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1.
Nutrients ; 13(7)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34371974

RESUMO

The consumption of capsaicinoids, the active components in chili peppers, has been associated with both positive and negative health effects, and the level of capsaicinoid exposure may be an important determinant. Dietary capsaicinoid exposure was estimated using a previously developed database for capsaicinoid content and a 24-h dietary recall dataset obtained from the Korea National Health and Nutrition Examination Survey. The estimated consumption level was evaluated to determine its potential effects on weight reduction and gastrointestinal distress. The estimated daily mean capsaicinoid intake was 3.25 mg (2.17 mg capsaicin), and most Koreans consumed 1-30 mg of capsaicinoids (0.67-20 mg capsaicin) in a day. No adverse effect of capsaicin consumption was reported other than abdominal pain. For long-term repeated consumption, 30 mg may be the maximum tolerable dose. However, the effects on body weight or energy balance were inconsistent in 4-12 week clinical studies conducted with various capsaicin doses (2-135 mg), which was likely due to the complex interplay between capsaicin dose, study length, and participant characteristics. Therefore, the capsaicin consumption of most Koreans was below the levels that may cause adverse effects. However, more long-term studies for the dose range of 2-20 mg are required to further characterize capsaicin's health benefits in Koreans.


Assuntos
Capsaicina/administração & dosagem , Capsaicina/efeitos adversos , Dieta , Dor Abdominal/induzido quimicamente , Adolescente , Adulto , Idoso , Peso Corporal/efeitos dos fármacos , Criança , Pré-Escolar , Estudos Transversais , Relação Dose-Resposta a Droga , Metabolismo Energético/efeitos dos fármacos , Feminino , Promoção da Saúde , Humanos , Lactente , Recém-Nascido , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Inquéritos Nutricionais , República da Coreia , Adulto Jovem
2.
Eur J Endocrinol ; 185(4): 553-563, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34342595

RESUMO

Objective: Brown adipose tissue (BAT) controls metabolic rate through thermogenesis. As its regulatory factors during the transition from hyperthyroidism to euthyroidism are not well established, our study investigated the relationships between supraclavicular brown adipose tissue (sBAT) activity and physiological/metabolic changes with changes in thyroid status. Design: Participants with newly diagnosed Graves' disease were recruited. A thionamide antithyroid drug (ATD) such as carbimazole (CMZ) or thiamazole (TMZ) was prescribed in every case. All underwent energy expenditure (EE) measurement and supraclavicular infrared thermography (IRT) within a chamber calorimeter, as well as 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scanning, with clinical and biochemical parameters measured during hyperthyroidism and repeated in early euthyroidism. PET sBAT mean/maximum standardized uptake value (SUV mean/max), MR supraclavicular fat fraction (sFF) and mean temperature (Tscv) quantified sBAT activity. Results: Twenty-one (16 female/5 male) participants aged 39.5 ± 2.5 years completed the study. The average duration to attain euthyroidism was 28.6 ± 2.3 weeks. Eight participants were BAT-positive while 13 were BAT-negative. sFF increased with euthyroidism (72.3 ± 1.4% to 76.8 ± 1.4%; P < 0.01), but no changes were observed in PET SUV mean and Tscv. Significant changes in serum-free triiodothyronine (FT3) levels were related to BAT status (interaction P value = 0.04). FT3 concentration at hyperthyroid state was positively associated with sBAT PET SUV mean (r = 0.58, P = 0.01) and resting metabolic rate (RMR) (P < 0.01). Conclusion: Hyperthyroidism does not consistently lead to a detectable increase in BAT activity. FT3 reduction during the transition to euthyroidism correlated with BAT activity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Hipertireoidismo/metabolismo , Hipertireoidismo/reabilitação , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/efeitos dos fármacos , Adulto , Idoso , Antitireóideos/farmacologia , Antitireóideos/uso terapêutico , Composição Corporal/efeitos dos fármacos , Composição Corporal/fisiologia , Carbimazol/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Feminino , Fluordesoxiglucose F18 , Doença de Graves/tratamento farmacológico , Doença de Graves/metabolismo , Doença de Graves/reabilitação , Humanos , Hipertireoidismo/diagnóstico , Hipertireoidismo/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Metimazol/uso terapêutico , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Indução de Remissão , Singapura , Termogênese/efeitos dos fármacos , Termogênese/fisiologia , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/fisiologia , Adulto Jovem
3.
Eur J Endocrinol ; 185(4): 539-552, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34342596

