RESUMEN
The purpose of this study was to verify the association between angiotensin-converting enzyme (ACE) genotypes DD, DI, and II and caffeine (CAF) ingestion on endurance performance, heart rate, ratio of perceived exertion (RPE), and habitual caffeine intake (HCI) of adolescent athletes. Seventy-four male adolescent athletes (age: DD=16±1.7; DI=16±2.0; II=15±1.7 years) ingested CAF (6 mg/kg) or placebo (PLA) one hour before performing the Yo-Yo Intermittent Recovery level 1 (Yo-Yo IR1) test. No difference was found among groups for HCI. However, CAF increased the maximal distance covered and VO2max in DI and II genotype carriers compared to PLA (DD: Δ=31 m and 0.3 mL·kg-1·min-1; DI: Δ=286 m and 1.1 mL·kg-1·min-1; II: Δ=160 m and 1.4 mL·kg-1·min-1). Heart rate of DI and II genotype carriers increased with CAF compared to PLA, while RPE was higher in the II and lower in the DD genotypes. The correlations between HCI and maximal distance covered or VO2max were significant in the II genotype carriers with CAF. CAF increased endurance capacity, heart rate, and RPE in adolescent athletes with allele I, while endurance performance and aerobic power had a positive correlation to HCI in the II genotype group. These findings suggested that DD genotype were less responsive to CAF and that genetic variations should be taken into account when using CAF supplementation to enhance exercise performance.
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Atletas , Cafeína , Genotipo , Frecuencia Cardíaca , Peptidil-Dipeptidasa A , Esfuerzo Físico , Humanos , Adolescente , Masculino , Frecuencia Cardíaca/efectos de los fármacos , Cafeína/administración & dosificación , Esfuerzo Físico/fisiología , Peptidil-Dipeptidasa A/genética , Rendimiento Atlético/fisiología , Resistencia Física/efectos de los fármacos , Resistencia Física/genética , Polimorfismo Genético/genética , Brasil , Consumo de Oxígeno/genética , Consumo de Oxígeno/efectos de los fármacos , Sustancias para Mejorar el Rendimiento/administración & dosificaciónRESUMEN
AIMS: Ischaemic heart disease remains a significant cause of mortality globally. A pharmacological agent that protects cardiac mitochondria against oxygen deprivation injuries is welcome in therapy against acute myocardial infarction. Here, we evaluate the effect of large-conductance Ca2+-activated K+ channels (BKCa) activator, Compound Z, in isolated mitochondria under hypoxia and reoxygenation. METHODS: Mitochondria from mice hearts were obtained by differential centrifugation. The isolated mitochondria were incubated with a BKCa channel activator, Compound Z, and subjected to normoxia or hypoxia/reoxygenation. Mitochondrial function was evaluated by measurement of O2 consumption in the complexes I, II, and IV in the respiratory states 1, 2, 3, and by maximal uncoupled O2 uptake, ATP production, ROS production, transmembrane potential, and calcium retention capacity. RESULTS: Incubation of isolated mitochondria with Compound Z under normoxia conditions reduced the mitochondrial functions and induced the production of a significant amount of ROS. However, under hypoxia/reoxygenation, the Compound Z prevented a profound reduction in mitochondrial functions, including reducing ROS production over the hypoxia/reoxygenation group. Furthermore, hypoxia/reoxygenation induced a large mitochondria depolarization, which Compound Z incubation prevented, but, even so, Compound Z created a small depolarization. The mitochondrial calcium uptake was prevented by the BKCa activator, extruding the mitochondrial calcium present before Compound Z incubation. CONCLUSION: The Compound Z acts as a mitochondrial BKCa channel activator and can protect mitochondria function against hypoxia/reoxygenation injury, by handling mitochondrial calcium and transmembrane potential.
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Calcio , Mitocondrias Cardíacas , Animales , Ratones , Calcio/metabolismo , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Masculino , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos C57BL , Hipoxia/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Oxígeno/metabolismoRESUMEN
The hemodynamic behavior of the elderly patient can be compromised during the intraoperative period by decreasing cardiac output, both in response to the physiological wear and tear of age, and because of anesthetic agents. The objective of the pre- sent study was to identify the usefulness of dobutamine to increase cardiac output and sustain systemic oxygenation during the perioperative period in the elderly surgical patient. MATERIAL AND METHOD: A descriptive study Case Series was carried out in surgical elderly patients, during the perioperative phase, to whom dobutamine was administered to 2 gammas. The variables of cardiac output and systemic oxygenation were analyzed in four phases, using repeated measures ANOVA and/or Friedman Analy- sis (p < 0.05). And in two phases using Paired T and/or Wilcoxon Marked Ranges (p < 0.05). RESULTS: A total of 18 patients were studied, who met the exclusion criteria, considered as ASA III, with an age of X = 81.9 years ± SD 8.23. An increase in cardiac output and oxygen availability was observed, in supra-optimal values, with statistically significant differences (p = 0.001; and p = 0.001 respectively). Systemic Vascular Resistances had a decreasing behavior during the intraoperative phase, with statistically significant differences (p = 0.001). The heart rate remained constant, despite presenting statistically significant differences (p = 0.027). CONCLUSIONS: The administration of dobutamine at a rate of 2 gammas is useful in favoring cardiac output and systemic oxygenation throughout the perioperative period in elderly patients.
