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1.
Eur J Endocrinol ; 185(5): R113-R129, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34478405

RESUMO

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is, therefore, critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11ß-hydroxysteroid dehydrogenases 1 and 2 (HSD11B1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive HSD11B1 activity and amplification of local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and ageing-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated mechanisms by which glucocorticoids exert their metabolic effects and have guided us towards more targeted future treatments for metabolic diseases.


Assuntos
Glucocorticoides/farmacologia , Metabolismo/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Glucocorticoides/fisiologia , Humanos , Doenças Metabólicas/metabolismo
2.
Mol Cell ; 81(18): 3659-3664, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34547228

RESUMO

To celebrate our Focus Issue, we asked a selection of researchers working on different aspects of metabolism what they are excited about and what is still to come. They discuss emerging concepts, unanswered questions, things to consider, and technologies that are enabling new discoveries, as well as developing and integrating approaches to drive the field forward.


Assuntos
Metabolismo/fisiologia , Pesquisa/tendências , Humanos , Pesquisadores
3.
Mol Cell ; 81(18): 3775-3785, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34547238

RESUMO

With the elucidation of myriad anabolic and catabolic enzyme-catalyzed cellular pathways crisscrossing each other, an obvious question arose: how could these networks operate with maximal catalytic efficiency and minimal interference? A logical answer was the postulate of metabolic channeling, which in its simplest embodiment assumes that the product generated by one enzyme passes directly to a second without diffusion into the surrounding medium. This tight coupling of activities might increase a pathway's metabolic flux and/or serve to sequester unstable/toxic/reactive intermediates as well as prevent their access to other networks. Here, we present evidence for this concept, commencing with enzymes that feature a physical molecular tunnel, to multi-enzyme complexes that retain pathway substrates through electrostatics or enclosures, and finally to metabolons that feature collections of enzymes assembled into clusters with variable stoichiometric composition. Lastly, we discuss the advantages of reversibly assembled metabolons in the context of the purinosome, the purine biosynthesis metabolon.


Assuntos
Redes e Vias Metabólicas/fisiologia , Metabolismo/fisiologia , Metaboloma/fisiologia , Animais , Humanos , Complexos Multienzimáticos/metabolismo , Mapas de Interação de Proteínas/fisiologia , Purinas/metabolismo
4.
Cells ; 10(9)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34572149

RESUMO

The inflammatory cytokine interleukin-26 (IL-26) is highly expressed in the serum and synovial fluid of patients with inflammatory arthritis. The effect of IL-26 on human articular chondrocytes (HACs) remains unclear. Obesity is associated with disability of patients with rheumatoid arthritis and disease activity in those with ankylosing spondylitis. The saturated free fatty acid palmitate with IL-1ß can synergistically induce catabolic effects in HACs. The aim of this study was to evaluate the effects of IL-26 and palmitate in HACs. In this study, palmitate markedly synergizes the IL-26-induced proinflammatory effects and matrix protease, including COX-2, IL-6, and MMP-1, in HACs via the toll-like receptor 4 (TLR4)-ERK1/2-c-Jun signal transduction pathway. The synergistic catabolic effects of palmitate and IL-26 were attenuated by inhibitors of TLR4 (TAK242), ERK1/2 (U0126), or c-Jun (SP600125) in HACs and cartilage matrix. In addition, metformin, a potential inhibitor of TLR4, also decreased expression of COX-2 and IL-6 induced by co-incubation with IL-26 and palmitate. IL-26 and palmitate synergistically induced expression of inflammatory and catabolic mediators, resulting in articular cartilage matrix breakdown. The present study also revealed a possible mechanism and therapeutic targets against articular cartilage degradation by increased saturated fatty acids in patients with inflammatory arthritis.


