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1.
Mol Genet Genomics ; 295(2): 515-523, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31897802

RESUMO

Adaptation to exercise training is a complex trait that may be influenced by genetic variants. We identified 36 single nucleotide polymorphisms (SNPs) that had been previously associated with endurance or strength performance, exercise-related phenotypes or exercise intolerant disorders. A MassARRAY multiplex genotyping assay was designed to identify associations with these SNPs against collected endurance fitness phenotype parameters obtained from two exercise cohorts (Gene SMART study; n = 58 and Hawaiian Ironman Triathlon 2008; n = 115). These parameters included peak power output (PP), a time trial (TT), lactate threshold (LT), maximal oxygen uptake (VO2 max) in recreationally active individuals and a triathlon time-to-completion (Hawaiian Ironman Triathlon cohort only). A nominal significance threshold of α < 0.05 was used to identify 17 variants (11 in the Gene SMART population and six in the Hawaiian Ironman Triathlon cohort) which were significantly associated with performance gains in highly trained individuals. The variant rs1474347 located in Interleukin 6 (IL6) was the only variant with a false discovery rate < 0.05 and was found to be associated with gains in VO2 max (additional 4.016 mL/(kg min) for each G allele inherited) after training in the Gene SMART cohort. In summary, this study found further evidence to suggest that genetic variance can influence training response in a moderately trained cohort and provides an example of the potential application of genomic research in the assessment of exercise trait response.


Assuntos
Adaptação Fisiológica/genética , Desempenho Atlético/fisiologia , Exercício/fisiologia , Resistência Física/genética , Adulto , Genoma Humano/genética , Genótipo , Humanos , Ácido Láctico/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único/genética
2.
Anticancer Res ; 40(1): 153-160, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892563

RESUMO

BACKGROUND/AIM: In this study, we evaluated the effect of galloflavin, an inhibitor of lactate dehydrogenase, in combination with metformin, an anti-diabetic drug and inhibitor of oxidative phosphorylation, on pancreatic ductal adenocarcinoma cells. MATERIALS AND METHODS: We explored the effect of galloflavin and metformin on proliferation and cell death of murine 6606PDA and human MIA PaCa-2 cells. RESULTS: We observed that monotherapies of galloflavin and metformin both inhibit proliferation and induce cancer cell death. Moreover, the combination of both agents increased these effects on pancreatic ductal adenocarcinoma cells. The inhibition of proliferation by this combination therapy can be detected under hypoxic and normoxic conditions, leading to the assumption that this therapy might impair insufficiently supplied solid tumors as well as small clusters of cancer cells, e.g. after metastatic dissemination. CONCLUSION: Galloflavin, especially in combination with metformin, has a strong anti-cancerous effect on pancreatic ductal adenocarcinoma cells.


Assuntos
Antineoplásicos/farmacologia , Isocumarinas/farmacologia , Metformina/farmacologia , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/farmacologia , Ácido Láctico/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo
3.
BMC Bioinformatics ; 21(1): 13, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924164

RESUMO

BACKGROUND: The rapid growth of available knowledge on metabolic processes across thousands of species continues to expand the possibilities of producing chemicals by combining pathways found in different species. Several computational search algorithms have been developed for automating the identification of possible heterologous pathways; however, these searches may return thousands of pathway results. Although the large number of results are in part due to the large number of possible compounds and reactions, a subset of core reaction modules is repeatedly observed in pathway results across multiple searches, suggesting that some subpaths between common compounds were more consistently explored than others.To reduce the resources spent on searching the same metabolic space, a new meta-algorithm for metabolic pathfinding, Hub Pathway search with Atom Tracking (HPAT), was developed to take advantage of a precomputed network of subpath modules. To investigate the efficacy of this method, we created a table describing a network of common hub metabolites and how they are biochemically connected and only offloaded searches to and from this hub network onto an interactive webserver capable of visualizing the resulting pathways. RESULTS: A test set of nineteen known pathways taken from literature and metabolic databases were used to evaluate if HPAT was capable of identifying known pathways. HPAT found the exact pathway for eleven of the nineteen test cases using a diverse set of precomputed subpaths, whereas a comparable pathfinding search algorithm that does not use precomputed subpaths found only seven of the nineteen test cases. The capability of HPAT to find novel pathways was demonstrated by its ability to identify novel 3-hydroxypropanoate (3-HP) synthesis pathways. As for pathway visualization, the new interactive pathway filters enable a reduction of the number of displayed pathways from hundreds down to less than ten pathways in several test cases, illustrating their utility in reducing the amount of presented information while retaining pathways of interest. CONCLUSIONS: This work presents the first step in incorporating a precomputed subpath network into metabolic pathfinding and demonstrates how this leads to a concise, interactive visualization of pathway results. The modular nature of metabolic pathways is exploited to facilitate efficient discovery of alternate pathways.


