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1.
Glob Health Epidemiol Genom ; 2024: 9293896, 2024.
Article in English | MEDLINE | ID: mdl-38410281

ABSTRACT

Fabry disease (FD) is a multisystem lysosomal storage disorder induced by genetic variants in the alpha-galactosidase A (αGalA) gene. Some FD patients have GLA variants with a reduction in overall αGalA enzymatic activity due to mutated proteins with reduced stability, caused by protein misfolding and premature degradation, but the αGalA catalytic activity remains conserved ("amenable" genetic variants). To correct this misfolding and to prevent premature degradation, migalastat, a small iminosugar molecule was developed. We report the clinical characteristics of FD "amenable" cohort patients from Argentina, prior to starting treatment with migalastat. Seventeen Fabry adult patients were recruited from 13 Argentinian Centers; 8 males (47.1%) and 9 females (52.9%) were included. All genotypes included were missense-type "amenables" mutations. Some classic FD typical early manifestations were more frequent in patients with "classic" versus "late-onset" FD phenotype (pain, p=0.002; cornea verticillata, p=0.019). There was a statistically significant difference in estimated glomerular filtration rate in the "classic" versus "late-onset" phenotype (p=0.026) but no difference between genders (p=0.695). Left ventricular mass was similar between genders (p=0.145) and phenotypes (p=0.303). Cardiovascular risk factors were present among "late-onset" females (obesity 50% and smoke 25%). In patients who started "de novo" migalastat, the main indications were (i) heart disease, (ii) kidney damage, and (iii) pain, while in "switched from prior enzyme replacement therapy" patients, the most frequent indication was "patient decision;" this coincides with publications by other authors.


Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Fabry Disease , Adult , Humans , Male , Female , Fabry Disease/epidemiology , Fabry Disease/genetics , Fabry Disease/drug therapy , 1-Deoxynojirimycin/therapeutic use , alpha-Galactosidase/genetics , alpha-Galactosidase/metabolism , alpha-Galactosidase/therapeutic use , Pain/chemically induced , Pain/drug therapy
2.
Braz J Microbiol ; 54(2): 1083-1091, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36972016

ABSTRACT

Cancer is a leading cause of death worldwide, reporting nearly 10 million deaths in 2020. One of the hallmarks of cancer cells is their capability to evade growth suppressors and sustain proliferative signaling resulting in uncontrolled growth. The AMPK pathway, a catabolic via to economize ATP, has been associated with cancer. AMPK activation is related to cancer progression in advanced stages, while its activation by metformin or phenformin is associated with cancer chemoprevention. Thus, the role of the AMPK pathway in cancer growth modulation is not clear. Saccharomyces cerevisiae might be a useful model to elucidate AMPK participation in growth regulation since it shares a highly conserved AMPK pathway. Therefore, this work is aimed at evaluating the role of the AMPK pathway on S. cerevisiae growth under different nutritional conditions. Herein, we provide evidence that the SNF1 gene is necessary to maintain S. cerevisiae growth with glucose as a sole carbon source at every concentration tested. Resveratrol supplementation inhibited the exponential growth of snf1∆ strain at low glucose levels and decreased it at high glucose levels. SNF1 gene deletion impaired exponential growth in a carbohydrate concentration-dependent manner independently of nitrogen source or concentration. Interestingly, deletion of genes encoding for upstream kinases (SAK1, ELM1, and TOS3) also had a glucose dose-dependent effect upon exponential growth. Furthermore, gene deletion of regulatory subunits of the AMPK complex impacted exponential growth in a glucose-dependent manner. Altogether, these results suggest that the SNF1 pathway affects the exponential growth of S. cerevisiae in a glucose-dependent manner.