Assuntos
Condrócitos/metabolismo , Interleucinas/metabolismo , Palmitatos/metabolismo , Artrite/imunologia , Artrite/metabolismo , Artrite/fisiopatologia , Artrite Reumatoide/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/fisiologia , Genes jun/fisiologia , Humanos , Interleucinas/imunologia , Sistema de Sinalização das MAP Quinases/fisiologia , Metabolismo/fisiologia , Osteoartrite/metabolismo , Transdução de Sinais/genética , Membrana Sinovial/metabolismo , Taiwan , Receptor 4 Toll-Like/metabolismo
5.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575972

RESUMO

Glutamine and lipids are two important components of proliferating cancer cells. Studies have demonstrated that glutamine synthetase (GS) boosts glutamine-dependent anabolic processes for nucleotide and protein synthesis, but the role of GS in regulating lipogenesis remains unclear. This study identified that insulin and glutamine deprivation activated the lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP1) that bound to the GS promoter and increased its transcription. Notably, GS enhanced the O-linked N-acetylglucosaminylation (O-GlcNAcylation) of the specificity protein 1 (Sp1) that induced SREBP1/acetyl-CoA carboxylase 1 (ACC1) expression resulting in lipid droplet (LD) accumulation upon insulin treatment. Moreover, glutamine deprivation induced LD formation through GS-mediated O-GlcNAc-Sp1/SREBP1/ACC1 signaling and supported cell survival. These findings demonstrate that insulin and glutamine deprivation induces SREBP1 that transcriptionally activates GS, resulting in Sp1 O-GlcNAcylation. Subsequently, O-GlcNAc-Sp1 transcriptionally upregulates the expression of SREBP1, resulting in a feedforward loop that increases lipogenesis and LD formation in liver and breast cancer cells.


Assuntos
Acetil-CoA Carboxilase/genética , Glutamato-Amônia Ligase/genética , Neoplasias Hepáticas/genética , Fator de Transcrição Sp1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Glutamina/metabolismo , Humanos , Insulina/metabolismo , Lipídeos/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metabolismo/genética , Regiões Promotoras Genéticas/genética , Biossíntese de Proteínas/genética , Transdução de Sinais , beta-N-Acetil-Hexosaminidases/genética
6.
Crit Care Med ; 49(12): 2112-2120, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34582409

RESUMO

OBJECTIVES: Sepsis is a common condition in the ICU. Despite much research, its prognosis remains poor. In 2017, a retrospective before/after study reported promising results using a combination of thiamine, ascorbic acid, and hydrocortisone called "metabolic resuscitation cocktail" and several randomized controlled trials assessing its effectiveness were performed. DESIGN: We conducted a systematic review and meta-analysis of randomized controlled trials in septic ICU patients to assess the effects of this combination therapy. SETTING: PubMed, Embase, and the Cochrane library databases were searched from inception to March of 2021. Data were extracted independently by two authors. The main outcome was the change in Sequential Organ Failure Assessment score within 72 hours. Secondary outcomes included renal composite endpoints (acute kidney injury) Kidney Disease - Improving Global Outcome organization stage 3 or need for renal replacement therapy, vasopressor duration, and 28-day mortality. SUBJECTS: We included randomized controlled trials with patients admitted to the ICU with sepsis or septic shock. INTERVENTION: The trials compared a combination of thiamine, ascorbic acid, and hydrocortisone to standard care or placebo in patients admitted to ICU with sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: We included eight randomized controlled trials (n = 1,335 patients). Within 72 hours, the median of mean improvement was -1.8 and -3.2 in the control and intervention groups, respectively (eight randomized controlled trials, n = 1,253 patients); weighted mean difference -0.82 (95% CI, -1.15 to -0.48). Data were homogeneous and the funnel plot did not suggest any publication bias. Duration of vasopressor requirement was significantly reduced in the intervention group (six randomized controlled trials). There was no evidence of a difference regarding the ICU mortality and the renal composite outcome (acute kidney injury KDIGO 3 or need for renal replacement therapy, seven randomized controlled trials). CONCLUSIONS: Metabolic resuscitation cocktail administrated in ICU septic patients improves change in Sequential Organ Failure Assessment score within 72 hours. However, this improvement is modest and its clinical relevance is questionable. The impact on renal failure and mortality remains unclear.


Assuntos
Ácido Ascórbico/metabolismo , Hidrocortisona/metabolismo , Metabolismo/efeitos dos fármacos , Sepse/tratamento farmacológico , Tiamina/metabolismo , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Combinação de Medicamentos , Humanos , Hidrocortisona/farmacologia , Hidrocortisona/uso terapêutico , Ontário , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Sepse/fisiopatologia , Tiamina/farmacologia , Tiamina/uso terapêutico
7.
Elife ; 102021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34350825

RESUMO

Understanding the origin and maintenance of biodiversity is a fundamental problem. Many theoretical approaches have been investigating ecological interactions, such as competition, as potential drivers of diversification. Classical consumer-resource models predict that the number of coexisting species should not exceed the number of distinct resources, a phenomenon known as the competitive exclusion principle. It has recently been argued that including physiological tradeoffs in consumer-resource models can lead to violations of this principle and to ecological coexistence of very high numbers of species. Here, we show that these results crucially depend on the functional form of the tradeoff. We investigate the evolutionary dynamics of resource use constrained by tradeoffs and show that if the tradeoffs are non-linear, the system either does not diversify or diversifies into a number of coexisting species that do not exceed the number of resources. In particular, very high diversity can only be observed for linear tradeoffs.