RESUMO

Objective: Sex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol (in combination with antiandrogenic compounds) could affect metabolism as well. Given that the underlying pathophysiological mechanisms are not fully understood, this study assessed circulating estradiol-driven microRNAs (miRs) in transwomen and their regulation of genes involved in metabolism in mice. Methods: Following plasma miR-sequencing (seq) in a transwomen discovery (n = 20) and validation cohort (n = 30), we identified miR-224 and miR-452. Subsequent systemic silencing of these miRs in male C57Bl/6 J mice (n = 10) was followed by RNA-seq-based gene expression analysis of brown and white adipose tissue in conjunction with mechanistic studies in cultured adipocytes. Results: Estradiol in transwomen lowered plasma miR-224 and -452 carried in extracellular vesicles (EVs) while their systemic silencing in mice and cultured adipocytes increased lipogenesis (white adipose) but reduced glucose uptake and mitochondrial respiration (brown adipose). In white and brown adipose tissue, differentially expressed (miR target) genes are associated with lipogenesis (white adipose) and mitochondrial respiration and glucose uptake (brown adipose). Conclusion: This study identified an estradiol-drive post-transcriptional network that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy.


Assuntos
Micropartículas Derivadas de Células/genética , Estradiol/fisiologia , MicroRNAs/genética , Transexualidade , Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Adulto , Animais , Micropartículas Derivadas de Células/efeitos dos fármacos , Micropartículas Derivadas de Células/metabolismo , Estudos de Coortes , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Estradiol/sangue , Estradiol/farmacologia , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Terapia de Reposição Hormonal , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Interferência de RNA/efeitos dos fármacos , Pessoas Transgênero , Transexualidade/genética , Transexualidade/metabolismo , Adulto Jovem
4.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445344

RESUMO

Thyroid hormones, including 3,5,3'-triiodothyronine (T3), cause a wide spectrum of genomic effects on cellular metabolism and bioenergetic regulation in various tissues. The non-genomic actions of T3 have been reported but are not yet completely understood. Acute T3 treatment significantly enhanced basal, maximal, ATP-linked, and proton-leak oxygen consumption rates (OCRs) of primary differentiated mouse brown adipocytes accompanied with increased protein abundances of uncoupling protein 1 (UCP1) and mitochondrial Ca2+ uniporter (MCU). T3 treatment depolarized the resting mitochondrial membrane potential (Ψm) but augmented oligomycin-induced hyperpolarization in brown adipocytes. Protein kinase B (AKT) and mammalian target of rapamycin (mTOR) were activated by T3, leading to the inhibition of autophagic degradation. Rapamycin, as an mTOR inhibitor, blocked T3-induced autophagic suppression and UCP1 upregulation. T3 increases intracellular Ca2+ concentration ([Ca2+]i) in brown adipocytes. Most of the T3 effects, including mTOR activation, UCP1 upregulation, and OCR increase, were abrogated by intracellular Ca2+ chelation with BAPTA-AM. Calmodulin inhibition with W7 or knockdown of MCU dampened T3-induced mitochondrial activation. Furthermore, edelfosine, a phospholipase C (PLC) inhibitor, prevented T3 from acting on [Ca2+]i, UCP1 abundance, Ψm, and OCR. We suggest that short-term exposure of T3 induces UCP1 upregulation and mitochondrial activation due to PLC-mediated [Ca2+]i elevation in brown adipocytes.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Cálcio/metabolismo , Mitocôndrias/efeitos dos fármacos , Tri-Iodotironina/farmacologia , Tecido Adiposo Marrom/metabolismo , Animais , Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Células Cultivadas , Metabolismo Energético/efeitos dos fármacos , Feminino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos
5.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298999

RESUMO

The development of drug resistance in tumors is a major obstacle to effective cancer chemotherapy and represents one of the most significant complications to improving long-term patient outcomes. Despite early positive responsiveness to platinum-based chemotherapy, the majority of lung cancer patients develop resistance. The development of a new combination therapy targeting cisplatin-resistant (CR) tumors may mark a major improvement as salvage therapy in these patients. The recent resurgence in research into cellular metabolism has again confirmed that cancer cells utilize aerobic glycolysis ("the Warburg effect") to produce energy. Hence, this observation still remains a characteristic hallmark of altered metabolism in certain cancer cells. However, recent evidence promotes another concept wherein some tumors that acquire resistance to cisplatin undergo further metabolic alterations that increase tumor reliance on oxidative metabolism (OXMET) instead of glycolysis. Our review focuses on molecular changes that occur in tumors due to the relationship between metabolic demands and the importance of NAD+ in redox (ROS) metabolism and the crosstalk between PARP-1 (Poly (ADP ribose) polymerase-1) and SIRTs (sirtuins) in CR tumors. Finally, we discuss a role for the tumor metabolites of the kynurenine pathway (tryptophan catabolism) as effectors of immune cells in the tumor microenvironment during acquisition of resistance in CR cells. Understanding these concepts will form the basis for future targeting of CR cells by exploiting redox-metabolic changes and their consequences on immune cells in the tumor microenvironment as a new approach to improve overall therapeutic outcomes and survival in patients who fail cisplatin.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Cisplatino/uso terapêutico , Glicólise/efeitos dos fármacos , Humanos , Cinurenina/metabolismo , NAD/metabolismo , Oxirredução , Poli(ADP-Ribose) Polimerase-1/metabolismo , Sirtuínas/metabolismo
6.
Am J Physiol Regul Integr Comp Physiol ; 321(3): R429-R440, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34318701