El comportamiento hemodinámico del paciente anciano se puede comprometer durante el transoperatorio al disminuir el gasto cardiaco, tanto como respuesta al desgaste fisiológico de la edad, como por el efecto de los agentes anestésicos. El objetivo del presente estudio, fue identificar la utilidad de la dobutamina para incrementar el gasto cardiaco y sostener la oxigenación sistémica durante el perioperatorio, en el paciente anciano quirúrgico. MATERIAL Y MÉTODO: Se realizó un estudio descriptivo -Serie de Casos-, en pacientes ancianos quirúrgicos, durante la fase del perioperatorio, a los cuales se les administró dobutamina a 2 gammas. Se analizaron las variables del gasto cardiaco y la oxigenación sistémica en cuatro fases, mediante ANOVA de medidas repetidas y/o análisis de Friedman (p < 0,05). Y en dos fases mediante T Pareada y/o Rangos Señalados de Wilcoxon (p < 0,05).RESULTADOS: Se estudiaron un total de 18 pacientes, que cubrieron los criterios de exclusión, considerados como ASA III, con una edad de X = 81,9 años ± DE 8.23. Se observó un incremento en el gasto cardiaco y en la disponibilidad de oxígeno, en valores supraóptimos, con diferencias estadísticamente significativas (p = 0,001; y p = 0,001 respectivamente). Las Resistencias Vasculares Sistémicas tuvieron un comportamiento de descenso durante la fase del transoperatorio, con diferencias estadísticamente significativas (p = 0,001). La frecuencia cardiaca se mantuvo constante, a pesar de presentar diferencias estadísticamente significativas (p = 0,027). CONCLUSIONES: La administración de dobutamina a razón de 2 gammas reporta utilidad al favorecer el gasto cardiaco y la oxigenación sistémica, durante todo el perioperatorio en el paciente anciano.
Asunto(s)
Humanos , Masculino , Femenino , Anciano , Anciano de 80 o más Años , Consumo de Oxígeno/efectos de los fármacos , Procedimientos Quirúrgicos Operativos , Gasto Cardíaco/efectos de los fármacos , Cardiotónicos/administración & dosificación , Dobutamina/administración & dosificación , Análisis de Varianza , Atención PerioperativaRESUMEN
The compound 3-bromopyruvate (3-BrPA) is well-known and studies from several researchers have demonstrated its involvement in tumorigenesis. It is an analogue of pyruvic acid that inhibits ATP synthesis by inhibiting enzymes from the glycolytic pathway and oxidative phosphorylation. In this work, we investigated the effect of 3-BrPA on energy metabolism of L. amazonensis. In order to verify the effect of 3-BrPA on L. amazonensis glycolysis, we measured the activity level of three glycolytic enzymes located at different points of the pathway: (i) glucose kinases, step 1, (ii) glyceraldehyde 3-phosphate dehydrogenase (GAPDH), step 6, and (iii) enolase, step 9. 3-BrPA, in a dose-dependent manner, significantly reduced the activity levels of all the enzymes. In addition, 3-BrPA treatment led to a reduction in the levels of phosphofruto-1-kinase (PFK) protein, suggesting that the mode of action of 3-BrPA involves the downregulation of some glycolytic enzymes. Measurement of ATP levels in promastigotes of L. amazonensis showed a significant reduction in ATP generation. The O2 consumption was also significantly inhibited in promastigotes, confirming the energy depletion effect of 3-BrPA. When 3-BrPA was added to the cells at the beginning of growth cycle, it significantly inhibited L. amazonensis proliferation in a dose-dependent manner. Furthermore, the ability to infect macrophages was reduced by approximately 50% when promastigotes were treated with 3-BrPA. Taken together, these studies corroborate with previous reports which suggest 3-BrPA as a potential drug against pathogenic microorganisms that are reliant on glucose catabolism for ATP supply.