Assuntos
Algoritmos , Redes e Vias Metabólicas , Ácido Láctico/análogos & derivados , Ácido Láctico/química , Ácido Láctico/metabolismo , Ácido Pirúvico/metabolismo
4.
J Sci Food Agric ; 100(3): 1164-1173, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31680258

RESUMO

BACKGROUND: This study was conducted to analyze the effects of endophytic Bacillus megaterium (BM 18-2) colonization on structure strengthening, microbial community, chemical composition and stabilization properties of Hybrid Pennisetum. RESULTS: The BM 18-2 had successfully colonized in the interior tissues in both leaf and stem of Hybrid Pennisetum. During ensiling, the levels of pH, acetic acid (AA), butyric acid (BA), propionic acid (PA), and the population of yeast and aerobic bacteria were significantly (P > 0.05) lower, while lactic acid bacteria (LAB) and lactic acid (LA) were significantly (P < 0.001) higher with the steps forward of ensiling in with BM 18-2 as compared to without BM 18-2 colonized of Hybrid Pennisetum. During the different ensiling days, at days 3, 6, 15, and 30, the genus Brevundimonas, Klebsiella, Lactococcus, Weissella, Enterobacter, Serratia, etc. population were significantly decreased, while genus Pediococcus acidilactici and Lactobacillus plantarum were significantly influenced in treated groups as compared to control. The genus Lactobacillus and Pediococcus were positively correlated with treatment groups. CONCLUSIONS: It is concluded that the endophytic bacteria strain BM 18-2 significantly promoted growth characteristics and biomass yield before ensiling and after ensiling inoculated with or without Lactobacillus plantarum could improve the distinct changes of the undesirable microbial diversity, chemical composition, and stabilization properties in with BM 18-2 as compared to without BM 18-2 colonized Hybrid Pennisetum. © 2019 Society of Chemical Industry.


Assuntos
Bacillus megaterium/crescimento & desenvolvimento , Endófitos/crescimento & desenvolvimento , Microbiota , Pennisetum/microbiologia , Ácido Acético/metabolismo , Bacillus megaterium/genética , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Ácido Butírico/metabolismo , Endófitos/genética , Ácido Láctico/metabolismo , Pennisetum/genética , Pennisetum/crescimento & desenvolvimento , Leveduras/classificação , Leveduras/genética , Leveduras/isolamento & purificação , Leveduras/metabolismo
5.
Aquat Toxicol ; 218: 105359, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31765944

RESUMO

Carbohydrate metabolism switches from aerobic to anaerobic (glycolysis) to supply energy in response to acute hypoxic stress. Acute hypoxic stress with dissolved oxygen (DO) levels of 1.2 ±â€¯0.1 mg/L for 24 h and 12 h re-oxygenation was used to investigate the response of the anaerobic glycolytic pathway in Micropterus salmoides muscle. The results showed that the glucose concentration was significantly lower in muscle, while the lactic acid and pyruvic acid concentrations tended to increase during hypoxic stress. No significant difference was observed in muscle glycogen, and ATP content fluctuated significantly. The activities of gluconeogenesis-related enzymes were slightly elevated, such as phosphoenolpyruvate carboxykinase (PEPCK). The activities of the glycolytic enzymes increased after the induction of hypoxia, such as hexokinase (HK), pyruvate kinase (PK), and lactate dehydrogenase (LDH). Curiously, phosphofructokinase (PFK) activity was significantly down-regulated within 4 h during hypoxia, although these effects were transient, and most indices returned to control levels after 12 h of re-oxygenation. Upregulated hif-1α, ampkα, hk, glut1, and ldh mRNA expression suggested that carbohydrate metabolism was reprogrammed under hypoxia. Lactate transport was regulated by miR-124-5p according to quantitative polymerase chain reaction and dual luciferase reporter assays. Our findings provide new insight into the molecular regulatory mechanism of hypoxia in Micropterus salmoides muscle.