RESUMO

Lipopolysaccharides (LPS) challenge the metabolic integrity of high-yielding dairy cows, activating the immune system and altering energy metabolism. Fatty acid oxidation, a major energy-gaining pathway, can be improved by supplementary carnitine, facilitating the transport of fatty acids into mitochondria. The metabolic response to the LPS challenge could alter both the plasma and the milk metabolome. Plasma and milk samples collected from cows treated with (n = 27) or without (n = 27) dietary carnitine, before and after intravenous administration of LPS, were subjected to a targeted metabolomics analysis. Multivariate statistical analyses revealed that both plasma and milk metabolome changed in response to the LPS challenge in both the carnitine-supplemented and the control cows. Short-chain acylcarnitines (carbon chain length C2, C3, C4, and C5) and long-chain acylcarnitines (C14, C16, and C18) had the highest performance to indicate LPS response when testing the predictive power of single metabolites using receiver-operator characteristics (ROC) analysis. The maximum area under a ROC curve (AUC) was 0.93. Biogenic amines, including sarcosine, and amino acids such as glutamine and isoleucine had AUC > 0.80 indicating metabolic changes due to the LPS challenge. In summary, the metabolites involved in the LPS response were acylcarnitines C2 and C5, sarcosine, glutamine, and isoleucine in plasma, and acylcarnitines C4 and C5 in milk. The interrelationship of plasma and milk metabolome included correlation of acylcarnitines C2, C4, and C5 between plasma and milk.


Assuntos
Carnitina/análogos & derivados , Lactação/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Leite/metabolismo , Animais , Carnitina/sangue , Bovinos , Dieta/veterinária , Suplementos Nutricionais , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Metabolômica/métodos , Leite/efeitos dos fármacos
8.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203800

RESUMO

Accumulating evidence support the cardioprotective properties of the nuclear receptor peroxisome proliferator activated receptor ß/δ (PPARß/δ); however, the underlying mechanisms are not yet fully elucidated. The aim of the study was to further investigate the mechanisms underlying PPARß/δ-mediated cardioprotection in the setting of myocardial ischemia/reperfusion (I/R). For this purpose, rats were treated with PPARß/δ agonist GW0742 and/or antagonist GSK0660 in vivo and hearts were subjected to ex vivo global ischemia followed by reperfusion. PPARß/δ activation improved left ventricular developed pressure recovery, reduced infarct size (IS) and incidence of reperfusion-induced ventricular arrhythmias while it also up-regulated superoxide dismutase 2, catalase and uncoupling protein 3 resulting in attenuation of oxidative stress as evidenced by the reduction in 4-hydroxy-2-nonenal protein adducts and protein carbonyl formation. PPARß/δ activation also increased both mRNA expression and enzymatic activity of aldehyde dehydrogenase 2 (ALDH2); inhibition of ALDH2 abrogated the IS limiting effect of PPARß/δ activation. Furthermore, upregulation of PGC-1α and isocitrate dehydrogenase 2 mRNA expression, increased citrate synthase activity as well as mitochondrial ATP content indicated improvement in mitochondrial content and energy production. These data provide new mechanistic insight into the cardioprotective properties of PPARß/δ in I/R pointing to ALDH2 as a direct downstream target and suggesting that PPARß/δ activation alleviates myocardial I/R injury through coordinated stimulation of the antioxidant defense of the heart and preservation of mitochondrial function.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Cardiotônicos/uso terapêutico , Metabolismo Energético , Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo , PPAR delta/metabolismo , PPAR beta/metabolismo , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Antioxidantes/metabolismo , Caderinas/metabolismo , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Catalase/metabolismo , Metabolismo Energético/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Modelos Biológicos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , PPAR delta/agonistas , PPAR beta/agonistas , Ratos Wistar , Superóxido Dismutase/metabolismo , Tiazóis/administração & dosagem , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Proteína Desacopladora 3/metabolismo , Regulação para Cima/efeitos dos fármacos
9.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299356

