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Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this membrane is an essential process in cell biology and metabolism. Monocarboxylate transporters (MCTs) belong to a vast family of solute carriers (SLCs) that facilitate the transport of certain hydrophylic small compounds through the bilipid cell membrane. The existence of 446 genes that code for SLCs is the best evidence of their importance. In-depth research on MCTs is quite recent and probably promoted by their role in cancer development and progression. Importantly, it has recently been realized that these transporters represent an interesting target for cancer treatment. The search for clinically useful monocarboxylate inhibitors is an even more recent field. There is limited pre-clinical and clinical experience with new inhibitors and their precise mechanism of action is still under investigation. What is common to all of them is the inhibition of lactate transport. This review discusses the structure and function of MCTs, their participation in cancer, and old and newly developed inhibitors. Some suggestions on how to improve their anticancer effects are also discussed.
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Although the critical velocity (CV) protocol has been used to determine the aerobic capacity in rodents, there is a lack of studies that compare CV with maximal lactate steady state intensity (iMLSS) in mice. As a consequence, their physiological and molecular responses after exercise until exhaustion at CV intensity remain unclear. Thus, we aimed to compare and correlate CV with iMLSS in running mice, following different mathematical models for CV estimation. We also evaluated their physiological responses and muscle MCT1 and MCT4 after running until exhaustion at CV. Thirty C57BL/6J mice were divided into two groups (exercised-E and control-C). Group E was submitted to a CV protocol (4 days), using linear (lin1 and lin2) and hyperbolic (hyp) mathematical models to determine the distance, velocity, and time to exhaustion (tlim) of each predictive CV trial, followed by an MLSS protocol. After a running effort until exhaustion at CV intensity, the mice were immediately euthanized, while group C was euthanized at rest. No differences were observed between iMLSS (21.1 ± 1.1 m.min-1) and CV estimated by lin1 (21.0 ± 0.9 m.min-1, p = 0.415), lin2 (21.3 ± 0.9 m.min-1, p = 0.209), and hyp (20.6 ± 0.9 m.min-1, p = 0.914). According to the results, CV was significantly correlated with iMLSS. After running until exhaustion at CV (tlim = 28.4 ± 8,29 min), group E showed lower concentrations of hepatic and gluteal glycogen than group C, but no difference in the content of MCT1 (p = 0.933) and MCT4 (p = 0.123) in soleus muscle. Significant correlations were not found between MCT1 and MCT4 and tlim at CV intensity. Our results reinforce that CV is a valid and non-invasive protocol to estimate the maximal aerobic capacity in mice and that the content of MCT1 and MCT4 was not decisive in determining the tlim at CV, at least when measured immediately after the running effort.
Assuntos
Ácido Láctico , Simportadores , Camundongos , Animais , Camundongos Endogâmicos C57BL , Músculo Esquelético/fisiologia , Fígado , Transportadores de Ácidos MonocarboxílicosRESUMO
There is a scarcity of data regarding the acclimation to high altitude (hypoxic environment) accompanied by training at low altitude (normoxic conditions), the so-called "living high-training low" (LHTL) model in rodents. We aimed to investigate the effects of aerobic training on C57BL/6J mice living in normoxic (NOR) or hypoxic (HYP) environments on several parameters, including critical velocity (CV), a parameter regarded as a measure of aerobic capacity, on monocarboxylate transporters (MCTs) in muscles and hypothalamus, as well as on hematological parameters and body temperature. In each environment, mice were divided into non-trained (N) and trained (T). Forty rodents were distributed into the following experimental groups (N-NOR; T-NOR; N-HYP and T-HYP). HYP groups were in a normobaric tent where oxygen-depleted air was pumped from a hypoxia generator set an inspired oxygen fraction [FiO2] of 14.5 %. The HYP-groups were kept (18 h per day) in a normobaric tent for consecutive 8-weeks. Training sessions were conducted in normoxic conditions ([FiO2] = 19.5 %), 5 times per week (40 min per session) at intensity equivalent to 80 % of CV. In summary, eight weeks of LHTL did not promote a greater improvement in the CV, protein expression of MCTs in different tissues when compared to the application of training alone. The LHTL model increased red blood cells count, but reduced hemoglobin per erythrocyte was found in mice exposed to LHTL. Although the LHTL did not have a major effect on thermographic records, exercise-induced hyperthermia (in the head) was attenuated in HYP groups when compared to NOR groups.