Assuntos
Aclimatação/fisiologia , Bass/metabolismo , Hipóxia/metabolismo , Ácido Láctico/metabolismo , MicroRNAs/genética , Transportadores de Ácidos Monocarboxílicos/genética , Músculos/metabolismo , Simportadores/genética , Aclimatação/genética , Animais , Bass/genética , Metabolismo dos Carboidratos/genética , Metabolismo dos Carboidratos/fisiologia , Regulação da Expressão Gênica , Hipóxia/genética , Músculos/enzimologia , Oxigênio/metabolismo
6.
Gene ; 726: 144158, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31629815

RESUMO

Cancer is the second most important cause of death and new therapy modalities continue to be developed and evolved. Cancer cells' metabolism is far different from the normal, healthy cells; they are more metabolically active, have higher proliferation rate and could able to resist to cell death pathways like apoptosis. It is known that in addition to increasing the expression of enzymes that are crucial in glycolysis for much more energy production, cancer cells produce energy from lactic acid fermentation after glycolysis. In 1920s, Warburg has claimed that cancer cells are more active in glycolysis than normal cells and use much more glucose in order to obtain more ATP for metabolic activities, then this is named as Warburg effect. After that; new methodologies and therapeutics that target metabolism, began to be attractive subject in cancer studies. Therefore, the main genes, enzymes and factors are begun to investigate and further studied for understanding their roles in metabolism of cancer cells.


Assuntos
Glicólise/fisiologia , Neoplasias/patologia , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/fisiologia , Progressão da Doença , Glucose/metabolismo , Humanos , Ácido Láctico/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/metabolismo
7.
Cancer Sci ; 111(1): 186-199, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746077

RESUMO

Activity of transcriptional co-activator with PDZ binding domain (TAZ) protein is strongly implicated in the pathogenesis of human cancer and is influenced by tumor metabolism. High levels of lactate concentration in the tumor microenvironment as a result of metabolic reprogramming are inversely correlated with patient overall survival. Herein, we investigated the role of lactate in the regulation of the activity of TAZ and showed that glycolysis-derived lactate efficiently increased TAZ expression and activity in lung cancer cells. We showed that the reactive oxygen species (ROS) generated by lactate-fueled oxidative phosphorylation (OXPHOS) in mitochondria activated AKT and thereby inhibited glycogen synthase kinase 3 beta/beta-transducin repeat-containing proteins (GSK-3ß/ß-TrCP)-mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1). Upregulation of DNMT1 by lactate caused hypermethylation of TAZ negative regulator of the LATS2 gene promoter, leading to TAZ activation. Moreover, TAZ binds to the promoter of DNMT1 and is necessary for DNMT1 transcription. Our study showed a molecular mechanism of DNMT1 in linking tumor metabolic reprogramming to the Hippo-TAZ pathway and functional significance of the DNMT1-TAZ feedback loop in the migratory and invasive potential of lung cancer cells.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/genética , Ácido Láctico/metabolismo , Estresse Oxidativo/genética , Transativadores/genética , Transcrição Genética/genética , Ativação Transcricional/genética , Linhagem Celular Tumoral , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Espécies Reativas de Oxigênio/metabolismo
8.
Food Chem Toxicol ; 135: 111043, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31836553

RESUMO

Tylorrhynchus heterochaetus (Hechong in Chinese) has been used in Chinese traditional medicine for treating various diseases. This study was aimed to assess the anti-fatigue effect of T. heterochaetus on Kunming mice and its primary mechanism of action using forced running, rotating rod and weight-loaded swimming tests. Low (2.70 mg/0.5 mL/20 g), medium (5.41 mg/0.5 mL/20 g) and high (6.58 mg/0.5 mL/20 g) doses of T. heterochaetus aqueous extract were treated to mice for 28 days. Among the doses, the low and medium doses showed significant (p ≤ 0.05) anti-fatigue effect on the weight-loaded swimming test. Also, T. heterochaetus extract showed significant (p ≤ 0.05) effects on fatigue-related blood parameters by increasing the GLU, TG and LDH levels and decreasing the LA, CK and BUN levels. The levels of liver and skeletal muscle glycogen were also significantly (p ≤ 0.05) increased after treatment. Further, on Western blot analysis, it has been found that T. heterochaetus enhanced the expressions of AMPK and PGC-1α in the liver and skeletal muscles of mice. From the study, our outcomes suggest that T. heterochaetus possess an anti-fatigue effect through the AMPK-linked pathway and thereby it can regularize the energy metabolism.