RESUMO

The hypothalamic peptide oxytocin and its receptor are involved in a range of physiological processes, including parturition, lactation, cell growth, wound healing, and social behavior. More recently, increasing evidence has established the effects of oxytocin on food intake, energy expenditure, and peripheral metabolism. In this review, we provide a comprehensive description of the central oxytocinergic system in which oxytocin acts to shape eating behavior and metabolism. Next, we discuss the peripheral beneficial effects oxytocin exerts on key metabolic organs, including suppression of visceral adipose tissue inflammation, skeletal muscle regeneration, and bone tissue mineralization. A brief summary of oxytocin actions learned from animal models is presented, showing that weight loss induced by chronic oxytocin treatment is related not only to its anorexigenic effects, but also to the resulting increase in energy expenditure and lipolysis. Following an in-depth discussion on the technical challenges related to endogenous oxytocin measurements in humans, we synthesize data related to the association between endogenous oxytocin levels, weight status, metabolic syndrome, and bone health. We then review clinical trials showing that in humans, acute oxytocin administration reduces food intake, attenuates fMRI activation of food motivation brain areas, and increases activation of self-control brain regions. Further strengthening the role of oxytocin in appetite regulation, we review conditions of hypothalamic insult and certain genetic pathologies associated with oxytocin depletion that present with hyperphagia, extreme weight gain, and poor metabolic profile. Intranasal oxytocin is currently being evaluated in human clinical trials to learn whether oxytocin-based therapeutics can be used to treat obesity and its associated sequela. At the end of this review, we address the fundamental challenges that remain in translating this line of research to clinical care.


Assuntos
Regulação do Apetite/efeitos dos fármacos , Apetite/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ocitocina/farmacologia , Ocitocina/uso terapêutico , Animais , Metabolismo Energético/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Motivação/efeitos dos fármacos , Obesidade/metabolismo
10.
Phytomedicine ; 88: 153605, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34107409

RESUMO

Osteoporosis is the process of bone loss, particular after menopause, when the production of estrogen in women is decreaing. Bioenergetic function is one of the critical roles in bone remodeling. Danggui Buxue Tang (DBT) is an herbal mixture containing Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), and which is consumed for "Qi-invigorating", i.e., stimulating energy metabolism, as a traditional Chinese medicine (TCM). However, the role of DBT in metabolism of osteoblast has not been examined. Here, we employed a metabolic flux to examine the mitochondrial functions of cultured osteoblast in the presence of herbal extracts, including DBT, ASR, AR, AR + ASR (single mixing of two herbal extracts), as well as DBT∆cal (a DBT extract depeleting calycosin), to examine their roles in osteoblastic metabolism, e.g. glycolysis and energy kinetics. By revealing the rates of oxygen consumption and extracellular acidification of mitochrondia, the DBT-treated osteoblasts were markedly strengthened with increases of maximal respiration, spare capacity, glycolysis capacity and glycolysis reserve, in comparing to other herbal extracts. In addition, the bioenergetic metabolism was modulated by DBT via the signaling of cellular Ca2+ and reactive oxgen species (ROS). Furthermore, DBT affected the morphology of mitochondria, as well as mitochondrial dynamic. Here, we propose that DBT can be regarded as benefit herbal extract in improving osteoblastic metabolism for bone disorders via central energy metabolism and mitochondrial bioenergetics.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Mitocôndrias/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Animais , Cálcio/metabolismo , Células Cultivadas , Medicamentos de Ervas Chinesas/química , Metabolismo Energético/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Osteoblastos/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Methods Mol Biol ; 2277: 391-403, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34080164

RESUMO

Cellular metabolism contributes to cell fate decisions. Bioenergetic profiling can therefore provide considerable insights into cellular identity and specification. Given the current importance of human pluripotent stem cells (hPSCs) for biomedical applications, assessing the bioenergetic properties of hPSCs and derivatives can unveil relevant mechanisms in the context of development biology and molecular disease modeling. Here, we describe a method to facilitate bioenergetic profiling of hPSCs in a reproducible and scalable manner. After simultaneous assessment of mitochondrial respiration and glycolytic capacity using Seahorse XFe96 Analyzer, we measure lactate concentration in the cellular media. Finally, we normalize the values based on DNA amount. We describe the procedures with specific requirements related to hPSCs . However, the same protocol can be easily adapted to other cell types, including differentiated progenies from hPSCs .