Assuntos
Biodiversidade , Evolução Biológica , Metabolismo , Fenômenos Bioquímicos , Ecossistema , Modelos Biológicos , Dinâmica Populacional , Especificidade da Espécie
8.
Bioessays ; 43(10): e2100103, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34426986

RESUMO

The systems view on life and its emergence from complex chemistry has remarkably increased the scientific attention on metabolism in the last two decades. However, during this time there has not been much theoretical discussion on what constitutes a metabolism and what role it actually played in biogenesis. A critical and updated review on the topic is here offered, including some references to classical models from last century, but focusing more on current and future research. Metabolism is considered as intrinsically related to the living but not necessarily equivalent to it. More precisely, the idea of "minimal metabolism", in contrast to previous, top-down conceptions, is formulated as a heuristic construct, halfway between chemistry and biology. Thus, rather than providing a complete or final characterization of metabolism, our aim is to encourage further investigations on it, particularly in the context of life's origin, for which some concrete methodological suggestions are provided. Also see the video abstract here: https://youtu.be/DP7VMKk2qpA.


Assuntos
Metabolismo/fisiologia
9.
Nat Protoc ; 16(9): 4299-4326, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34321638

RESUMO

Metabolic phenotyping is an important tool in translational biomedical research. The advanced analytical technologies commonly used for phenotyping, including mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy, generate complex data requiring tailored statistical analysis methods. Detailed protocols have been published for data acquisition by liquid NMR, solid-state NMR, ultra-performance liquid chromatography (LC-)MS and gas chromatography (GC-)MS on biofluids or tissues and their preprocessing. Here we propose an efficient protocol (guidelines and software) for statistical analysis of metabolic data generated by these methods. Code for all steps is provided, and no prior coding skill is necessary. We offer efficient solutions for the different steps required within the complete phenotyping data analytics workflow: scaling, normalization, outlier detection, multivariate analysis to explore and model study-related effects, selection of candidate biomarkers, validation, multiple testing correction and performance evaluation of statistical models. We also provide a statistical power calculation algorithm and safeguards to ensure robust and meaningful experimental designs that deliver reliable results. We exemplify the protocol with a two-group classification study and data from an epidemiological cohort; however, the protocol can be easily modified to cover a wider range of experimental designs or incorporate different modeling approaches. This protocol describes a minimal set of analyses needed to rigorously investigate typical datasets encountered in metabolic phenotyping.


Assuntos
Técnicas Genéticas , Metabolômica/métodos , Fenótipo , Software , Estatística como Assunto , Humanos , Metabolismo
10.
Acta Orthop Traumatol Turc ; 55(3): 246-252, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34100366

RESUMO

OBJECTIVE: The aim of this study was to explore the alterations in levels of pro-inflammatory and catabolic mediators following vertebral fusion in a rabbit model of intervertebral disc degeneration. METHODS: In this study, 24 female New Zealand albino rabbits (aged 4 to 5 months and weighing 3 to 3.5 kg) were used. All the animals were randomly categorized into four groups, and dorsal spinal exposure of all lumbar vertebrae was routinely performed in each group. While disc degeneration was created in groups B, C, and D, spinal fusion was added to disc degeneration in groups C and D. Disc degeneration was typically created by puncturing the discs with an 18-gauge needle under the guidance of C-arm imaging. Fusion was achieved with posterior/posterolateral decortication and iliac bone grafts. The rabbits in groups A, B, and C were euthanized, and the discs were removed in the first week after the surgery. The rabbits in Group D were sacrificed, and the discs were harvested at 5 weeks after the surgery. The levels of Interleukin (IL)-1ß, IL-6, Nitric Oxide (NO), Matrix Metalloproteinase (MMP)-3, MMP-13, and Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) in the discs were analyzed using enzyme-linked immunosorbent assay kits. RESULTS: Significant increase was observed in the protein levels of both pro-inflammatory and catabolic mediators in disc degeneration groups (Group B, C, and D) compared to Group A. In the fusion groups (Group C and D), these increased mediators decreased, compared to non-fusion group (Group B), (IL1-ß P = 0.017, TIMP-1 P = 0.03, NO P = 0.03). However, there was no statistically significant difference in mediator levels between the short- and long-term fusion (Group C versus D). CONCLUSION: The results of this study have shown that a significant decrease in pro-inflammatory and catabolic mediators may be expected after vertebral fusion whereas there may be no significant difference between the first and fourth week of fusion surgery. These findings may contribute to clarifying the mechanism of action of vertebral fusion in the treatment of low back pain.