Assuntos
Adenilato Quinase/metabolismo , Produtos Biológicos/farmacologia , Fadiga/prevenção & controle , Poliquetos/química , Animais , Nitrogênio da Ureia Sanguínea , Peso Corporal/efeitos dos fármacos , Creatina Quinase/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , L-Lactato Desidrogenase/metabolismo , Ácido Láctico/metabolismo , Fígado/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Teste de Desempenho do Rota-Rod , Corrida , Natação , Triglicerídeos/metabolismo
9.
Food Chem ; 302: 125335, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31416001

RESUMO

Cocoa bean fermentation still remains a rather empirical process. The research presented here employed an artificial system of fermentation, using controlled incubations, in order to achieve greater control over the external influences that cocoa beans are exposed to, with the aim of experimentally modelling changes to bean components (responses). Experimental design was used, in a first-ever attempt, to study the effects of five factors and their interactions on the profiles of pH, peptides, and flavanols in the bean during the incubations. Temperature, incubation time and the concentration of acetic acid were the main factors influencing the three responses. Moreover, there was a significant amount of factor interaction, revealing the process to be more complex than initially thought, especially with respect to the role of ethanol. Using the model, one was also able to accurately predict the response of the bean to the exposure to specific factors.


Assuntos
Cacau/metabolismo , Indústria de Processamento de Alimentos/métodos , Modelos Teóricos , Ácido Acético/metabolismo , Cacau/química , Etanol/metabolismo , Fermentação , Concentração de Íons de Hidrogênio , Ácido Láctico/metabolismo , Reprodutibilidade dos Testes , Temperatura Ambiente
10.
Food Microbiol ; 86: 103317, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31703862

RESUMO

The famous French dessert "ile flottante" consists of a sweet egg white foam floating on a vanilla custard cream, which contains highly nutritive raw materials, including milk, sugar and egg. Spoilage issues are therefore a key concern for the manufacturers. This study explored the bacterial diversity of 64 spoiled custard cream desserts manufactured by 2 French companies. B. cereus group bacteria, coagulase negative Staphylococcus, Enterococcus and Leuconostoc spp. were isolated from spoiled products. Thirty-one bacterial isolates representative of the main spoilage species were tested for their spoilage abilities. Significant growth and pH decrease were observed regardless of species. While off-odours were detected with B. cereus group and staphylococci, yoghurt odours were detected with Enterococcus spp. and Leuconostoc spp. B. cereus group bacteria produced various esters and several compounds derived from amino acid and sugar metabolism. Most Staphylococci produced phenolic compounds. Enterococcus spp. and Leuconostoc spp. isolates produced high levels of compounds derived from sugar metabolism. Each type of spoilage bacteria was associated with a specific volatile profile and lactic acid was identified as a potential marker of spoilage of custard cream-based desserts. These findings provide valuable information for manufacturers to improve food spoilage detection and prevention of chilled desserts made with milk and egg.


Assuntos
Bactérias/isolamento & purificação , Bactérias/metabolismo , Clara de Ovo/microbiologia , Microbiologia de Alimentos , Leite/microbiologia , Animais , Bactérias/genética , Galinhas , Humanos , Ácido Láctico/análise , Ácido Láctico/metabolismo , Paladar
11.
Food Microbiol ; 86: 103341, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31703875