Assuntos
Mitocôndrias/metabolismo , Biologia Molecular/métodos , Células-Tronco Pluripotentes/metabolismo , Antimicina A/farmacologia , Carbonil Cianeto p-Trifluormetoxifenil Hidrazona/farmacologia , Técnicas de Cultura de Células/métodos , DNA/análise , Metabolismo Energético/efeitos dos fármacos , Humanos , Ácido Láctico/análise , Mitocôndrias/efeitos dos fármacos , Oligomicinas/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Células-Tronco Pluripotentes/efeitos dos fármacos , Rotenona/farmacologia
12.
Methods Mol Biol ; 2277: 405-421, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34080165

RESUMO

The more recent studies of human pathologies have essentially revealed the complexity of the interactions involved at the different levels of integration in organ physiology. Integrated organ thus reveals functional properties not predictable by underlying molecular events. It is therefore obvious that current fine molecular analyses of pathologies should be fruitfully combined with integrative approaches of whole organ function. It follows that an important issue in the comprehension of the link between molecular events in pathologies and whole organ function/dysfunction is the development of new experimental strategies aimed at the study of the integrated organ physiology. Cardiovascular diseases are a good example as heart submitted to ischemic conditions has to cope both with a decreased supply of nutrients and oxygen, and the necessary increased activity required to sustain whole body-including the heart itself-oxygenation.By combining the principles of control analysis with noninvasive 31P NMR measurement of the energetic intermediates and simultaneous measurement of heart contractile activity, we developed MoCA (for Modular Control and regulation Analysis), an integrative approach designed to study in situ control and regulation of cardiac energetics during contraction in intact beating perfused isolated heart (Diolez et al., Am J Physiol Regul Integr Comp Physiol 293(1):R13-R19, 2007). Because it gives real access to integrated organ function, MoCA brings out a new type of information-the "elasticities," referring to integrated internal responses to metabolic changes-that may be a key to the understanding of the processes involved in pathologies. MoCA can potentially be used not only to detect the origin of the defects associated with the pathology, but also to provide the quantitative description of the routes by which these defects-or also drugs-modulate global heart function, therefore opening therapeutic perspectives. This review presents selected examples of the applications to isolated intact beating heart that evidence different modes of energetic regulation of cardiac contraction. We also discuss the clinical application by using noninvasive 31P cardiac energetics examination under clinical conditions for detection of heart pathologies.


Assuntos
Metabolismo Energético , Espectroscopia de Ressonância Magnética/métodos , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Animais , Cálcio/metabolismo , Cardiotônicos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Epinefrina/metabolismo , Cobaias , Coração/efeitos dos fármacos , Homeostase , Humanos , Masculino , Mitocôndrias Cardíacas/metabolismo , Miofibrilas/metabolismo , Técnicas de Cultura de Órgãos/métodos , Ratos , Simendana/farmacologia
13.
Methods Mol Biol ; 2275: 173-186, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34118038

RESUMO

Creatine kinase (CK) enzyme overexpression has been suggested to play a role in the process of tumorigenesis and metastasis. Cyclocreatine (CCR) is a substrate analog of creatine kinase (CK), where its phosphorylated form is a poor phosphate donor in comparison with native bioenergetic molecule, creatine phosphate (Cr-P). The compound CCR has been shown to markedly inhibit the growth of a broad spectrum of cancers, both in vitro and in vivo. Intracellularly, CCR is phosphorylated by CK to yield a synthetic phosphagen [(N-phosphorylcyclocreatine (CCR ~P)], with thermodynamic and kinetic properties distinct from those of creatine phosphate (Cr-P). Distinct inhibition of tumor growth and metastasis has been attributed to CCR accumulation as CCR ~P in tumor cells, especially in those expressing a high level of CK protein, with minimal adverse effects. Unfortunately, the clinical use of CCR against malignancies is quite limited due to its amphoteric nature, which accounts for most of its extremely low membrane permeability, as well as limited oral bioavailability (BA) and poor systemic pharmacokinetics (PK).Our current work describes the encapsulation of CCR , utilizing freeze and thaw vesicles (FTV )-composed mostly of saturated PC, DOPE, and Chol-into stealth™ liposomes , postcoated with 4.5 M% PEG-PE. Following physicochemical characterization, in vitro release and cellular uptake kinetics confirmed efficient delivery of liposomal CCR (CCR-Lip), leading to intracellular accumulation of its CC-P metabolic product. Successful delivery of CCR to cancer cell effectively depleted low energetic cancer cells of ATP significantly mediating myc-induced metabolic changes. CCR-Lip showed significant antimetastatic and anticancer effectiveness against both MCF-7 and PC-3 human carcinoma models (p < 0.05-0.01), with 4- to 6-fold lower IC50 values vs. closest drug control. Such shift in bioenergetics was coupled via AMPK and phospho-p53 to the mitochondrial apoptosis effector Bak , thus inducing a cell-intrinsic mechanism to counteract uncontrolled neoplastic proliferation, in target cancer cells. Our novel liposomal delivery system of the CCR substrate analog demonstrated strong inhibition of malignant cell bioenergetics, leading to significant antineoplastic and proapoptotic actions, against different cancers.