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Leishmania mexicana/efectos de los fármacos , Leishmaniasis Cutánea Difusa/parasitología , Piruvatos/farmacología , Animales , Western Blotting , Brasil , Cricetinae , Humanos , Leishmania mexicana/enzimología , Leishmania mexicana/crecimiento & desarrollo , Leishmania mexicana/metabolismo , Macrófagos/parasitología , Ratones , Consumo de Oxígeno/efectos de los fármacos , Fosfopiruvato Hidratasa/metabolismo , Células RAW 264.7RESUMEN
Subcellular organelles communicate with each other to regulate function and coordinate responses to changing cellular conditions. The physical-functional coupling of the endoplasmic reticulum (ER) with mitochondria allows for the direct transfer of Ca2+ between organelles and is an important avenue for rapidly increasing mitochondrial metabolic activity. As such, increasing ER-mitochondrial coupling can boost the generation of ATP that is needed to restore homeostasis in the face of cellular stress. The mitochondrial unfolded protein response (mtUPR) is activated by the accumulation of unfolded proteins in mitochondria. Retrograde signaling from mitochondria to the nucleus promotes mtUPR transcriptional responses aimed at restoring protein homeostasis. It is currently unknown whether the changes in mitochondrial-ER coupling also play a role during mtUPR stress. We hypothesized that mitochondrial stress favors an expansion of functional contacts between mitochondria and ER, thereby increasing mitochondrial metabolism as part of a protective response. Hela cells were treated with doxycycline, an antibiotic that inhibits the translation of mitochondrial-encoded proteins to create protein disequilibrium. Treatment with doxycycline decreased the abundance of mitochondrial encoded proteins while increasing expression of CHOP, C/EBPß, ClpP, and mtHsp60, markers of the mtUPR. There was no change in either mitophagic activity or cell viability. Furthermore, ER UPR was not activated, suggesting focused activation of the mtUPR. Within 2 h of doxycycline treatment, there was a significant increase in physical contacts between mitochondria and ER that was distributed throughout the cell, along with an increase in the kinetics of mitochondrial Ca2+ uptake. This was followed by the rise in the rate of oxygen consumption at 4 h, indicating a boost in mitochondrial metabolic activity. In conclusion, an early phase of the response to doxycycline-induced mitochondrial stress is an increase in mitochondrial-ER coupling that potentiates mitochondrial metabolic activity as a means to support subsequent steps in the mtUPR pathway and sustain cellular adaptation.
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Antibacterianos/farmacología , Doxiciclina/farmacología , Retículo Endoplásmico/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Calcio/metabolismo , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Femenino , Células HeLa , Humanos , Cinética , Mitocondrias/metabolismo , Mitocondrias/patología , Proteínas Mitocondriales/metabolismo , Consumo de Oxígeno/efectos de los fármacosRESUMEN
Tissue accumulation and high urinary excretion of ethylmalonic acid (EMA) are found in ethylmalonic encephalopathy (EE), an inherited disorder associated with cerebral and cerebellar atrophy whose pathogenesis is poorly established. The in vitro and in vivo effects of EMA on bioenergetics and redox homeostasis were investigated in rat cerebellum. For the in vitro studies, cerebellum preparations were exposed to EMA, whereas intracerebellar injection of EMA was used for the in vivo evaluation. EMA reduced state 3 and uncoupled respiration in vitro in succinate-, glutamate-, and malate-supported mitochondria, whereas decreased state 4 respiration was observed using glutamate and malate. Furthermore, mitochondria permeabilization and succinate supplementation diminished the decrease in state 3 with succinate. EMA also inhibited the activity of KGDH, an enzyme necessary for glutamate oxidation, in a mixed manner and augmented mitochondrial efflux of α-ketoglutarate. ATP levels were markedly reduced by EMA, reflecting a severe bioenergetic disruption. Docking simulations also indicated interactions between EMA and KGDH and a competition with glutamate and succinate for their mitochondrial transporters. In vitro findings also showed that EMA decreased mitochondrial membrane potential and Ca2+ retention capacity, and induced swelling in the presence of Ca2+ , which were prevented by cyclosporine A and ADP and ruthenium red, indicating mitochondrial permeability transition (MPT). Moreover, EMA, at high concentrations, mildly increased ROS levels and altered antioxidant defenses in vitro and in vivo. Our data indicate that EMA-induced impairment of glutamate and succinate oxidation and MPT may contribute to the pathogenesis of the cerebellum abnormalities in EE.
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Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Metabolismo Energético/efectos de los fármacos , Glutamatos/metabolismo , Malonatos/toxicidad , Poro de Transición de la Permeabilidad Mitocondrial , Succinatos/metabolismo , Animales , Ácidos Cetoglutáricos/metabolismo , Malatos/metabolismo , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteínas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Simulación del Acoplamiento Molecular , Oxidación-Reducción , Consumo de Oxígeno/efectos de los fármacos , Ratas , Ratas Wistar , Succinatos/farmacologíaRESUMEN
Cyclooxygenase (COX) and lipoxygenase (LOX) are key targets for the development of new anti-inflammatory agents. LOX, which is involved in the biosynthesis of mediators in inflammation and allergic reactions, was selected for a biochemical screening campaign to identify LOX inhibitors by employing the main natural product library of Brazilian biodiversity. Two prenyl chalcones were identified as potent inhibitors of LOX-1 in the screening. The most active compound, (E)-2-O-farnesyl chalcone, decreased the rate of oxygen consumption to an extent similar to that of the positive control, nordihydroguaiaretic acid. Additionally, studies on the mechanism of the action indicated that (E)-2-O-farnesyl chalcone is a competitive LOX-1 inhibitor. Molecular modeling studies indicated the importance of the prenyl moieties for the binding of the inhibitors to the LOX binding site, which is related to their pharmacological properties.