RESUMO

The genomic and metabolic features of Lactobacillus sakei were investigated using its pan-genome and by analyzing the metatranscriptome of kimchi fermentation. In the genome-based relatedness analysis, the strains were divided into the Lb. sakei ssp. sakei and Lb. sakei ssp. carnosus lineage groups. Genomic and metabolic pathway analysis revealed that all Lb. sakei strains have the capability of producing d/l-lactate, ethanol, acetate, CO2, formate, l-malate, diacetyl, acetoin, and 2,3-butanediol from d-glucose, d-fructose, d-galactose, sucrose, d-lactose, l-arabinose, cellobiose, d-mannose, d-gluconate, and d-ribose through homolactic and heterolactic fermentation, whereas their capability of d-maltose, d-xylose, l-xylulose, d-galacturonate, and d-glucuronate metabolism is strain-specific. All strains carry genes for the biosynthesis of folate and thiamine, whereas genes for biogenic amine and toxin production, hemolysis, and antibiotic resistance were not identified. The metatranscriptomic analysis showed that the expression of Lb. sakei transcripts involved in carbohydrate metabolism increased as kimchi fermentation progressed, suggesting that Lb. sakei is more competitive during late fermentation stage. Homolactic fermentation pathway was highly expressed and generally constant during kimchi fermentation, whereas expression of heterolactic fermentation pathway increased gradually as fermentation progressed. l-Lactate dehydrogenase was more highly expressed than d-lactate dehydrogenase, suggesting that l-lactate is the major lactate metabolized by Lb. sakei.


Assuntos
Brassica/microbiologia , Genoma Bacteriano , Lactobacillus sakei/genética , Lactobacillus sakei/metabolismo , Verduras/microbiologia , Aminas Biogênicas/metabolismo , Fermentação , Microbiologia de Alimentos , Perfilação da Expressão Gênica , Genômica , Ácido Glucurônico/metabolismo , Ácido Láctico/metabolismo , Lactobacillus sakei/isolamento & purificação , Redes e Vias Metabólicas
12.
PLoS One ; 14(12): e0226094, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31846455

RESUMO

Lactate in the brain is considered an important fuel and signalling molecule for neuronal activity, especially during neuronal activation. Whether lactate is shuttled from astrocytes to neurons or from neurons to astrocytes leads to the contradictory Astrocyte to Neuron Lactate Shuttle (ANLS) or Neuron to Astrocyte Lactate Shuttle (NALS) hypotheses, both of which are supported by extensive, but indirect, experimental evidence. This work explores the conditions favouring development of ANLS or NALS phenomenon on the basis of a model that can simulate both by employing the two parameter sets proposed by Simpson et al. (J Cereb. Blood Flow Metab., 27:1766, 2007) and Mangia et al. (J of Neurochemistry, 109:55, 2009). As most mathematical models governing brain metabolism processes, this model is multi-scale in character due to the wide range of time scales characterizing its dynamics. Therefore, we utilize the Computational Singular Perturbation (CSP) algorithm, which has been used extensively in multi-scale systems of reactive flows and biological systems, to identify components of the system that (i) generate the characteristic time scale and the fast/slow dynamics, (ii) participate to the expressions that approximate the surfaces of equilibria that develop in phase space and (iii) control the evolution of the process within the established surfaces of equilibria. It is shown that a decisive factor on whether the ANLS or NALS configuration will develop during neuronal activation is whether the lactate transport between astrocytes and interstitium contributes to the fast dynamics or not. When it does, lactate is mainly generated in astrocytes and the ANLS hypothesis is realised, while when it doesn't, lactate is mainly generated in neurons and the NALS hypothesis is realised. This scenario was tested in exercise conditions.


Assuntos
Encéfalo/metabolismo , Ácido Láctico/metabolismo , Modelos Teóricos , Algoritmos , Astrócitos/citologia , Astrócitos/metabolismo , Humanos , Neurônios/citologia , Neurônios/metabolismo
13.
Adv Neurobiol ; 23: 331-346, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667814

RESUMO

Brain glycogen stored in astrocytes produces lactate as a neuronal energy source transported by monocarboxylate transporters (MCTs) to maintain neuronal functions, such as hippocampus-regulated memory formation. Although exercise activates brain neurons, the role of astrocytic glycogen in the brain during exercise remains unknown. Since muscle glycogen fuels active muscles during exercise, we hypothesized that astrocytic glycogen plays an energetic role in the brain during exercise to maintain endurance capacity through lactate transport. To explore this hypothesis, we have used a rat model of prolonged exercise, microwave irradiation for the accurate detection of brain glycogen, capillary electrophoresis-mass spectrometry-based metabolomics, and inhibitors of glycogenolysis (1,4-dideoxy-1,4-imino-D-arabinitol; DAB) and lactate transport (α-cyano-4-hydroxycinnamate; 4-CIN). During prolonged exhaustive exercise, muscle glycogen was depleted and brain glycogen decreased when associated with decreased blood glucose levels and increased serotonergic activity known as central fatigue factors, suggesting brain glycogen decrease as an integrative factor for central fatigue. Prolonged exhaustive exercise also increased MCT2 protein in the brain, which takes up lactate in neurons, just as muscle MCTs are increased. Metabolomics revealed that brain but not muscle adenosine triphosphate (ATP) was maintained with lactate and other glycogenolytic and glycolytic sources. Intracerebroventricular (icv) injection of DAB suppressed brain lactate production and decreased hippocampal ATP levels at exhaustion. An icv injection of 4-CIN also decreased hippocampal ATP, resulting in lower endurance capacity. Our findings provide direct evidence that astrocytic glycogen-derived lactate fuels the brain to maintain endurance capacity during exhaustive exercise. Brain ATP levels maintained by glycogen might serve as a possible defense mechanism for neurons in the exhausted state.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Fadiga/metabolismo , Glicogênio/metabolismo , Resistência Física/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Encéfalo/citologia , Glicogenólise , Hipocampo/citologia , Hipocampo/metabolismo , Ácido Láctico/metabolismo , Metabolômica , Neurônios/metabolismo , Ratos
14.
Adv Neurobiol ; 23: 347-361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667815