Assuntos
Degeneração do Disco Intervertebral , Disco Intervertebral , Vértebras Lombares/cirurgia , Fusão Vertebral/métodos , Animais , Mediadores da Inflamação/análise , Interleucina-1beta/análise , Interleucina-6/análise , Disco Intervertebral/metabolismo , Disco Intervertebral/cirurgia , Degeneração do Disco Intervertebral/imunologia , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/cirurgia , Dor Lombar/etiologia , Dor Lombar/imunologia , Dor Lombar/prevenção & controle , Metaloproteinase 3 da Matriz/análise , Metabolismo , Óxido Nítrico/análise , Coelhos
11.
Curr Opin Pediatr ; 33(4): 423, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34138779
12.
J Trauma Acute Care Surg ; 91(2S Suppl 2): S176-S181, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34117171

RESUMO

BACKGROUND: Severe burn injury results in profound catabolic deterioration. Although burn-related catabolism has been well stated, it is unclear when the catabolic response begins. This study characterized acute changes of muscle protein breakdown at the admission and the day after in severely burned adults. METHODS: Twelve patients (43 ± 19 years old) with 40% ± 21% total body surface area burns were prospectively enrolled into an observational study approved by institutional review board. Urinary samples were collected on admission day and the day after (day 1). Patient demographic and clinical data of vital signs, blood gas and chemistry, and coagulation status were collected. Catabolic changes of muscle breakdown were quantified by urinary excretion of 3-methylhisitidine, determined by gas chromatography and mass spectrometry analysis. RESULTS: Compared with admission day, burned patients had elevated mean ± SD arterial pressure (from 90 ± 5 mm Hg to 108 ± 7 mm Hg) and heart rate (from 102 ± 7 beats per minute to 119 ± 4 beats per minute both p < 0.05) after 24 hours. Their 24-hour urinary output was 1,586 ± 813 mL at admission day to 1,911 ± 1,048 mL on day 1. The 24-hour urea excretion was elevated from 172 ± 101 mg/kg per day at admission day to 302 ± 183 mg/kg per day on day 1 (both p < 0.05), with no change in creatinine excretion. Urinary 3-methylhisitidine excretion increased from 0.75 ± 0.74 mg/kg per day at admission to 1.14 ± 0.86 mg/kg per day on day 1 (p < 0.05). The estimated skeletal muscle protein breakdown was increased from 1.1 ± 1.0 g/kg per day at admission day to 1.6 ± 1.2 g/kg per day on day 1 (p < 0.05). There were no changes in prothrombin time, activated partial thromboplastin time, or platelets. CONCLUSION: In severely burned patients, catabolic muscle protein breakdown is elevated within 24 hours after admission and before changes in coagulation. These findings suggest that early interventions may be needed to effectively attenuate the catabolic responses in burn patients. LEVEL OF EVIDENCE: Prospective and observational study, level II.


Assuntos
Queimaduras/complicações , Músculo Esquelético/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Proteínas Sanguíneas/análise , Queimaduras/patologia , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Hemodinâmica , Humanos , Masculino , Metabolismo , Metilistidinas/urina , Pessoa de Meia-Idade , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Estudos Prospectivos , Fatores de Tempo , Equilíbrio Hidroeletrolítico , Adulto Jovem
13.
Arch. latinoam. nutr ; 71(2): 114-126, jun. 2021. tab
Artigo em Espanhol | LILACS, LIVECS | ID: biblio-1290833