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Chalconas/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores de la Lipooxigenasa/farmacología , Modelos Moleculares , Prenilación , Chalconas/química , Concentración 50 Inhibidora , Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/química , Simulación del Acoplamiento Molecular , Consumo de Oxígeno/efectos de los fármacosRESUMEN
The effects of respiratory inhibitors, quinone analogues and artificial substrates on the membrane-bound electron transport system of the fastidious ß-proteobacterium Eikenella corrodens grown under O2-limited conditions were studied. NADH respiration in isolated membrane particles were partially inhibited by rotenone, dicoumarol, quinacrine, flavone, and capsaicin. A similar response was obtained when succinate oxidation was performed in the presence of thenoyltrifluoroacetone and N,N'-dicyclohexylcarbodiimide. NADH respiration was resistant to site II inhibitors and cyanide, indicating that a percentage of the electrons transported can reach O2 without the bc1 complex. Succinate respiration was sensitive to myxothiazol, antimycin A and 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO). Juglone, plumbagin and menadione had higher reactivity with NADH dehydrogenase. The membrane particles showed the highest oxidase activities with ascorbate-TCHQ (tetrachlorohydroquinone), TCHQ alone, and NADH-TMPD (N,N,N',N'-tetramethyl-p-phenylenediamine), and minor activity levels with ascorbate-DCPIP (2,6-dichloro-phenolindophenol) and NADH-DCPIP. The substrates NADH-DCPIP, NADH-TMPD and TCHQ were electron donors to cyanide-sensitive cbb' cytochrome c oxidase. The presence of dissimilatory nitrate reductase in the aerobic respiratory system of E. corrodens ATCC 23834 was demonstrated by first time. Our results indicate that complexes I and II have resistance to their classic inhibitors, that the oxidation of NADH is stimulated by juglone, plumbagin and menadione, and that sensitivity to KCN is stimulated by the substrates TCHQ, NADH-DCPIP and NADH-TMPD.
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Proteínas Bacterianas , Eikenella corrodens/enzimología , Complejo I de Transporte de Electrón , Consumo de Oxígeno/efectos de los fármacos , Quinonas , Desacopladores , Aerobiosis/efectos de los fármacos , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Transporte de Electrón/efectos de los fármacos , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Complejo I de Transporte de Electrón/metabolismo , NAD/metabolismo , Quinonas/química , Quinonas/farmacología , Desacopladores/química , Desacopladores/farmacologíaRESUMEN
A pandemia do novo coronavírus trouxe grande sobrecarga aos sistemas de saúde de todo o mundo, especialmente aos países de baixa e média renda (BONG CL et al, 2020). O atraso da vacinação tem agravado a situação nestes países, aumentando o índice de novos casos e a mortalidade pela doença (WHO, 2021). Um dos problemas enfrentados tem sido a escassez da oferta de oxigênio (O2) hospitalar. Agências internacionais como Wellcome Trust, Unitaid e MS criaram uma força tarefa em busca de uma resposta emergencial para a situação, estimando a necessidade de um aporte financeiro de cerca de 90 milhões de dólares, a fim de se evitar mortes preveníveis pela falta de oxigênio para o manejo clínico dos pacientes hospitalizados por COVID-19 (USHER AD, 2021).
The pandemic of the new coronavirus has brought great burden to health systems around the world, especially to low- and middle-income countries (BONG CL et al, 2020). The delay of vaccination has aggravated the situation in these countries, increasing the rate of new cases and mortality from the disease (WHO, 2021). One of the problems faced has been the scarcity of hospital oxygen (O2) supply. International agencies such as Wellcome Trust, Unitaid and MS have set up a task force in search of an emergency response to the situation, estimating the need for a financial contribution of about US$90 million in order to avoid preventable deaths from the lack of oxygen for the clinical management of patients hospitalized by COVID-19 (USHER AD, 2021).
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Humanos , Masculino , Femenino , Embarazo , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Oxígeno/fisiología , Oxígeno/provisión & distribución , Consumo de Oxígeno/efectos de los fármacosRESUMEN
The aim of the study was to verify the effects of creatine (Cr) supplementation on functional capacity (walking capacity; primary outcome) and calf muscle oxygen saturation (StO2) (secondary outcome) in symptomatic peripheral arterial disease (PAD) patients. Twenty-nine patients, of both sexes, were randomized (1:1) in a double-blind manner for administration of placebo (PLA, n = 15) or creatine monohydrate (Cr, n = 14). The supplementation protocol consisted of 20 g/day for 1 week divided into four equal doses (loading phase), followed by single daily doses of 5 g in the subsequent 7 weeks (maintenance phase). Functional capacity (total walking distance) was assessed by the 6 min walk test, and calf muscle StO2 was assessed through near infrared spectroscopy. The measurements were collected before and after loading and after the maintenance phase. The level of significance was p < 0.05. No significant differences were found for function capacity (total walking distance (PLA: pre 389 ± 123 m vs. post loading 413 ± 131 m vs. post maintenance 382 ± 99 m; Cr: pre 373 ± 149 m vs. post loading 390 ± 115 m vs. post maintenance 369 ± 115 m, p = 0.170) and the calf muscle StO2 parameters (p > 0.05). Short- and long-term Cr supplementation does not influence functional capacity and calf muscle StO2 parameters in patients with symptomatic PAD.