RESUMO

The astrocyte-neuron lactate transfer shuttle (ANLS) is one of the important metabolic systems that provides a physiological infrastructure for glia-neuronal interactions where specialized architectural organization supports the function. Perivascular astrocyte end-feet take up glucose via glucose transporter 1 to actively regulate glycogen stores, such that high ambient glucose upregulates glycogen and low levels of glucose deplete glycogen stores. A rapid breakdown of glycogen into lactate during increased neuronal activity or low glucose conditions becomes essential for maintaining axon function. However, it fails to benefit axon function during an ischemic episode in white matter (WM). Aging causes a remarkable change in astrocyte architecture characterized by thicker, larger processes oriented parallel to axons, as opposed to vertically-transposing processes. Subsequently, aging axons become more vulnerable to depleted glycogen, although aging axons can use lactate as efficiently as young axons. Lactate equally supports function during aglycemia in corpus callosum (CC), which consists of a mixture of myelinated and unmyelinated axons. Moreover, axon function in CC shows greater resilience to a lack of glucose compared to optic nerve, although both WM tracts show identical recovery after aglycemic injury. Interestingly, emerging evidence implies that a lactate transport system is not exclusive to astrocytes, as oligodendrocytes support the axons they myelinate, suggesting another metabolic coupling pathway in WM. Future studies are expected to unravel the details of oligodendrocyte-axon lactate metabolic coupling to establish that all WM components metabolically cooperate and that lactate may be the universal metabolite to sustain central nervous system function.


Assuntos
Envelhecimento/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Encéfalo/citologia , Encéfalo/metabolismo , Comunicação Celular , Glicogênio/metabolismo , Ácido Láctico/metabolismo , Axônios/metabolismo , Encéfalo/patologia , Glucose/metabolismo , Oligodendroglia/metabolismo
15.
Adv Neurobiol ; 23: 363-383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667816

RESUMO

Cognitive dysfunction is one of the comorbidities of diabetes mellitus, but hippocampus-dependent learning and memory, a component of cognitive function, shows particular decline in type 2 diabetes, suggesting an increased risk for dementia and Alzheimer's disease. Cognitive function is related to dysregulated glucose metabolism, which is the typical cause of type 2 diabetes; however, hippocampal glycogen and its metabolite lactate are also crucial for hippocampus-dependent memory function. Type 2 diabetes induced hippocampus-dependent learning and memory dysfunction can be improved by chronic exercise and this improvement may possibly mediate through an adaptation of the astrocyte-neuron lactate shuttle (ANLS). This chapter focuses on the dysregulation of hippocampal glycometabolism in type 2 diabetes examining both existing evidence as well as the potential underlying pathophysiological mechanism responsible for memory dysfunction in type 2 diabetes, and showing for the first time that chronic exercise could be an effective therapy for type-2-diabetes-induced hippocampal memory decline.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Exercício/fisiologia , Glicogênio/metabolismo , Hipocampo/metabolismo , Memória Espacial , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Terapia por Exercício , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Ácido Láctico/metabolismo , Neurônios/metabolismo
16.
Adv Neurobiol ; 23: 385-433, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667817