RESUMO

La mayoría de los estudios apoyan la tesis de que el desayuno es la comida más importante del día. Un desayuno adecuado contribuye a lograr un patrón dietético global saludable y a mejorar la calidad de la dieta. El objetivo de este estudio fue determinar los principales patrones de desayuno en tres poblaciones universitarias de España, Túnez y Estados Unidos, analizar sus semejanzas y diferencias y estudiar la influencia de factores antropométricos, sociodemográficos y de estilo de vida en la adherencia a cada patrón. Se realizó un estudio transversal con datos de 730 estudiantes matriculados en las Universidades de Castilla-La Mancha, Cartago e Internacional de Florida en 2013. El consumo de alimentos se obtuvo mediante dos recordatorios de 24 horas, no consecutivos, uno de ellos en fin de semana. Los patrones se identificaron mediante análisis factorial exploratorio. La adherencia de los estudiantes a cada patrón se evaluó usando las puntuaciones factoriales. Se obtuvieron cuatro patrones para cada país. El principal patrón de los universitarios españoles incluyó pan, tomate, sal y aceite de oliva (varianza explicada: 20,85%); el principal de los tunecinos contenía pan, mermelada, nata y mantequilla (varianza explicada: 12,73%) y el principal de los americanos incluyó huevos, leche entera y azúcares (varianza explicada: 10,77%). Género, peso, IMC o comer fuera de casa fueron factores que influyeron en la adherencia a diferentes patrones. El estudio mostró la coexistencia de patrones tradicionales con otros occidentalizados y modelos transicionales intermedios. No se determinó un patrón generalizable asociado a mejores resultados del IMC(AU)


Most studies support the conclusion that breakfast is the most important meal of the day. An adequate breakfast contributes to achieving a healthy global dietary pattern and improving quality of diet. The objective of this study was to determine the main breakfast patterns of three university populations from Spain, Tunisia, and The United States of America, analyze their similarities and differences, and study the impact of anthropometric, sociodemographic and lifestyle factors on the adherence to each pattern. A cross-sectional study was developed with data from 730 students enrolled at the University of Castilla-La Mancha, University of Carthage, and Florida International University, during 2013. Food consumption data were obtained by means of two non-consecutive 24-hour recalls including one weekend day. Exploratory factor analysis was conducted to identify breakfast patterns. Factor scores were used to assess students' adherence to each pattern. Four breakfast patterns were obtained for each country. The main pattern of the Spanish students included bread, tomato, salt, and olive oil (explained variance: 20.85%); the main model of the Tunisians included bread, jam, cream and butter (explained variance: 12.73%); and the first pattern of the Americans was characterized by eggs, whole milk and sugars (explained variance: 10.77%). Gender, weight, BMI or eating out of home were factors that influenced the adherence to different patterns. Breakfast patterns obtained in this work showed the coexistence of traditional models with westernized and transitional ones. It was not determined a generalizable pattern associated with better BMI results(AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Ingestão de Alimentos , Comportamento Alimentar , Desjejum , Estilo de Vida , Índice de Massa Corporal , Nutrientes , Antropometria , Metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-34118407

RESUMO

Fish skeletal muscles are composed of two distinct types, slow and fast muscles, and they play important roles in maintaining the body's movement and energy metabolism. The two types of muscle are easy to separate, so they are often used as the model system for studies on their physiological and functional characteristics. In this study, we revealed that the carbohydrate and lipid metabolic KEGG pathways are different between slow and fast muscles of Chinese perch with transcriptome analysis. In fast muscle, glucose metabolism was catabolic with higher glycolysis capacity, while in slow muscle, glucose metabolism was anabolic with more glycogen synthesis. In addition, oxidative metabolism in slow muscle was stronger than that in fast muscle. By analyzing the expression levels of 40 miRNAs involved in metabolism in the muscles of Chinese perch, 18 miRNAs were significantly upregulated and 7 were significantly downregulated in slow muscle compared with fast muscle. Based on functional enrichment analysis of their target genes, the differential expression levels of 17 miRNAs in slow and fast muscles were reflected in their carbohydrate and lipid metabolism. Among these, 15 miRNAs were associated with carbohydrate metabolism, and 6 miRNAs were associated with lipid metabolism. After 3 days of starvation, the expression levels of 15 miRNAs involved in glucose metabolism in fast and slow muscles increased. However, after 7 days of starvation, the mRNA levels of miR-22a, miR-23a, miR-133a-3p, miR-139, miR-143, miR-144, miR-181a and miR-206 decreased to basal levels. Our data suggest that the possible reason for the difference in glucose and lipid metabolism is that more miRNAs inhibit the expression of target genes in slow muscle.