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Creatina/administración & dosificación , Suplementos Dietéticos , Músculo Esquelético/metabolismo , Oxígeno/metabolismo , Enfermedad Arterial Periférica/dietoterapia , Enfermedad Arterial Periférica/metabolismo , Anciano , Biomarcadores , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Consumo de Oxígeno/efectos de los fármacos , Evaluación del Resultado de la Atención al Paciente , Enfermedad Arterial Periférica/etiología , Proyectos Piloto , Resultado del TratamientoRESUMEN
Depletion of oxygen (O2) levels and reduction in the ATP synthesis (or even its complete blockage) are important characteristics of mitochondrial dysfunction; features that are often correlated with neurodegeneration. The measurement of oxygen consumption rate (OCR) is thus essential to evaluate cellular metabolism, survival, and neuroprotective strategies. In the present chapter, we describe the oxygen consumption assay using a Clark-type oxygen electrode in different types of samples named cells suspension (from primary and established cell culture), brain slices (ex vivo), and fresh brain tissues. In addition, we demonstrate herein how the program Oxygraph can be used in order to analyze the data and different approaches to normalize it.
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Adenosina Trifosfato/metabolismo , Bioensayo , Encéfalo/metabolismo , Mitocondrias/metabolismo , Neuronas/metabolismo , Fosforilación Oxidativa , Consumo de Oxígeno , Animales , Encéfalo/efectos de los fármacos , Línea Celular , Humanos , Técnicas In Vitro , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Cultivo Primario de Células , Ratas , Factores de TiempoRESUMEN
Aims: Liraglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist used as an anti-hyperglycemic agent in type 2 diabetes treatment and recently approved for obesity management. Weight loss is attributed to appetite suppression, but therapy may also increase energy expenditure. To further investigate the effect of GLP-1 signaling in thermogenic fat, we assessed adipose tissue oxygen consumption and type 2 deiodinase (D2) activity in mice treated with liraglutide, both basally and after ß3-adrenergic treatment. Methods: Male C57BL/6J mice were randomly assigned to receive liraglutide (400 µg/kg, n=12) or vehicle (n=12). After 16 days, mice in each group were co-treated with the selective ß3-adrenergic agonist CL316,243 (1 mg/kg, n=6) or vehicle (n=6) for 5 days. Adipose tissue depots were assessed for gene and protein expression, oxygen consumption, and D2 activity. Results: Liraglutide increased interscapular brown adipose tissue (iBAT) oxygen consumption and enhanced ß3-adrenergic-induced oxygen consumption in iBAT and inguinal white adipose tissue (ingWAT). These effects were accompanied by upregulation of UCP-1 protein levels in iBAT and ingWAT. Notably, liraglutide increased D2 activity without significantly upregulating its mRNA levels in iBAT and exhibited additive effects to ß3-adrenergic stimulation in inducing D2 activity in ingWAT. Conclusions: Liraglutide exhibits additive effects to those of ß3-adrenergic stimulation in thermogenic fat and increases D2 activity in BAT, implying that it may activate this adipose tissue depot by increasing intracellular thyroid activation, adding to the currently known mechanisms of GLP-1A-induced weight loss.
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Tejido Adiposo/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Yoduro Peroxidasa/metabolismo , Liraglutida/farmacología , Termogénesis/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Dioxoles/farmacología , Activación Enzimática , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Consumo de Oxígeno/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Proteína Desacopladora 1/metabolismo , Yodotironina Deyodinasa Tipo IIRESUMEN
NAD(P)+ transhydrogenase (NNT) is located in the inner mitochondrial membrane and catalyzes a reversible hydride transfer between NAD(H) and NADP(H) that is coupled to proton translocation between the intermembrane space and mitochondrial matrix. NNT activity has an essential role in maintaining the NADPH supply for antioxidant defense and biosynthetic pathways. In the present report, we evaluated the effects of chemical compounds used as inhibitors of NNT over the last five decades, namely, 4-chloro-7-nitrobenzofurazan (NBD-Cl), N,N'-dicyclohexylcarbodiimide (DCC), palmitoyl-CoA, palmitoyl-l-carnitine, and rhein, on NNT activity and mitochondrial respiratory function. Concentrations of these compounds that partially inhibited the forward and reverse NNT reactions in detergent-solubilized mouse liver mitochondria significantly impaired mitochondrial respiratory function, as estimated by ADP-stimulated and nonphosphorylating respiration. Among the tested compounds, NBD-Cl showed the best relationship between NNT inhibition and low impact on respiratory function. Despite this, NBD-Cl concentrations that partially inhibited NNT activity impaired mitochondrial respiratory function and significantly decreased the viability of cultured Nnt-/- mouse astrocytes. We conclude that even though the tested compounds indeed presented inhibitory effects on NNT activity, at effective concentrations, they cause important undesirable effects on mitochondrial respiratory function and cell viability.