Assuntos
Neoplasias da Mama/metabolismo , Creatina Quinase/metabolismo , Creatinina/análogos & derivados , Neoplasias da Próstata/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Creatinina/química , Creatinina/farmacologia , Composição de Medicamentos , Metabolismo Energético/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lipossomos , Células MCF-7 , Masculino , Células PC-3 , Fosforilação , Neoplasias da Próstata/tratamento farmacológico
14.
Life Sci ; 281: 119755, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34175318

RESUMO

AIMS: Polycystic ovarian syndrome (PCOS) is a reproductive, endocrine and metabolic disorder. Less is known about the mechanism of its effect on uterine function and therapeutic potential of melatonin. Our aim was to evaluate uterine dysfunction(s) in letrozole induced PCOS and its possible rectification by melatonin. MAIN METHODS: Adult female golden hamsters were divided into groups of Control (C), Melatonin (M; 1 mg/kg b.w.), Letrozole (L; 3 mg/kg b.w.) and combination of Letrozole+Melatonin (L + M; 3 mg/kg b.w. + 1 mg/kg b.w.) which were treated for 40 days. Analysis of serum testosterone/estradiol/progesterone/leptin/insulin, uterine histomorphometry, immunohistochemistry for proliferation cell nuclear antigen (PCNA), homeostatic assessment model of insulin resistance (HOMA-IR), western blotting for PCNA, androgen receptor (AR), insulin receptor (InsR), glucose tansporter-4 (GLUT-4), nuclear factor-kappa B (NFκB), cyclooxygenase-2 (COX-2) and biochemical analysis of superoxide dismutase (SOD)/catalase/lipid peroxidation (LPO) were done. KEY FINDINGS: Serum testosterone, leptin and insulin increased while uterine InsR/GLUT-4 expression decreased in L group indicating metabolic abnormalities. Endometrial hyperplasia, increased expression of PCNA and AR indicated abnormal proliferation in L compared to C. Increased uterine oxidative load (SOD/catalase/LPO) and inflammatory markers NFκB/COX-2 expression in L was responsible for high tissue oxidative stress and inflammation. M administration normalized all the above parameters suggesting its ameliorative effect in L + M group. SIGNIFICANCE: We report PCOS induced uterine dysfunction in Mesocricetus auratus for the first time. M administration restores uterine functions modulating cellular dynamicity, metabolic status, decreased oxidative and inflammatory load in PCOS hamsters. Therefore, we suggest the therapeutic potential of M against PCOS led uterine abnormalities to restore female fertility.


Assuntos
Proliferação de Células/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Melatonina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Útero/patologia , Animais , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Glicemia/metabolismo , Cricetinae , Modelos Animais de Doenças , Feminino , Hormônios Esteroides Gonadais/sangue , Infertilidade Feminina/tratamento farmacológico , Insulina/sangue , Resistência à Insulina , Letrozol/administração & dosagem , Letrozol/farmacologia , Letrozol/uso terapêutico , Melatonina/administração & dosagem , Melatonina/farmacologia , Mesocricetus , Camundongos , Ovário/patologia , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Útero/metabolismo
15.
Methods Mol Biol ; 2310: 33-45, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34095996

RESUMO

In recent years, a number of advancements have been made in the study of entire mitochondrial proteomes in both physiological and pathological conditions. Naturally occurring iodothyronines (i.e., T3 and T2) greatly influence mitochondrial oxidative capacity, directly or indirectly affecting the structure and function of the respiratory chain components. Blue native PAGE (BN-PAGE) can be used to isolate enzymatically active oxidative phosphorylation (OXPHOS) complexes in one step, allowing the clinical diagnosis of mitochondrial metabolism by monitoring OXPHOS catalytic and/or structural features. Protocols for isolating mammalian liver mitochondria and subsequent one-dimensional (1D) BN-PAGE will be described in relation to the impact of thyroid hormones on mitochondrial bioenergetics.