Assuntos
Equilíbrio Ácido-Base , Hipóxia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Hipóxia/metabolismo , Oxigênio , Tolerância ao Exercício/fisiologia , Consumo de Oxigênio/fisiologiaRESUMO
Müller cells, the glial cells of the retina, provide metabolic support for photoreceptors and inner retinal neurons, and have been proposed as source of the significant lactate production of this tissue. To better understand the role of lactate in retinal metabolism, we expressed a lactate and a glucose nanosensor in organotypic mouse retinal explants cultured for 14 days, and used FRET imaging in acute vibratome sections of the explants to study metabolite flux in real time. Pharmacological manipulation with specific monocarboxylate transporter (MCT) inhibitors and immunohistochemistry revealed the functional expression of MCT1, MCT2 and MCT4 in Müller cells of retinal explants. The introduction of FRET nanosensors to measure key metabolites at the cellular level may contribute to a better understanding of heretofore poorly understood issues in retinal metabolism.
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Células Ependimogliais , Transferência Ressonante de Energia de Fluorescência , Camundongos , Animais , Células Ependimogliais/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Retina/metabolismo , Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismoRESUMO
Abstract Oral potentially malignant disorders (OPMD) are associated with an increased risk of oral squamous cell carcinoma (OSCC). OSCC has an aggressive profile and is the most prevalent among different head and neck malignancies. Most OSCC patients are diagnosed with advanced stage tumors and have a poor prognosis. Cancer cells are able to reprogram their metabolism, even in the presence of oxygen, enhancing the conversion of glucose to lactate via the glycolytic pathway, a phenomenon mainly regulated by hypoxia-inducible factor (HIF) signaling. Thus, several glycometabolism-related biomarkers are upregulated. Objectives This study aimed to evaluate the immunoexpression of the HIF targets GLUT1, GLUT3, HK2, PFKL, PKM2, pPDH, LDHA, MCT4, and CAIX in OPMD and OSCC samples, in order to identify potential correlations between biomarkers' immunoexpression, clinicopathological features, and prognostic parameters. Methodology OSCC and OPMD samples from 21 and 34 patients (respectively) were retrospectively collected and stained for the different biomarkers by immunohistochemistry. Results CAIX and MCT4 expressions were significantly higher in OSCC samples when compared with OPMD samples, while the rest were also expressed by OPMD. GLUT3 and PKM2 alone, and the concomitant expression of more than four glycometabolism-related biomarkers were significantly correlated with the presence of dysplasia in OPMD. When considering OSCC cases, a trend toward increased expression of biomarkers and poor clinicopathological features was observed, and the differences regarding HK2, PFKL, LDHA and MCT4 expression were significant. Moreover, HK2 and CAIX were correlated with low survival rates. GLUT1 and GLUT3 were significantly associated with poor outcome when their expression was observed in the hypoxic region of malignant lesions. Conclusion OPMD and OSCC cells overexpress glycolysis-related proteins, which is associated with aggressive features and poor patient outcome. Further research is needed to deeply understand the glycolic phenotype in the process of oral carcinogenesis.
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AIMS: The synthesis of monocarboxylate transporters (MCTs) can be stimulated by aerobic training, but few is known about this effect associated or not with non-voluntary daily activities. We examined the effect of eight weeks of aerobic training in MCTs on the skeletal muscle and hypothalamus of less or more physically active mice, which can be achieved by keeping them in two different housing models, a small cage (SC) and a large cage (LC). MAIN METHODS: Forty male C57BL/6J mice were divided into four groups. In each housing condition, mice were divided into untrained (N) and trained (T). For 8 weeks, the trained animals ran on a treadmill with an intensity equivalent to 80 % of the individual critical velocity (CV), considered aerobic capacity, 40 min/day, 5 times/week. Protein expression of MCTs was determined with fluorescence Western Blot. KEY FINDINGS: T groups had higher hypothalamic MCT2 than N groups (ANOVA, P = 0.032). Significant correlations were detected between hypothalamic MCT2 and CV. There was a difference between the SC and LC groups in relation to MCT4 in the hypothalamus (LC > SC, P = 0.044). Trained mice housed in LC (but not SC-T) exhibited a reduction in MCT4 muscle (P < 0.001). SIGNIFICANCE: Our findings indicate that aerobically trained mice increased the expression of MCT2 protein in the hypothalamus, which has been related to the uptake of lactate in neurons. Changes in energy metabolism in physically active mice (kept in LC) may be related to upregulation of hypothalamic MCT4, probably participating in the regulation of satiety.