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Inhibidores Enzimáticos/farmacología , Mitocondrias Hepáticas/enzimología , NADP Transhidrogenasa AB-Específica/antagonistas & inhibidores , NADP Transhidrogenasa AB-Específica/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Animales , Inhibidores Enzimáticos/química , Femenino , Ratones , Ratones Noqueados , Mitocondrias Hepáticas/genética , Proteínas Mitocondriales/antagonistas & inhibidores , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , NADP Transhidrogenasa AB-Específica/genética , Consumo de Oxígeno/genéticaRESUMEN
Amyloid-ß (Aß) peptides play a significant role in the pathogenesis of Alzheimer's disease (AD). Neurotoxic effects promoted by Aß peptides involve glutamate transmission impairment, decrease of neurotrophic factors, mitochondrial dysfunction, oxidative stress, synaptotoxicity, and neuronal degeneration. Here, we assessed the early events evoked by Aß1-40 on the hippocampus. Additionally, we sought to unravel the molecular mechanisms of atorvastatin preventive effect on Aß-induced hippocampal damage. Mice were treated orally (p.o.) with atorvastatin 10 mg/kg/day during 7 consecutive days before the intracerebroventricular (i.c.v.) infusion of Aß1-40 (400 pmol/site). Twenty-four hours after Aß1-40 infusion, a reduced content of mature BDNF/proBDNF ratio was observed in Aß-treated mice. However, there is no alteration in synaptophysin, PSD-95, and doublecortin immunocontent in the hippocampus. Aß1-40 promoted an increase in reactive oxygen species (ROS) and nitric oxide (NO) generation in hippocampal slices, and atorvastatin prevented this oxidative burst. Mitochondrial OXPHOS was measured by high-resolution respirometry. At this time point, Aß1-40 did not alter the O2 consumption rates (OCR) related to phosphorylating state associated with complexes I and II, and the maximal OCR. However, atorvastatin increased OCR of phosphorylating state associated with complex I and complexes I and II, maximal OCR of complexes I and II, and OCR associated with mitochondrial spare capacity. Atorvastatin treatment improved mitochondrial function in the rodent hippocampus, even after Aß infusion, pointing to a promising effect of improving brain mitochondria bioenergetics. Therefore, atorvastatin could act as an adjuvant in battling the symptoms of AD to preventing or delaying the disease progression.
Asunto(s)
Péptidos beta-Amiloides/administración & dosificación , Atorvastatina/farmacología , Hipocampo/patología , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Transporte de Electrón/efectos de los fármacos , Humanos , Inyecciones Intraventriculares , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
ß-hydroxybutyrate is the main ketone body generated by the liver under starvation. Under these conditions, it can sustain ATP levels by its oxidation in mitochondria. As mitochondria can modify its shape and function under different nutritional challenges, we study the chronic effects of ß-hydroxybutyrate supplementation on mitochondrial morphology and function, and its relation to exercise capacity. Male C57BL/6 mice were supplemented with ß-hydroxybutyrate mineral salt (3.2%) or control (CT, NaCl/KCl) for six weeks and submitted to a weekly exercise performance test. We found an increase in distance, maximal speed, and time to exhaustion at two weeks of supplementation. Fatty acid metabolism and OXPHOS subunit proteins declined at two weeks in soleus but not in tibialis anterior muscles. Oxygen consumption rate on permeabilized fibers indicated a decrease in the presence of pyruvate in the short-term treatment. Both the tibialis anterior and soleus showed decreased levels of Mitofusin 2, while electron microscopy assessment revealed a significant reduction in mitochondrial cristae shape in the tibialis anterior, while a reduction in the mitochondrial number was observed only in soleus. These results suggest that short, but not long-term, ßhydroxybutyrate supplementation increases exercise capacity, associated with modifications in mitochondrial morphology and function in mouse skeletal muscle.