Subject(s)
Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolism , Protein Serine-Threonine Kinases/genetics , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Carbon/metabolism , Nitrogen/metabolism , Signal Transduction/physiology , Glucose/metabolism , Protein Kinases/genetics
3.
J Food Biochem ; 43(9): e13008, 2019 09.
Article in English | MEDLINE | ID: mdl-31385323

ABSTRACT

Resveratrol is a phytochemical that may promote health. However, it has also been reported to be a toxic compound. The molecular mechanism by which resveratrol acts remains unclear. The inhibition of the oxidative phosphorylation (OXPHOS) pathway appears to be the molecular mechanism of resveratrol. Taking this into account, we propose that the cytotoxic properties of resveratrol depend on the energy (e.g., carbohydrates, lipids, and proteins) availability in the cells. In this regard, in a condition with low energy accessibility, resveratrol could enhance ATP starvation to lethal levels. In contrast, when cells are supplemented with high quantities of energy and resveratrol, the inhibition of OXPHOS might produce a low-energy environment, mimicking the beneficial effects of caloric restriction. This review suggests that investigating a possible complex relationship between caloric intake and the differential effects of resveratrol on OXPHOS may be justified. PRACTICAL APPLICATIONS: A low-calorie diet accompanied by significant levels of resveratrol might modify cellular bioenergetics, which could impact cellular viability and enhance the anti-cancer properties of resveratrol.


Subject(s)
Energy Intake/physiology , Resveratrol/toxicity , Adenosine Triphosphate/metabolism , Animals , Cell Survival/drug effects , Homeostasis/drug effects , Homeostasis/physiology , Humans , Oxidative Phosphorylation/drug effects
4.
Yeast ; 36(8): 487-494, 2019 08.
Article in English | MEDLINE | ID: mdl-31074533

ABSTRACT

The switch between mitochondrial respiration and fermentation as the main ATP production pathway through an increase glycolytic flux is known as the Crabtree effect. The elucidation of the molecular mechanism of the Crabtree effect may have important applications in ethanol production and lay the groundwork for the Warburg effect, which is essential in the molecular etiology of cancer. A key piece in this mechanism could be Snf1p, which is a protein that participates in the nutritional response including glucose metabolism. Thus, this work aimed to recognize the role of the SNF1 gene on the glycolytic flux and mitochondrial respiration through the glucose concentration variation to gain insights about its relationship with the Crabtree effect. Herein, we found that SNF1 deletion in Saccharomyces cerevisiae cells grown at 1% glucose, decreased glycolytic flux, increased NAD(P)H concentration, enhanced HXK2 gene transcription, and decreased mitochondrial respiration. Meanwhile, the same deletion increased the mitochondrial respiration of cells grown at 10% glucose. Altogether, these findings indicate that SNF1 is important to respond to glucose concentration variation and is involved in the switch between mitochondrial respiration and fermentation.


Subject(s)
Glucose/metabolism , Mitochondria/metabolism , Protein Serine-Threonine Kinases/metabolism , Saccharomyces cerevisiae/metabolism , Fermentation , Glucose/analysis , Glycolysis , Hexokinase/genetics , NAD/metabolism , Protein Serine-Threonine Kinases/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Sequence Deletion , Transcription, Genetic
5.
Appl Microbiol Biotechnol ; 102(10): 4535-4548, 2018 May.
Article in English | MEDLINE | ID: mdl-29602984

ABSTRACT

Nutritional homeostasis is fundamental for alcoholic fermentation in Saccharomyces cerevisiae. Carbon and nitrogen have been related to this metabolic process; nevertheless, little is known about their interactions with the media and the energetic metabolism. Rim15p kinase is a point of convergence among different nutrient-activated signaling pathways; this makes it a target to investigate the relationship between nutritional status and energetic metabolism. To improve the current knowledge of nutrient interactions and their association with RIM15, we validated the doubling time as an indicator of growth phenotype, confirming that this kinetic parameter can be related to the cellular bioenergetic status. This endorses the usefulness of a threshold in doubling time values as an indicator of fermentative (≤ 6.5 h) and respiratory growth (≥ 13.2 h). Using the doubling time as response variable, we find that (i) two second-order interactions between type and concentration of carbon and nitrogen sources significantly affected the growth phenotype of S. cerevisiae; (ii) these metabolic interactions changed when RIM15 was deleted, suggesting a dependence on this gene; (iii) high concentration of ammonium (5% w/v) is toxic for S. cerevisiae cells; (iv) proline prompted fermentative growth phenotype regardless presence or absence of RIM15; (v) RIM15 deletion reverted ammonium toxicity when cells were grown in glucose (10% w/v); and (vi) RIM15 deletion improves fermentative metabolism probably by a partial inhibition of the respiration capacity. This study reveals the existence of synergic and diverse roles of carbon and nitrogen sources that are affected by RIM15, influencing the fermentative and respiratory growth of S. cerevisiae.