Assuntos
Transportadores de Ácidos Monocarboxílicos , Músculo Esquelético , Animais , Hipotálamo/metabolismo , Ácido Láctico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transportadores de Ácidos Monocarboxílicos/metabolismo , Músculo Esquelético/metabolismoRESUMO
Breast tumors belong to the type of desmoplastic lesion in which a stiffer tissue structure is a determinant of breast cancer progression and constitutes a risk factor for breast cancer development. It has been proposed that cancer-associated stromal cells (responsible for this fibrotic phenomenon) are able to metabolize glucose via lactate production, which supports the catabolic metabolism of cancer cells. The aim of this work was to investigate the possible functional link between these two processes. To measure the effect of matrix rigidity on metabolic determinations, we used compliant elastic polyacrylamide gels as a substrate material, to which matrix molecules were covalently linked. We evaluated metabolite transport in stromal cells using two different FRET (Fluorescence Resonance Energy Transfer) nanosensors specific for glucose and lactate. Cell migration/invasion was evaluated using Transwell devices. We show that increased stiffness stimulates lactate production and glucose uptake by mammary fibroblasts. This response was correlated with the expression of stromal glucose transporter Glut1 and monocarboxylate transporters MCT4. Moreover, mammary stromal cells cultured on stiff matrices generated soluble factors that stimulated epithelial breast migration in a stiffness-dependent manner. Using a normal breast stromal cell line, we found that a stiffer extracellular matrix favors the acquisition mechanistical properties that promote metabolic reprograming and also constitute a stimulus for epithelial motility. This new knowledge will help us to better understand the complex relationship between fibrosis, metabolic reprogramming, and cancer malignancy.
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Cervical cancer continues to be a public health problem in developing countries. Previous studies have shown that cervical cancer cells display markers of aerobic glycolysis, indicating that these tumors are likely to secrete lactate. Mostly, lactate is recognized as a molecule capable of suppressing immune responses, through inhibition of T cells, MÏs, and dendritic cells. We and others have previously shown that MÏs are frequent cells infiltrating cervical cancers with the ability to inhibit antitumor immune responses and promote tumor growth through angiogenesis. Here, we have tested the hypothesis that lactate, secreted by cervical cancer cells, can modulate MÏ phenotype. First, we showed higher lactate plasma concentrations in patients with increasing cervical lesion grades, with maximum concentration in the plasma of cancer patients, which supported our hypothesis. We then inhibited lactate production in tumor cell spheroids established from cervical cancer derived cell lines, using the lactate dehydrogenase inhibitor, oxamate, prior to co-culture with monocytes. Lactate mediated part of the crosstalk between tumor cells and MÏs, promoting secretion of IL-1ß, IL-10, IL-6, and up-regulation of hypoxia induced factor-1α expression, and down-regulation of p65-NFκB phosphorylation in MÏs. We also showed that MÏs from co-cultures treated with oxamate were better inducers of T cell activation. Of note, experiments performed with inhibition of the monocarboxylate transporters rendered similar results. Our data confirms the hypothesis that lactate, secreted by cervical tumor cells, influences the phenotype of tumor MÏs, promoting a suppressive phenotype.