Assuntos
Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida Nativa , Hormônios Tireóideos/farmacologia , Fracionamento Celular , Mitocôndrias Hepáticas/enzimologia , Fosforilação Oxidativa/efeitos dos fármacos
16.
Cell Death Dis ; 12(7): 625, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135312

RESUMO

Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Clobetasol/farmacologia , Glucocorticoides/farmacologia , Proteínas Hedgehog/metabolismo , Atividade Motora/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Músculo Esquelético/inervação , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Coluna Vertebral/efeitos dos fármacos , Esclerose Amiotrófica Lateral/induzido quimicamente , Esclerose Amiotrófica Lateral/imunologia , Esclerose Amiotrófica Lateral/metabolismo , Animais , Estudos de Casos e Controles , Toxina da Cólera , Bases de Dados Genéticas , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos da Linhagem 129 , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Neurônios Motores/imunologia , Neurônios Motores/metabolismo , Teste de Campo Aberto , Saporinas , Transdução de Sinais , Receptor Smoothened/agonistas , Receptor Smoothened/metabolismo , Coluna Vertebral/imunologia , Coluna Vertebral/metabolismo , Coluna Vertebral/fisiopatologia
17.
Am J Physiol Endocrinol Metab ; 321(1): E190-E201, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34121448

RESUMO

This experiment investigated which hypothalamic nuclei were activated by a dose of leptin that inhibited food intake. Foodnot intake, energy expenditure, respiratory exchange ratio (RER), and intrascapular brown adipose tissue (IBAT) temperature were measured in male and female Sprague Dawley rats for 36 h following an intraperitoneal injection of 0, 50, 200, 500, or 1,000 µg leptin/kg with each rat tested with each dose of leptin in random order. In both males and females, RER and 12-h food intake were inhibited only by 1,000 µg leptin/kg, but there was no effect on energy expenditure or IBAT temperature. At the end of the experiment, phosphorylated signal transducer and activator of transcription 3 (pSTAT3) immunoreactivity was measured 1 h after injection of 0, 50, 500, or 1,000 µg leptin/kg. In male rats, the lowest dose of leptin produced a maximal activation of STAT3 in the Arc and nucleus of the solitary tract (NTS). There was no response in the dorsomedial hypothalamus, but there was a progressive increase in ventromedial nucleus of the hypothalamus (VMH) pSTAT3 with increasing doses of leptin. In female rats, there was no significant change in Arc and pSTAT3 NTS activation was maximal with 500 mg leptin/kg, but only the highest dose of leptin increased VMH pSTAT3. These results suggest that the VMH plays an important role in the energetic response to elevations of circulating leptin but do not exclude the possibility that multiple nuclei provide the appropriate integrated response to hyperleptinemia.NEW & NOTEWORTHY The results of this experiment show that doses of leptin too small to inhibit food intake produce a maximal response to leptin in the arcuate nucleus. By contrast the VMH shows a robust response that correlates with inhibition of food intake. This suggests that the VMH plays an important role in the energetic response to hyperleptinemia.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/metabolismo , Leptina/administração & dosagem , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Metabolismo Energético/efeitos dos fármacos , Feminino , Hipotálamo/química , Leptina/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/análise , Núcleo Solitário/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo
18.
FASEB J ; 35(7): e21712, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34110637

RESUMO

Palmitic acid (PA) is a saturated fatty acid whose high consumption has been largely associated with the development of different metabolic alterations, such as insulin resistance, metabolic syndrome, and type 2 diabetes. Particularly in the brain, insulin signaling disruption has been linked to cognitive decline and is considered a risk factor for Alzheimer's disease. Cumulative evidence has demonstrated the participation of PA in the molecular cascade underlying cellular insulin resistance in peripheral tissues, but its role in the development of neuronal insulin resistance and the mechanisms involved are not fully understood. It has generally been accepted that the brain does not utilize fatty acids as a primary energy source, but recent evidence shows that neurons possess the machinery for fatty acid ß-oxidation. However, it is still unclear under what conditions neurons use fatty acids as energy substrates and the implications of their oxidative metabolism in modifying insulin-stimulated effects. In the present work, we have found that neurons differentiated from human neuroblastoma MSN exposed to high but nontoxic concentrations of PA generate ATP through mitochondrial metabolism, which is associated with an increase in the cytosolic Ca2+ and diminished insulin signaling in neurons. These findings reveal a novel mechanism by which saturated fatty acids produce Ca2+ entry and insulin resistance that may play a causal role in increasing neuronal vulnerability associated with metabolic diseases.


