. The experimentally derived conformation bears partial resemblance to the low energy conformations predicted by molecular mechanics calculations. The proposed conformational model and its possible relevance to the p-agonist activity of dermorphin are discussed.
Intracellular Na+ Accumulation in Hypoxic vs Ischemic Rat-Heart - Evidence for Na+-H+ Exchange
Circulation, 1987
Accumulation of major organic osmolytes in rat renal inner medulla in dehydration
American Journal of Physiology-Renal Physiology, 1988
Osmotically active organic solutes, osmolytes, exist at high concentrations in the renal inner me... more Osmotically active organic solutes, osmolytes, exist at high concentrations in the renal inner medulla; however, their modulation during antidiuresis remains largely undefined. Renal osmolyte levels were measured by nuclear magnetic resonance spectroscopy and biochemical assays in perchloric acid extracts from normal and dehydrated (3 days) rats. Dehydration increased urine osmolality from 1,503 to 3,748 mosmol/kg and inner medullary urea content from 2,036 to 4,405 nmol/mg protein. In addition, inner medullary trimethylamines [glycerophosphorylcholine (GPC) and betaine] and polyhydric alcohols (inositol and sorbitol) significantly increased by 95 and 78%, respectively. Ninhydrin-positive substances (amino acids), although abundant, were unchanged. Renal cortex also contained GPC, betaine, and inositol but only inositol increased with dehydration. Analysis of correlations among inner medullary osmolytes showed that only GPC was consistently elevated by dehydration and was not direct...
Organic osmolytes in inner medulla of Brattleboro rat: effects of ADH and dehydration
American Journal of Physiology-Renal Physiology, 1989
Inner medullary methylamine [glycerophosphorylcholine (GPC) and glycine betaine (betaine)] and po... more Inner medullary methylamine [glycerophosphorylcholine (GPC) and glycine betaine (betaine)] and polyol [sorbitol and myo-inositol (inositol)] osmolytes were measured in water-restricted and antidiuretic hormone (ADH)-infused Brattleboro (DI) rats. Compared with DI rats allowed water ad libitum, rats dehydrated for 3 days had higher urinary osmolality (Uosmol) (812 vs. 239 mosmol/kgH2O) and plasma osmolality (Posmol) (333 vs. 296 mosmol/kgH2O). Dehydration reduced betaine content (36 vs. 66 nmol/mg protein) but had no significant effect on GPC, sorbitol, or inositol. In separate protocols, DI rats, allowed water ad libitum, were infused for either 3 or 12 days with either ADH in saline (+ADH) or saline alone (-ADH). Compared with -ADH controls, 3- or 12-day ADH-infused rats were antidiuretic (Uosmol, 1,000–1,300 mosmol/kgH2O) but not dehydrated (Posmol, 297-300 mosmol/kgH2O). Three days of ADH infusion caused an increase in GPC (340%), betaine (80%), and sorbitol (248%) but not in ino...
Neuroscience Research Communications, 1999
The molecular conformations of dermorphin, Tyr'-D-Ala2-Phe3-Gly4-Tyr5-Pro6-Ser7-NH2, are derived ... more The molecular conformations of dermorphin, Tyr'-D-Ala2-Phe3-Gly4-Tyr5-Pro6-Ser7-NH2, are derived from FT-IR, Raman, CD, and 2D NMR spectroscopic studies in aqueous solution. Segawa et al. (1994,1995) have recently reported NMR studies of dermorphin in aqueous solution from which a folded conformation has been postulated. The folded conformation of dermorphin suggested by this study is characterized by a stacking of the aromatic side chains of Tyr' and Phe3. This appears to be critical to the pharmacological profile of dermorphin. The experimentally derived conformation bears partial resemblance to the low energy conformations predicted by molecular mechanics calculations. The proposed conformational model and its possible relevance to the p-agonist activity of dermorphin are discussed.
Chemischer Informationsdienst, Nov 22, 1983
ChemInform Abstract A comparison of the paramagnetic shifts caused on the 7Li+ NMR resonance by t... more ChemInform Abstract A comparison of the paramagnetic shifts caused on the 7Li+ NMR resonance by the shift reagents (I)-(IV) is carried out under the same ionic conditions. Shift reagents are tested for their specificity for Li+ over the alkali and alkaline-earth metal cations. The shift reagents (Ia), (Ib), and (IIa) induce, in decreasing order, the largest Li+ shifts. Application of these three shift reagents to the study of Li+ transport in human red blood cells by 7Li+ NMR spectroscopy is briefly discussed.