Assuntos
Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Ácido Láctico/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Neoplasias do Colo do Útero/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Inibidores Enzimáticos/farmacologia , Feminino , Regulação da Expressão Gênica , Glicólise/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/patologia , Gradação de Tumores , Fosforilação Oxidativa/efeitos dos fármacos , Fenótipo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
Some horse breeds are highly selected for athletic activities. The athletic potential of each animal can be measured by its performance in sports. High athletic performance depends on the animal capacity to produce energy through aerobic and anaerobic metabolic pathways, among other factors. Transmembrane proteins called monocarboxylate transporters, mainly the isoform 1 (MCT1) and its ancillary protein CD147, can help the organism to adapt to physiological stress caused by physical exercise, transporting lactate and H+ ions. Horse breeds are selected for different purposes so we might expect differences in the amount of those proteins and in the genotypic frequencies for genes that play a significant role in the performance of the animals. The study of MCT1 and CD147 gene polymorphisms, which can affect the formation of the proteins and transport of lactate and H+, can provide enough information to be used for selection of athletic horses increasingly resistant to intense exercise. Two other candidate genes, the PDK4 and DMRT3, have been associated with athletic potential and indicated as possible markers for performance in horses. The oxidation of fatty acids is highly effective in generating ATP and is controlled by the expression of PDK4 (pyruvate dehydrogenase kinase, isozyme 4) in skeletal muscle during and after exercise. The doublesex and mab-3 related transcription factor 3 (DMRT3) gene encodes an important transcription factor in the setting of spinal cord circuits controlling movement in vertebrates and may be associated with gait performance in horses. This review describes how the monocarboxylate transporters work during physical exercise in athletic horses and the influence of polymorphisms in candidate genes for athletic performance in horses.(AU)
Algumas raças de equinos são altamente selecionadas para atividades desportivas. O potencial atlético de cada animal pode ser medido pelo seu desempenho nas competições equestres. Um alto potencial atlético depende, entre outros fatores, da capacidade do animal de produzir energia através dos metabolismos aeróbio e anaeróbio. As proteínas transmembrana chamadas transportadores de monoxarboxilato, principalmente a isoforma 1 (MCT1) e sua proteína auxiliar CD147, podem ajudam o organismo a se adaptar ao estresse fisiológico causado pelo exercício físico, transportando íons lactato e H+. Algumas raças de equinos são selecionadas para diferentes objetivos, portanto é provável que existam diferenças nas quantidades de transportadores monocarboxilatos e na frequência genotípica dos seus respectivos genes. O estudo de polimorfismos nos genes das proteínas MCT1 e CD147, afetando a sua formação e o transporte dos íons lactato e H+, podem fornecer informações suficientes para a seleção de equinos com capacidade de serem altamente treinados e resistentes a intensos exercícios. Dois outros genes candidatos que têm sido relacionados com potencial atlético e utilizados como possíveis marcadores para desempenho em equinos são o PDK4 e o DMRT3. A oxidação de ácidos graxos é altamente efetiva para produção de ATP e é controlada pela expressão do gene PDK4 (pyruvate dehydrogenase kinase, isozyme 4) no musculo esquelético durante e após do exercício físico. O gene DMRT3 (doublesex and mab-3 related transcription factor 3) codifica um importante fator de transcrição no controle dos movimentos em vertebrados e pode ser associado com a marcha em algumas raças de equinos. Esta revisão descreve como agem os transportadores de monocarboxilatos durante o exercício físico em equinos atletas e qual a influência de alguns polimorfismos em genes candidatos para o desempenho atlético em equinos.(AU)
Assuntos
Animais , Cavalos/genética , Cavalos/fisiologia , Lactatos/análise , Fadiga Muscular , Estudos de Associação Genética , Estresse Fisiológico , Polimorfismo GenéticoRESUMO
Some horse breeds are highly selected for athletic activities. The athletic potential of each animal can be measured by its performance in sports. High athletic performance depends on the animal capacity to produce energy through aerobic and anaerobic metabolic pathways, among other factors. Transmembrane proteins called monocarboxylate transporters, mainly the isoform 1 (MCT1) and its ancillary protein CD147, can help the organism to adapt to physiological stress caused by physical exercise, transporting lactate and H+ ions. Horse breeds are selected for different purposes so we might expect differences in the amount of those proteins and in the genotypic frequencies for genes that play a significant role in the performance of the animals. The study of MCT1 and CD147 gene polymorphisms, which can affect the formation of the proteins and transport of lactate and H+, can provide enough information to be used for selection of athletic horses increasingly resistant to intense exercise. Two other candidate genes, the PDK4 and DMRT3, have been associated with athletic potential and indicated as possible markers for performance in horses. The oxidation of fatty acids is highly effective in generating ATP and is controlled by the expression of PDK4 (pyruvate dehydrogenase kinase, isozyme 4) in skeletal muscle during and after exercise. The doublesex and mab-3 related transcription factor 3 (DMRT3) gene encodes an important transcription factor in the setting of spinal cord circuits controlling movement in vertebrates and may be associated with gait performance in horses. This review describes how the monocarboxylate transporters work during physical exercise in athletic horses and the influence of polymorphisms in candidate genes for athletic performance in horses.(AU)