RESUMO

Recent studies of glycogen in brain have suggested a much more important role in brain energy metabolism and function than previously recognized, including findings of much higher than previously recognized concentrations, consumption at substantial rates compared with utilization of blood-borne glucose, and involvement in ion pumping and in neurotransmission and memory. However, it remains unclear how glycogenolysis is coupled to neuronal activity and provides support for neuronal as well as astroglial function. At present, quantitative aspects of glycogenolysis in brain functions are very difficult to assess due to its metabolic lability, heterogeneous distributions within and among cells, and extreme sensitivity to physiological stimuli. To begin to address this problem, the present study develops a model based on pathway fluxes, mass balance, and literature relevant to functions and turnover of pathways that intersect with glycogen mobilization. A series of equations is developed to describe the stoichiometric relationships between net glycogen consumption that is predominantly in astrocytes with the rate of the glutamate-glutamine cycle, rates of astrocytic and neuronal glycolytic and oxidative metabolism, and the energetics of sodium/potassium pumping in astrocytes and neurons during brain activation. Literature supporting the assumptions of the model is discussed in detail. The overall conclusion is that astrocyte glycogen metabolism is primarily coupled to neuronal function via fueling glycolytically pumping of Na+ and K+ and sparing glucose for neuronal oxidation, as opposed to previous proposals of coupling neurotransmission via glutamate transport, lactate shuttling, and neuronal oxidation of lactate.


Assuntos
Astrócitos/metabolismo , Glucose/metabolismo , Glutamina/metabolismo , Glicogenólise , Modelos Biológicos , Neurônios/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Astrócitos/enzimologia , Metabolismo Energético , Ácido Láctico/metabolismo , Neurônios/enzimologia
17.
Environ Sci Pollut Res Int ; 26(36): 36236-36247, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31713134

RESUMO

Poly(L-lactic acid) (PLLA) can be used as an external electron donor in denitrification reactors to treat drinking water, aquaculture water, and industrial wastewater with an imbalanced carbon/nitrogen ratio. However, for PLLA to function in these applications, its chemical hydrolyzability requires improvement. Although the adjustment of the crystallinity (Xc) is effective in improving the hydrolyzability of PLLA, the condition for the Xc of PLLA, in which a sufficient amount of lactic acid is released for denitrification, must be clarified. Therefore, this study investigated the effective Xc range and optimal PLLA content as an electron donor for continuous nitrate removal in denitrification reactors. This study also explored the abundance, succession, and diversity of active denitrifying bacteria in denitrification reactors. The nitrate removal activity of activated sludge using the highly crystalline PLLA (Xc = 39.4%) was 1.8 mg NO3- -N g MLSS-1 h-1, which is 2.4 times higher than that using the nearly amorphous PLLA (Xc = 0.9%). During the 57 days of operation, the denitrification reactor with 3% (w/v) highly crystalline PLLA continued to completely remove nitrate, with a maximum nitrate removal activity of 22.8 mg NO3- -N g MLSS-1 h-1. The 16S rRNA amplicon sequencing and clone library analyses are using transcripts of two nitrite reductase genes, encoding cytochrome cd1 nitrite reductase, and copper-containing nitrite reductase revealed that bacteria belonging to the families Comamonadaceae, Rhodocyclaceae, and Alcaligenaceae were active denitrifying bacteria in the denitrification reactor using PLLA.


Assuntos
Bactérias/metabolismo , Reatores Biológicos/microbiologia , Desnitrificação , Nitratos/metabolismo , Poliésteres/metabolismo , Poluentes Químicos da Água/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biodegradação Ambiental , Biodiversidade , Desnitrificação/genética , Hidrólise , Ácido Láctico/química , Ácido Láctico/metabolismo , Nitrito Redutases/genética , Nitrito Redutases/metabolismo , Poliésteres/química , RNA Ribossômico 16S/genética , Eliminação de Resíduos Líquidos/normas
18.
Aquat Toxicol ; 216: 105298, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31586484