Abstract 10678: Butyrate Improves Energetics, Diastolic Function and Contractile Reserve in Hearts from Mice with Hypertrophic Cardiomyopathy Due to Myosin R403Q Mutation
Circulation, 2021
Background: It is well established that hearts with hypertrophic cardiomyopathy (HCM) are energy ... more Background: It is well established that hearts with hypertrophic cardiomyopathy (HCM) are energy starved as reflected by a decreased phosphocreatine to ATP ratio that corresponds to increased ADP and decreased free energy of ATP hydrolysis (ΔG ~ATP ). Notably, worsened energetics precedes hypertrophy in development of HCM and mitochondrial mutations impeding ATP synthesis frequently lead to a hypertrophic phenotype similar to HCM. It remains unclear whether targeted strategies to boost mitochondrial ATP synthesis may improve chronically depressed diastolic function and contractile reserve. Here we hypothesize that saturating mitochondria with an accessible substrate, butyrate, acutely improves energetics and function in HCM. Methods and Results: Isolated hearts from 6 months old mice with HCM due to R403Q myosin mutation (R403Q) vs. the wild type littermates (WT) were studied using 31 P NMR spectroscopy to measure ATP synthesis, ADP and ΔG ~ATP at low (LW) and high workload (HW) and...
Méthode et appareil utilisant l'imagerie par résonance magnétique pour la détermination du phénotype et la surveillance de tissus
La presente invention concerne une technique d'imagerie par resonance magnetique (IRM) et eve... more La presente invention concerne une technique d'imagerie par resonance magnetique (IRM) et eventuellement un logiciel, collectivement designes sous le nom de modele de « vitesse d'obturation », permettant d'analyser des donnees d'image de patients atteints de cancer. Dans certains modes de realisation, l'invention porte sur une approche minimalement invasive, et neanmoins extremement precise, permettant de determiner si des tumeurs sont malignes ou benignes par distinction des caracteristiques de l'activite de reactif de contraste dans des tumeurs benignes et malignes. Des modes de realisation donnes a titre d'exemple portent sur des biomarqueurs mesures par IRM pour la determination et la surveillance de la malignite d'une tumeur, l'elimination efficace ou la limitation des faux positifs qui affectent les techniques d'IRM existantes, tout en ameliorant la determination du phenotype de tissus et la surveillance et la prevision d'interventio...
NMR in Biomedicine, 2020
Metabolic heart disease (MHD), which is strongly associated with heart failure with preserved eje... more Metabolic heart disease (MHD), which is strongly associated with heart failure with preserved ejection fraction (HFpEF), is characterized by reduced mitochondrial energy production and contractile performance. In this study, we tested the hypothesis that an acute increase in ATP synthesis, via short chain fatty acid (butyrate) perfusion, restores contractile function in MHD. Isolated hearts of mice with MHD due to consumption of a high fat high sucrose (HFHS) or on control diet (CD) for 4 months were studied using 31 P NMR spectroscopy to measure high energy phosphates and ATP synthesis rates during increased work demand. At baseline, HFHS hearts had increased ADP and decreased free energy of ATP hydrolysis (ΔG ~ATP ), though contractile function was similar between the two groups. At high work demand, the ATP synthesis rate in HFHS hearts was reduced by over 50%. Unlike CD hearts, HFHS hearts did not increase contractile function at high work demand, indicating a lack of contractile reserve. However, acutely supplementing HFHS hearts with 4mM butyrate normalized ATP synthesis, ADP, ΔG ~ATP , and contractile reserve. Thus, acute reversal of depressed mitochondrial ATP production improves contractile dysfunction in MHD. These findings suggest that energy starvation may be a reversible cause of myocardial dysfunction in MHD, and opens new therapeutic opportunities.
Antioxidants & Redox Signaling, 2019
Aims: Metabolic syndrome is associated with metabolic heart disease (MHD) that is characterized b... more Aims: Metabolic syndrome is associated with metabolic heart disease (MHD) that is characterized by left ventricular (LV) hypertrophy, interstitial fibrosis, contractile dysfunction, and mitochondrial dysfunction. Overexpression of catalase in mitochondria (transgenic expression of catalase targeted to the mitochondria [mCAT]) prevents the structural and functional features of MHD caused by a high-fat, high-sucrose (HFHS) diet for ‡4 months. However, it is unclear whether the effect of mCAT is due to prevention of reactive oxygen species (ROS)-mediated cardiac remodeling, a direct effect on mitochondrial function, or both. To address this question, we measured myocardial function and energetics in mice, with or without mCAT, after 1 month of HFHS, before the development of cardiac structural remodeling. Results: HFHS diet for 1 month had no effect on body weight, heart weight, LV structure, myocyte size, or interstitial fibrosis. Isolated cardiac mitochondria from HFHS-fed mice produced 2.2-to 3.8-fold more H 2 O 2 , and 16%-29% less adenosine triphosphate (ATP). In isolated beating hearts from HFHS-fed mice, [phosphocreatine (PCr)] and the free energy available for ATP hydrolysis (DG *ATP ) were decreased, and they failed to increase with work demands. Overexpression of mCAT normalized ROS and ATP production in isolated mitochondria, and it corrected myocardial [PCr] and DG *ATP in the beating heart. Innovation: This is the first demonstration that in MHD, mitochondrial ROS mediate energetic dysfunction that is sufficient to impair contractile function. Conclusion: ROS produced and acting in the mitochondria impair myocardial energetics, leading to slowed relaxation and decreased contractile reserve. These effects precede structural remodeling and are corrected by mCAT, indicating that ROS-mediated energetic impairment, per se, is sufficient to cause contractile dysfunction in MHD. Antioxid. Redox Signal. 31,[539][540][541][542][543][544][545][546][547][548][549]