Algumas raças de equinos são altamente selecionadas para atividades desportivas. O potencial atlético de cada animal pode ser medido pelo seu desempenho nas competições equestres. Um alto potencial atlético depende, entre outros fatores, da capacidade do animal de produzir energia através dos metabolismos aeróbio e anaeróbio. As proteínas transmembrana chamadas transportadores de monoxarboxilato, principalmente a isoforma 1 (MCT1) e sua proteína auxiliar CD147, podem ajudam o organismo a se adaptar ao estresse fisiológico causado pelo exercício físico, transportando íons lactato e H+. Algumas raças de equinos são selecionadas para diferentes objetivos, portanto é provável que existam diferenças nas quantidades de transportadores monocarboxilatos e na frequência genotípica dos seus respectivos genes. O estudo de polimorfismos nos genes das proteínas MCT1 e CD147, afetando a sua formação e o transporte dos íons lactato e H+, podem fornecer informações suficientes para a seleção de equinos com capacidade de serem altamente treinados e resistentes a intensos exercícios. Dois outros genes candidatos que têm sido relacionados com potencial atlético e utilizados como possíveis marcadores para desempenho em equinos são o PDK4 e o DMRT3. A oxidação de ácidos graxos é altamente efetiva para produção de ATP e é controlada pela expressão do gene PDK4 (pyruvate dehydrogenase kinase, isozyme 4) no musculo esquelético durante e após do exercício físico. O gene DMRT3 (doublesex and mab-3 related transcription factor 3) codifica um importante fator de transcrição no controle dos movimentos em vertebrados e pode ser associado com a marcha em algumas raças de equinos. Esta revisão descreve como agem os transportadores de monocarboxilatos durante o exercício físico em equinos atletas e qual a influência de alguns polimorfismos em genes candidatos para o desempenho atlético em equinos.(AU)
Assuntos
Animais , Estudos de Associação Genética , Cavalos/genética , Cavalos/fisiologia , Lactatos/análise , Fadiga Muscular , Polimorfismo Genético , Estresse FisiológicoRESUMO
Hyperpalatable diets (HP) impair brain metabolism, and regular physical exercise has an apparent opposite effect. Here, we combined a prior long-term exposure to HP diet followed by physical exercise and evaluated the impact on some neuroenergetic components and on cognitive performance. We assessed the extracellular lactate concentration, expression of monocarboxylate transporters (MCTs), pyruvate dehydrogenase (PDH), and mitochondrial function in the hippocampus. Male C57BL/6J mice were fed 4 months with HP or a control diet. Subsequently, they were divided in the following groups: control diet sedentary (CDS), control diet exercise (CDE), HP diet sedentary (HPS), and HP diet exercise (HPE) (n = 15 per group) and were engaged for an additional 30-day period of voluntary exercise and HP diet. Relative to the control situation, exercise increased MCT1, MCT4, and PDH protein levels, while the HP diet increased MCT1 and MCT4 protein levels. The production of hydrogen peroxide (H2O2) and the mitochondrial membrane potential (∆Ñ°m) stimulated by succinate in hippocampal homogenates were not significantly different between groups. ADP phosphorylation and the maximal respiratory rate induced by FCCP showed similar responses between groups, implying a normal mitochondrial function. Also, extracellular brain lactate levels were increased in the HPE group compared to other groups soon after performing the Y-maze task. However, such enhanced lactate levels were not associated with improved memory performance. In summary, hippocampal protein expression levels of MCT1 and 4 were increased by physical exercise and HP diet, whereas PDH was only increased by exercise. These observations indicate that a hippocampal metabolic reprogramming takes place in response to these environmental factors.
Assuntos
Dieta , Peróxido de Hidrogênio/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Neuroglia/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Masculino , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Simportadores/metabolismoRESUMO
ABSTRACT: Some horse breeds are highly selected for athletic activities. The athletic potential of each animal can be measured by its performance in sports. High athletic performance depends on the animal capacity to produce energy through aerobic and anaerobic metabolic pathways, among other factors. Transmembrane proteins called monocarboxylate transporters, mainly the isoform 1 (MCT1) and its ancillary protein CD147, can help the organism to adapt to physiological stress caused by physical exercise, transporting lactate and H+ ions. Horse breeds are selected for different purposes so we might expect differences in the amount of those proteins and in the genotypic frequencies for genes that play a significant role in the performance of the animals. The study of MCT1 and CD147 gene polymorphisms, which can affect the formation of the proteins and transport of lactate and H+, can provide enough information to be used for selection of athletic horses increasingly resistant to intense exercise. Two other candidate genes, the PDK4 and DMRT3, have been associated with athletic potential and indicated as possible markers for performance in horses. The oxidation of fatty acids is highly effective in generating ATP and is controlled by the expression of PDK4 (pyruvate dehydrogenase kinase, isozyme 4) in skeletal muscle during and after exercise. The doublesex and mab-3 related transcription factor 3 (DMRT3) gene encodes an important transcription factor in the setting of spinal cord circuits controlling movement in vertebrates and may be associated with gait performance in horses. This review describes how the monocarboxylate transporters work during physical exercise in athletic horses and the influence of polymorphisms in candidate genes for athletic performance in horses.