Subject(s)
Carbon/metabolism , Nitrogen/metabolism , Protein Kinases/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/physiology , Fermentation , Glucose/metabolism , Saccharomyces cerevisiae/growth & development
6.
J Bioenerg Biomembr ; 49(3): 241-251, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28401438

ABSTRACT

A broad range of health benefits have been attributed to resveratrol (RSV) supplementation in mammalian systems, including the increases in longevity. Nonetheless, despite the growing number of studies performed with RSV, the molecular mechanism by which it acts still remains unknown. Recently, it has been proposed that inhibition of the oxidative phosphorylation activity is the principal mechanism of RSV action. This mechanism suggests that RSV might induce mitochondrial dysfunction resulting in oxidative damage to cells with a concomitant decrease of cell viability and cellular life span. To prove this hypothesis, the chronological life span (CLS) of Saccharomyces cerevisiae was studied as it is accepted as an important model of oxidative damage and aging. In addition, oxygen consumption, mitochondrial membrane potential, and hydrogen peroxide (H2O2) release were measured in order to determine the extent of mitochondrial dysfunction. The results demonstrated that the supplementation of S. cerevisiae cultures with 100 µM RSV decreased CLS in a glucose-dependent manner. At high-level glucose, RSV supplementation increased oxygen consumption during the exponential phase yeast cultures, but inhibited it in chronologically aged yeast cultures. However, at low-level glucose, oxygen consumption was inhibited in yeast cultures in the exponential phase as well as in chronologically aged cultures. Furthermore, RSV supplementation promoted the polarization of the mitochondrial membrane in both cultures. Finally, RSV decreased the release of H2O2 with high-level glucose and increased it at low-level glucose. Altogether, this data supports the hypothesis that RSV supplementation decreases CLS as a result of mitochondrial dysfunction and this phenotype occurs in a glucose-dependent manner.


Subject(s)
Longevity/drug effects , Mitochondria/drug effects , Saccharomyces cerevisiae/cytology , Stilbenes/pharmacology , Antioxidants/pharmacology , Glucose/pharmacology , Hydrogen Peroxide/metabolism , Oxidative Phosphorylation/drug effects , Oxygen Consumption , Resveratrol , Saccharomyces cerevisiae/drug effects
7.
Rev. nefrol. diál. traspl ; Rev. nefrol. diál. traspl. (En línea);35(1): 15-23, ene. 2015. ilus, tab
Article in Spanish | LILACS | ID: biblio-908365

ABSTRACT

Introducción: el hiperparatiroidismo secundarioes una complicación frecuente de laenfermedad renal crónica. Cinacalcet, un moduladoralostérico del receptor sensor del calcio incrementasu sensibilidad a la activación por partedel calcio iónico extracelular, demostró ser efectivoen reducir los niveles de PTH. Objetivo:Evaluar la eficacia de cinacalcet en pacientes enhemodiálisis con HPTS. Material y métodos: Se realizó un estudio retrospectivo, multicéntrico, observacional, en 76 pacientes que recibieronal menos 3 meses de cinacalcet como tratamientodel HPTS...


Introduction: secondary Hyperparathyroidism is a frequent chronic renal disease complication. Cinacalcet, an allosteric modulator of the calcium sensing receptor, increases its sensitivity to activation by extracellular calcium ions, proved to be effective in reducing PTH levels. Objetive: To evaluate cinacalcet effectiveness in hemodialysis patients with HPTS. Methods: A retrospective, multicenter, observational study was carried out, on 76 patients who received Cinacalcet for at least 3 months, as a treatment for HPTS...


Subject(s)
Male , Female , Humans , Calcium Metabolism Disorders , Drug Therapy , Hyperparathyroidism, Secondary , Hyperparathyroidism, Secondary/therapy , Renal Insufficiency, Chronic , Renal Insufficiency, Chronic/therapy , Therapeutics , Argentina , Renal Dialysis
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