Asunto(s)
Ácido 3-Hidroxibutírico/administración & dosificación , Suplementos Dietéticos , Tolerancia al Ejercicio/efectos de los fármacos , Mitocondrias Musculares/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Animales , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacosRESUMEN
HIV-1 proteins and highly active antiretroviral therapy (HAART) have been associated with microvascular endothelial dysfunction. Although nitrate-rich beetroot juice (NR-BJ) consumption has been shown to improve endothelial function in clinical population, its effects in HIV-infected patients has not been addressed. We investigated the effect of a single dose of NR-BJ on muscle oxygen saturation parameters in response to a handgrip exercise in HIV-infected patients. Fifteen HIV-infected patients received NR-BJ or nitrate-depleted beetroot juice (ND-BJ) in a double-blind cross-over design. Near-IR spectroscopy was utilised to assess muscle oxygen saturation parameters during rhythmic handgrip exercise after NR-BJ or ND-BJ supplementation. A significant faster muscle oxygen desaturation rate during exercise (-7·97 (sd 5·00) v. -5·45 (3·94) %/s, P = 0·005) and muscle oxygen resaturation rate during exercise recovery (0·43 (0·24) v. 0·28 (0·24) %/s, P = 0·030) after NR-BJ ingestion was found. However, no significant difference in exercise time until fatigue was observed. Salivary nitrite and urinary nitrate concentration were analysed after NR-BJ or ND-BJ. A significant increase in salivary nitrite and urinary nitrate in NR-BJ was observed compared with ND-BJ (P < 0·05). Our findings suggest that NR-BJ consumption may acutely improve muscle oxygen saturation during exercise and exercise recovery in HIV-infected patients undergoing HAART and who are expected to present microvascular damage. Thus, future studies investigating the chronic effects of NR-BJ are warranted to delineate a better nutritional strategy based on nitrate-rich foods.
Asunto(s)
Terapia Antirretroviral Altamente Activa/efectos adversos , Beta vulgaris , Jugos de Frutas y Vegetales , Nitratos/administración & dosificación , Consumo de Oxígeno/efectos de los fármacos , Adulto , Estudios Cruzados , Suplementos Dietéticos , Método Doble Ciego , Células Endoteliales , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , VIH-1 , Fuerza de la Mano , Humanos , Masculino , Microvasos/metabolismo , Persona de Mediana Edad , Músculo Esquelético/irrigación sanguínea , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Nutritional ergogenic aids are commonly used to boost physiological adaptations to exercise and promote greater fitness gains. However, there is a paucity of data about multi-ingredient pre-workout supplementation (MIPS). Therefore, the aim of the present study was to investigate the acute effects of MIPS on the oxidative, glycolytic and ATP-CP energy systems contribution, time spent above 90% VÌO2max (T90% VÌO2max), excess post-exercise oxygen consumption (EPOC) magnitude, number of efforts and time to exhaustion during a high-intensity interval exercise (HIIE) session. METHODS: Twelve physically-active and healthy men completed the HIIE sessions that involved running bouts of 15 s on the treadmill at 120% of the maximum aerobic speed (MAS), interspersed with 15 s of passive recovery. Blood lactate was collected at immediately post, 3, 5, and 7 min post exercise. The contribution of ATP-CP, glycolytic and oxidative systems was analyzed at rest, during the HIIE sessions and for 20 min post. Performance variables (time to exhaustion, number of efforts) and oxygen consumption were also analyzed. RESULTS: MIPS significantly increased the number of efforts performed (MIPS: 41 ± 10 vs Placebo: 36 ± 12, p = 0.0220) and time to exhaustion (MIPS: 20.1 ± 6 min vs Placebo: 17 ± 5 min, p = 0.0226). There was no difference between supplements for both T90% VÌO2max (p = 0.9705) and EPOC (p = 0.4930). Consuming MIPS significantly increased the absolute oxidative energy system contribution by 23.8% (p = 0.0163) and the absolute ATP-CP contribution by 28.4% (p = 0.0055) compared to placebo. There was only a non-significant tendency for a higher glycolytic system contribution after MIPS ingestion (p = 0.0683). CONCLUSION: Acute MIPS ingestion appears effective at increasing both aerobic and anaerobic alactic energy contribution and time to exhaustion during a HIIE protocol.
Asunto(s)
Suplementos Dietéticos , Metabolismo Energético/efectos de los fármacos , Entrenamiento de Intervalos de Alta Intensidad , Consumo de Oxígeno/efectos de los fármacos , Sustancias para Mejorar el Rendimiento/administración & dosificación , Resistencia Física/efectos de los fármacos , Adolescente , Adulto , Estudios Cruzados , Método Doble Ciego , Humanos , Ácido Láctico/sangre , Masculino , Carrera , Fenómenos Fisiológicos en la Nutrición Deportiva , Adulto JovenRESUMEN
Based on the fact that taurine can increase lipid metabolism, the objective of the present study was to evaluate the effects of different doses of acute taurine supplementation on lipid oxidation levels in healthy young men after a single bout of fasting aerobic exercise. A double-blind, acute, and crossover study design was conducted. Seventeen men (age 24.8 ± 4.07y; BMI: 23.9 ± 2.57 kg/m²) participated in the present study. Different doses of taurine (TAU) (3 g or 6 g) or placebo were supplemented 90 minutes before a single bout of fasting aerobic exercise (on a treadmill at 60% of VO2 max). The subjects performed three trials, and each one was separated by seven days. Blood samples were collected at baseline and after the exercise protocol of each test to analyze plasma levels of glycerol and taurine. Lipid and carbohydrate oxidation were determined immediately after exercise for 15 minutes by indirect calorimetry. We observed that TAU supplementation (6 g) increased lipid oxidation (38%) and reduced the respiratory coefficient (4%) when compared to the placebo (p < 0.05). However, no differences in lipid oxidation were observed between the different doses of taurine (3 g and 6 g). For glycerol concentrations, there were no differences between trials. Six grams of TAU supplementation 90 minutes before a single bout of aerobic exercise in a fasted state was sufficient to increase the lipid oxidation post-exercise in healthy young men.