Assuntos
Cálcio/metabolismo , Metabolismo Energético/efeitos dos fármacos , Resistência à Insulina/fisiologia , Neurônios/efeitos dos fármacos , Ácido Palmítico/farmacologia , Trifosfato de Adenosina/metabolismo , Linhagem Celular Tumoral , Citosol/efeitos dos fármacos , Citosol/metabolismo , Ácidos Graxos/farmacologia , Humanos , Insulina/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neuroblastoma/metabolismo , Neurônios/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Int J Biol Macromol ; 183: 2074-2087, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34097961

RESUMO

Lycium barbarum polysaccharides (LBPs) are known for their beneficial effects on diabetes, NAFLD and related chronic metabolic diseases induced by high-fat diet (HFD). However, the relevant researches are mainly about the whole crude polysaccharides, the specific active ingredient of LBPs and its bioactivity have been rarely explored. Herein, a homogeneous polysaccharide (LBP-W) was isolated and purified from crude LBPs. Structure characterizations indicated that LBP-W contained a main chain consisting of a repeated unit of →6)-ß-Galp(1 â†’ residues with branches composed of α-Araf, ß-Galp and α-Rhap residues at position C-3. The objective of this study was to evaluate the anti-obesogenic effect of LBP-W and figure out the underlying mechanisms. In vivo efficacy trial illustrated that LBP-W supplements can alleviate HFD-induced mice obesity significantly. Gut microbiota analysis showed that LBP-W not only improved community diversity of intestinal flora, but also regulated their specific genera. Moreover, LBP-W can increase the content of short-chain fatty acids (SCFAs), a metabolite of the intestinal flora. In summary, all these results demonstrated that the homogeneous polysaccharide purified from L. barbarum could be used as a prebiotic agent to improve obesity by modulating the composition of intestinal flora and the metabolism of SCFAs.


Assuntos
Fármacos Antiobesidade/farmacologia , Bactérias/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Prebióticos , Animais , Fármacos Antiobesidade/química , Arabinose/química , Arabinose/farmacologia , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Disbiose , Ácidos Graxos/sangue , Galactose/química , Galactose/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Obesidade/sangue , Obesidade/microbiologia , Ramnose/química , Ramnose/farmacologia , Relação Estrutura-Atividade
20.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063173

RESUMO

Recent studies have suggested that flavonoids such as quercetin and probiotics such as Bifidobacterium bifidum (Bf) and Lactobacillus gasseri (Lg) could play a relevant role in inhibiting colon cancer cell growth. Our study investigated the role of dietary supplementation with microencapsulated probiotics (Bf and Lg) along with quercetin in the development of mouse colorectal cancer (CRC). Methods: Adenomatous polyposis coli/multiple intestinal neoplasia (ApcMin/+) mice were fed a standard diet or the same diet supplemented with microencapsulated probiotics (Bf and Lg strains, 107 CFU/100 g food) or both probiotics strains plus microencapsulated quercetin (15 mg/100 g food) for 73 days. Changes in body and organ weights, energy metabolism, intestinal microbiota, and colon tissue were determined. The expression of genes related to the Wnt pathway was also analyzed in colon samples. Results: Dietary supplementation with microencapsulated probiotics or microencapsulated probiotics plus quercetin reduced body weight loss and intestinal bleeding in ApcMin/+ mice. An improvement in energy expenditure was observed after 8 weeks but not after 10 weeks of treatment. A supplemented diet with microencapsulated Bf and Lg reduced the number of aberrant crypt foci (ACF) and adenomas by 45% and 60%, respectively, whereas the supplementation with Bf, Lg and quercetin decreased the number of ACF and adenomas by 57% and 80%, respectively. Microencapsulated Bf and Lg in combination with quercetin could exert inhibition of the canonical Wnt/ß-catenin signaling pathway in the colon of ApcMin/+ mice Conclusions: The administration of microencapsulated Bf and Lg, individually or in combination with quercetin, inhibits the CRC development in ApcMin/+ mice.


Assuntos
Polipose Adenomatosa do Colo/metabolismo , Bifidobacterium bifidum/citologia , Carcinogênese/patologia , Células Imobilizadas/citologia , Neoplasias Colorretais/patologia , Lactobacillus gasseri/citologia , Quercetina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Colo/patologia , Contagem de Colônia Microbiana , Neoplasias Colorretais/genética , Metabolismo Energético/efeitos dos fármacos , Fezes/microbiologia , Comportamento Alimentar , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Sangue Oculto , Tamanho do Órgão/efeitos dos fármacos , Probióticos/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
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