Assuntos
Metabolismo Energético , Perfilação da Expressão Gênica , MicroRNAs/metabolismo , Músculo Esquelético/metabolismo , Percas/fisiologia , Ciências da Nutrição Animal , Animais , Comportamento Alimentar , Biblioteca Gênica , Glucose/metabolismo , Glicogênio/metabolismo , Glicólise , Metabolismo dos Lipídeos , Metabolismo , Miosinas/química , Oxigênio/metabolismo , Isoformas de Proteínas
15.
Dev Cell ; 56(13): 1961-1975.e5, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34107300

RESUMO

Autophagy is an essential catabolic process induced to provide cellular energy sources in response to nutrient limitation through the activation of kinases, like AMP-activated protein kinase (AMPK) and ULK1. Although glucose starvation induces autophagy, the exact mechanism underlying this signaling has yet to be elucidated. Here, we reveal a role for ULK1 in non-canonical autophagy signaling using diverse cell lines. ULK1 activated by AMPK during glucose starvation phosphorylates the lipid kinase PIKfyve on S1548, thereby increasing its activity and the synthesis of the phospholipid PI(5)P without changing the levels of PI(3,5)P2. ULK1-mediated activation of PIKfyve enhances the formation of PI(5)P-containing autophagosomes upon glucose starvation, resulting in an increase in autophagy flux. Phospho-mimic PIKfyve S1548D drives autophagy upregulation and lowers autophagy substrate levels. Our study has identified how ULK1 upregulates autophagy upon glucose starvation and induces the formation of PI(5)P-containing autophagosomes by activating PIKfyve.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Autofagia/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Quinases/genética , Autofagossomos/genética , Autofagossomos/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/genética , Glucose/metabolismo , Humanos , Metabolismo/genética , Fosfatos de Fosfatidilinositol/genética , Fosfolipídeos/genética , Transdução de Sinais/genética
16.
Dev Cell ; 56(13): 1989-2006.e6, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34118203

RESUMO

Oncogenes can alter metabolism by changing the balance between anabolic and catabolic processes. However, how oncogenes regulate tumor cell biomass remains poorly understood. Using isogenic MCF10A cells transformed with nine different oncogenes, we show that specific oncogenes reduce the biomass of cancer cells by promoting extracellular vesicle (EV) release. While MYC and AURKB elicited the highest number of EVs, each oncogene selectively altered the protein composition of released EVs. Likewise, oncogenes alter secreted miRNAs. MYC-overexpressing cells require ceramide, whereas AURKB requires ESCRT to release high levels of EVs. We identify an inverse relationship between MYC upregulation and activation of the RAS/MEK/ERK signaling pathway for regulating EV release in some tumor cells. Finally, lysosome genes and activity are downregulated in the context of MYC and AURKB, suggesting that cellular contents, instead of being degraded, were released via EVs. Thus, oncogene-mediated biomass regulation via differential EV release is a new metabolic phenotype.


Assuntos
Aurora Quinase B/genética , Vesículas Extracelulares/metabolismo , Oncogenes/genética , Proteínas Proto-Oncogênicas c-myc/genética , Metabolismo Energético/genética , Vesículas Extracelulares/genética , Regulação Neoplásica da Expressão Gênica , Genes ras/genética , Humanos , Lisossomos/genética , MAP Quinase Quinase Quinases/genética , Sistema de Sinalização das MAP Quinases/genética , Metabolismo/genética , Transdução de Sinais/genética
17.
Res Vet Sci ; 137: 159-162, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33984619