RESUMO: Algumas raças de equinos são altamente selecionadas para atividades desportivas. O potencial atlético de cada animal pode ser medido pelo seu desempenho nas competições equestres. Um alto potencial atlético depende, entre outros fatores, da capacidade do animal de produzir energia através dos metabolismos aeróbio e anaeróbio. As proteínas transmembrana chamadas transportadores de monoxarboxilato, principalmente a isoforma 1 (MCT1) e sua proteína auxiliar CD147, podem ajudam o organismo a se adaptar ao estresse fisiológico causado pelo exercício físico, transportando íons lactato e H+. Algumas raças de equinos são selecionadas para diferentes objetivos, portanto é provável que existam diferenças nas quantidades de transportadores monocarboxilatos e na frequência genotípica dos seus respectivos genes. O estudo de polimorfismos nos genes das proteínas MCT1 e CD147, afetando a sua formação e o transporte dos íons lactato e H+, podem fornecer informações suficientes para a seleção de equinos com capacidade de serem altamente treinados e resistentes a intensos exercícios. Dois outros genes candidatos que têm sido relacionados com potencial atlético e utilizados como possíveis marcadores para desempenho em equinos são o PDK4 e o DMRT3. A oxidação de ácidos graxos é altamente efetiva para produção de ATP e é controlada pela expressão do gene PDK4 (pyruvate dehydrogenase kinase, isozyme 4) no musculo esquelético durante e após do exercício físico. O gene DMRT3 (doublesex and mab-3 related transcription factor 3) codifica um importante fator de transcrição no controle dos movimentos em vertebrados e pode ser associado com a marcha em algumas raças de equinos. Esta revisão descreve como agem os transportadores de monocarboxilatos durante o exercício físico em equinos atletas e qual a influência de alguns polimorfismos em genes candidatos para o desempenho atlético em equinos.
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Although aerobic training has been shown to affect the lactate transport of skeletal muscle, there is no information concerning the effect of continuous aerobic training on spontaneous physical activity (SPA). Because every movement in daily life (i.e., SPA) is generated by skeletal muscle, we think that it is possible that an improvement of SPA could affect the physiological properties of muscle with regard to lactate transport. The aim of this study was to evaluate the effect of 12 weeks of continuous aerobic training in individualized intensity on SPA of rats and their gene expressions of monocarboxylate transporters (MCT) 1 and 4 in soleus (oxidative) and white gastrocnemius (glycolytic) muscles. We also analyzed the effect of continuous aerobic training on aerobic and anaerobic parameters using the lactate minimum test (LMT). Sixty-day-old rats were randomly divided into three groups: a baseline group in which rats were evaluated prior to initiation of the study; a control group (Co) in which rats were kept without any treatment during 12 weeks; and a chronic exercise group (Tr) in which rats swam for 40 min/day, 5 days/week at 80% of anaerobic threshold during 12 weeks. After the experimental period, SPA of rats was measured using a gravimetric method. Rats had their expression of MCTs determined by RT-PCR analysis. In essence, aerobic training is effective in maintaining SPA, but did not prevent the decline of aerobic capacity and anaerobic performance, leading us to propose that the decline of SPA is not fully attributed to a deterioration of physical properties. Changes in SPA were concomitant with changes in MCT1 expression in the soleus muscle of trained rats, suggestive of an additional adaptive response toward increased lactate clearance. This result is in line with our observation showing a better equilibrium on lactate production-remotion during the continuous exercise (LMT). We propose an approach to combat the decline of SPA of rats in their home cages. This new finding is worth for scientists who work with animal models to study the protective effects of exercise.