RESUMO

Organisms are routinely subjected to a variety of environmental and chemical perturbations simultaneously. Often, multi-stressor exposures result in unpredictable toxicity that occurs through unidentified mechanisms. Here, we focus on polycyclic aromatic hydrocarbons (PAHs) and hypoxia, two environmental and physiological stressors that are known to co-occur in the environment. The aim of this study was to assess whether interactive mitochondrial dysfunction resulted from co-exposures of PAHs and hypoxia. Zebrafish embryos were co-exposed to non-teratogenic concentrations of an environmental PAH mixture and hypoxia beginning at 6 hpf for an acute period of 24 h and afterwards were given either no recovery period, 45 min, 5 -hs, or 18 -hs of recovery time in clean conditions. Mitochondrial function and integrity were assessed through the use of both in ovo and in vitro assays. Hypoxia exposures resulted in drastic reductions in parameters relating to mitochondrial respiration, ATP turnover, and mitochondrial DNA integrity. PAH exposures affected ATP production and content, as well as mitochondrial membrane dynamics and lactate content. While PAH and hypoxia exposures caused a broad range of effects, there appeared to be very little interaction between the two stressors in the co-exposure group. However, because hypoxia significantly altered mitochondrial function, the possibility remains that these effects may limit an individual's ability to respond to PAH toxicity and therefore could cause downstream interactive effects.


Assuntos
Exposição Ambiental , Hipóxia/patologia , Mitocôndrias/patologia , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Área Sob a Curva , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Metabolismo Energético/efeitos dos fármacos , Genoma Mitocondrial , Ácido Láctico/metabolismo , Mitocôndrias/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Peixe-Zebra/genética
19.
J Basic Microbiol ; 59(12): 1195-1207, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31617952

RESUMO

Klebsiella pneumoniae can naturally synthesize 3-hydroxypropionic acid (3-HP), 1,3-propanediol (1,3-PD), and 2,3-butanediol (2,3-BD) from glycerol. However, biosynthesis of these industrially important chemicals is constrained by troublesome byproducts. To clarify the influences of byproducts on 3-HP production, in this study, a total of eight byproduct-producing enzyme genes including pmd, poxB, frdB, fumC, dhaT, ilvH, adhP, and pflB were individually deleted from the K. pneumoniae genome. The resultant eight mutants presented different levels of metabolites. In 24-h shake-flask cultivation, the adhP- and pflB-deletion mutants produced 0.41 and 0.44 g/L 3-HP, respectively. Notably, the adhP and pflB double deletion mutant K. pneumoniaeΔadhPΔpflB produced 1.58 g/L 3-HP in 24-h shake-flask cultivation. When K. pneumoniaeΔadhPΔpflB was harnessed as a host strain to overexpress PuuC, a native aldehyde dehydrogenase (ALDH) catalyzing 3-hydroxypropionaldehyde (3-HPA) to 3-HP, the resulting recombinant strain K. pneumoniaeΔadhPΔpflB(pTAC-puuC) (pTAC-puuC is PuuC expression vector) generated 66.91 g/L 3-HP with a cumulative yield of 70.84% on glycerol in 60-h bioreactor cultivation. Additionally, this strain showed 2.3-, 5.1-, and 0.67-fold decrease in the concentrations of 1,3-PD, 2,3-BD, and acetic acid compared with the reference strain K. pneumoniae(pTAC-puuC). These results indicated that the byproducts exerted differential impacts on the production of 3-HP, 1,3-PD, and 2,3-BD. Although combinatorial elimination of byproduct pathways could reprogram glycerol flux, the enzyme 1,3-propanediol oxidoreductase (DhaT) that catalyzes 3-HPA to 1,3-PD and the enzymes ALDHs, especially, PuuC are most pivotal for 3-HP production. This study provides a deep understanding of how byproducts affect the production of 3-HP, 1,3-PD, and 2,3-BD in K. pneumoniae.


Assuntos
Vias Biossintéticas/fisiologia , Glicerol/metabolismo , Klebsiella pneumoniae/metabolismo , Ácido Láctico/análogos & derivados , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Reatores Biológicos , Vias Biossintéticas/genética , Butileno Glicóis/metabolismo , Expressão Gênica , Técnicas de Inativação de Genes , Klebsiella pneumoniae/genética , Ácido Láctico/metabolismo , Engenharia Metabólica , Propilenoglicóis/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
20.
Nature ; 574(7779): 575-580, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645732

RESUMO

The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases1,2. Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1. Collectively, our results suggest that an endogenous 'lactate clock' in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.


Assuntos
Epigênese Genética , Glicólise/genética , Histonas/química , Histonas/metabolismo , Ácido Láctico/metabolismo , Acetilação , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Homeostase , Humanos , Hipóxia/metabolismo , Lisina/química , Lisina/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Transcrição Genética
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