Asunto(s)
Suplementos Dietéticos , Ejercicio Físico , Ayuno , Metabolismo de los Lípidos/efectos de los fármacos , Taurina/administración & dosificación , Adulto , Índice de Masa Corporal , Peso Corporal , Calorimetría Indirecta , Estudios Cruzados , Método Doble Ciego , Prueba de Esfuerzo , Humanos , Masculino , Oxidación-Reducción/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Taurina/sangre , Adulto JovenRESUMEN
The receptor activator of nuclear factor-κB (NF-κB) (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG) are a triad of proteins that regulate bone metabolism, and serum OPG is considered a biomarker for cardiovascular diseases and Type 2 diabetes; however, the implications of OPG in adipose tissue metabolism remains elusive. In this study, we investigate RANK-RANKL-OPG signaling in white adipose tissue browning. Histological analysis of osteoprotegerin knockout (OPG-/-) mice showed subcutaneous white adipose tissue (sWAT) browning, resistance for high-fat diet-induced weight gain, and preserved glucose metabolism compared with wild-type (WT) mice. Stromal vascular fraction (SVF) cells from sWAT of OPG-/- mice showed multilocular morphology and higher expression of brown adipocyte marker genes compared with those from the WT group. Infusion of RANKL induced browning and elevated respiratory rates in sWAT, along with increased whole body oxygen consumption in mice measured by indirect calorimetry. Subcutaneous WAT-derived SVF and 3T3-L1 cells, but not mature white adipocytes, differentiated into beige adipose tissue in the presence of RANKL. Moreover, SVF cells, even under white adipocyte differentiation, showed multilocular lipid droplet, lower lipid content, and increased expression of beige adipocyte markers with RANKL stimulation. In this study, we show for the first time the contribution of RANKL to increase energy expenditure by inducing beige adipocyte differentiation in preadipocytes.
Asunto(s)
Adipocitos Beige/metabolismo , Adipogénesis/genética , Tejido Adiposo Blanco/metabolismo , Obesidad/metabolismo , Osteoprotegerina/genética , Ligando RANK/metabolismo , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Células 3T3-L1 , Adipocitos Beige/citología , Adipocitos Beige/ultraestructura , Adipocitos Blancos/citología , Adipocitos Blancos/metabolismo , Adipocitos Blancos/ultraestructura , Tejido Adiposo Beige/citología , Tejido Adiposo Beige/metabolismo , Tejido Adiposo Blanco/citología , Animales , Calorimetría Indirecta , Dieta Alta en Grasa , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Gotas Lipídicas/ultraestructura , Ratones , Ratones Noqueados , Osteoprotegerina/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Consumo de Oxígeno/genética , Ligando RANK/farmacología , Transducción de Señal , Grasa Subcutánea/efectos de los fármacos , Grasa Subcutánea/metabolismo , Aumento de Peso/efectos de los fármacos , Aumento de Peso/genéticaRESUMEN
Ethanol (EtOH) consumption is a primary health risk worldwide, which generally starts during adolescence in a binge pattern (i.e., the episodic consumption of high amounts). Binge EtOH consumption can lead to modifications of the innate and adaptive immune responses, including fever. The present study evaluated the febrile response that was induced by lipopolysaccharide (LPS) and prostaglandins E2 (PGE2) and the mechanisms of thermoregulation in adolescent rats that were exposed to EtOH in a binge-like pattern. Male Wistar rats were treated with an intraperitoneal (i.p.) injection of EtOH or saline on postnatal days (PND) 25, 26, 29, 30, 33, 34, 37, and 38. On PND 51, they received a pyrogenic challenge with LPS (i.p.) or PGE2 (intracerebroventricular) to induce a febrile response. Interscapular brown adipose tissue (BAT) mass and uncoupling protein (UCP) activity in isolated mitochondria were evaluated on PND 51. The rats were then subjected to cold challenges to analyze adaptive thermogenesis. Intermittent EtOH exposure during adolescence impaired the LPS- and PGE2-induced febrile response 12 days after the end of EtOH exposure. Ethanol exposure decreased interscapular BAT mass, oxygen consumption, and UCP activity in isolated mitochondria, resulting in an impairment in thermogenesis at 5 °C. No morphological changes in BAT were observed. These findings indicate that binge-like EtOH exposure during adolescence impairs thermoregulation by reducing BAT mass and function. This reduction may last for a prolonged period of time after the cessation of EtOH exposure and may affect both cold defenses and the febrile response during the development of infectious diseases.