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BRAF mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi. Samples included 20 benign nevi, 282 primary melanomas, 117 lymph node and 54 distant metastases samples. BRAF mutation was observed in 29/92 (31.5%) melanoma patients and 17/20 (85%) benign nevi samples. NRAS mutation was observed in 4/36 (11.1%) melanoma patients and 1/19 (5.3%) benign nevi samples. MCT4 and GLUT1 expression was significantly increased in metastatic samples, and MCT1, MCT4 and GLUT1 were significantly associated with poor prognostic variables. Importantly, MCT1 and MCT4 were associated with shorter overall survival. In conclusion, the present study brings new insights on metabolic aspects of melanoma, paving the way for the development of new-targeted therapies.
Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Musculares/genética , Neoplasias/genética , Nevo/genética , Neoplasias Cutâneas/genética , Simportadores/genética , Adulto , Idoso , Anidrase Carbônica IX/genética , Anidrase Carbônica IX/metabolismo , Estudos de Casos e Controles , Metabolismo Energético/genética , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Masculino , Melanoma/diagnóstico , Melanoma/mortalidade , Melanoma/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Neoplasias/diagnóstico , Neoplasias/mortalidade , Neoplasias/patologia , Nevo/diagnóstico , Nevo/mortalidade , Nevo/patologia , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Simportadores/metabolismoRESUMO
Tanycytes are elongated hypothalamic glial cells that cover the basal walls of the third ventricle; their apical regions contact the cerebrospinal fluid (CSF), and their processes reach hypothalamic neuronal nuclei that control the energy status of an organism. These nuclei maintain the balance between energy expenditure and intake, integrating several peripheral signals and triggering cellular responses that modify the feeding behaviour and peripheral glucose homeostasis. One of the most important and well-studied signals that control this process is glucose; however, the mechanism by which this molecule is sensed remains unknown. We along with others have proposed that tanycytes play a key role in this process, transducing changes in CSF glucose concentration to the neurons that control energy status. Recent studies have demonstrated the expression and function of monocarboxylate transporters and canonical pancreatic ß cell glucose sensing molecules, including glucose transporter 2 and glucokinase, in tanycytes. These and other data, which will be discussed in this review, suggest that hypothalamic glucosensing is mediated through a metabolic interaction between tanycytes and neurons through lactate. This article will summarize the recent evidence that supports the importance of tanycytes in hypothalamic glucosensing, and discuss the possible mechanisms involved in this process. Finally, it is important to highlight that a detailed analysis of this mechanism could represent an opportunity to understand the evolution of associated pathologies, including diabetes and obesity, and identify new candidates for therapeutic intervention.
Assuntos
Células Ependimogliais/metabolismo , Glucose/metabolismo , Hipotálamo/citologia , Animais , Comunicação Celular , Glucoquinase/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , HumanosRESUMO
AIM: To assess the immunoexpression of hypoxia-related markers in samples from cirrhosis and primary and metastatic hepatocellular carcinoma (HCC). METHODS: From a total of 5836 autopsies performed at the Pathology Department - University of Sao Paulo School of Medicine Hospital - from 2003 to 2009, 188 presented primary liver tumors. Immunohistochemical reactivity for monocarboxylate transporters (MCTs)-1, 2 and 4, CD147 and glucose transporter-1 (GLUT1) was assessed in necropsies from 80 cases of HCC. Data were stored and analyzed using the IBM SPSS statistical software (version 19, IBM Company, Armonk, NY). All comparisons were examined for statistical significance using Pearson's χ (2) test and Fisher's exact test (when n < 5). The threshold for significant P values was established as P < 0.05. RESULTS: Plasma membrane expression of MCT4 and overall expression of GLUT1 showed progressively higher expression from non-neoplastic to primary HCC and to metastases. In contrast, overall expression of MCT2 was progressively decreased from non-neoplastic to primary HCC and to metastases. MCT1 (overall and plasma membrane expression), MCT2 and CD147 plasma membrane expression were associated with absence of cirrhosis, while plasma membrane expression of CD147 was also associated with absence of HBV infection. MCT2 overall expression was associated with lower liver weight, absence of metastasis and absence of abdominal dissemination. Additionally, MCT4 plasma membrane positivity was strongly associated with Ki-67 expression. CONCLUSION: MCT4 and GLUT1 appear to play a role in HCC progression, while MCT2 is lost during progression and associated with better prognosis.