RESUMO

Indoleamine 2,3-deoxygenase (IDO) produced by cancer cells catabolizes tryptophan (TRP) to kynurenine (KYN) in the environment, resulting induction of cancer immune escape through induction of T cell anergy and enhancement of regulatory T cells. Recently, inhibition of IDO has been recognized as one of therapeutic strategies for human neoplastic diseases. However, there have been few reports about IDO-expressing cancers in dogs. In this study, we attempted to examine whether canine mast cell tumour (MCT) cells express IDO and modulate the concentration of TRP and KYN in the environment. BR, MPT-1.2, and MPT-3 cells were used as canine MCT cells. Expression of IDO was examined with RT-PCR and western blotting. Concentrations of TRP and KYN in the culture medium after incubation with canine MCT cells were detected with liquid chromatography-tandem mass spectrometry. The expression of mRNA and protein of IDO were confirmed in all samples extracted from canine MCT cells. TRP concentration in the culture medium was decreased and that of KYN was increased on incubation with canine MCT cells. The ratio of KYN/TRP, widely considered to represent IDO activity, was also significantly elevated. Moreover, treatment with an IDO inhibitor L-1-methyl-tryptophan (L-1MT) clearly diminished the elevation of KYN/TRP ratio induced by the incubation with canine MCT cells. Our results indicate that canine MCT cells could directly regulate the concentrations of TRP and KYN through expressing IDO, suggesting that canine MCT have an immune escape ability. Therefore, inhibition of IDO might be a novel strategy for the treatment of dogs with MCT.


Assuntos
Doenças do Cão/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Mastócitos , Neoplasias/metabolismo , Triptofano/metabolismo , Animais , Linhagem Celular Tumoral , Cães , Humanos , Cinurenina/metabolismo , Metabolismo
18.
Rev. Pesqui. Fisioter ; 11(2): 328-333, Maio 2021. ilus, tab
Artigo em Inglês, Português | LILACS | ID: biblio-1253509

RESUMO

OBJETIVO: Verificar os efeitos do treinamento de escada e atividade física na histomorfometria do tecido adiposo marrom em camundongos C57BL/6. MATERIAIS E MÉTODOS: Amostra composta por 16 camundongos, divididos aleatoriamente: controle (n=4), exercício de escada com estímulo elétrico (n=4), exercício de escada (n=4) e atividade física em ambiente enriquecido (n=4). Grupo de atividade física em ambiente enriquecido foi realizada em caixa com brinquedos. Grupo exercício de escada e escada com estímulo elétrico foram realizadas com escada vertical. Com a utilização da escada os animais realizaram 6 séries, 8 repetições com intervalos de 90 segundos entre séries, sendo 10 sessões. No exercício de escada com estimulo elétrico, o animal foi estimulado a subir usando uma placa de aço na base da escada, com uma corrente elétrica de 20V de intensidade e 45 hz de frequência. A coleta de tecido adiposo marrom foi feita na região escapular e manchado em Hematoxilina-Eosina (HE). O nível de significância das análises era 95% (p < 0.05). RESULTADOS: Não houve diferença significativa no comparativo do tamanho da célula de TAM em comparação com o tecido recolhido dos camundongos dos quatro grupos. CONCLUSÃO: A atividade física e o exercício resistido não promoveram diferenças morfometricas no TAM dos camundongos C57BL/6.


OBJECTIVE: To verify the effects of stair training and physical activity on brown adipose tissue histomorphometry in C57BL / 6 mice. MATERIALS AND METHODS: Sample composed of 16 mice, randomly divided: control (n = 4), stair exercise with electrical stimulus (n = 4), stair exercise (n = 4) and physical activity in an enriched environment (n = 4). A Group of physical activity in an enriched environment was performed in a box with toys. Ladder exercise group and ladder with electrical stimulus were performed with vertical ladder. With the ladder's use, the animals performed six sets, eight repetitions with 90-second intervals between sets, with ten sessions. In the stairway exercise with electrical stimulation, the animal was encouraged to climb using a steel plate at the base of the stairs, with an electric current of 20V intensity and 45Hz frequency. Brown adipose tissue collection was performed in the scapular region and stained with Hematoxylin-Eosin (HE). The level of significance of the analyzes was 95% (p <0.05). RESULTS: There was no significant difference when comparing the TAM cell size compared to the tissue collected from the mice in the four groups. CONCLUSION: Physical activity and resistance exercise did not promote morphometric differences in the TAM of C57BL/6 mice.


Assuntos
Exercício Físico , Metabolismo , Camundongos
19.
Sci Rep ; 11(1): 10185, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986319

RESUMO

Pronounced temporal and spatial variation in the availability of food resources can produce energetic deficits in organisms. Fruit-dependent Bornean orangutans face extreme variation in fruit availability and experience negative energy and protein balance during episodes of fruit scarcity. We evaluate the possibility that orangutans of different sexes and ages catabolize muscle tissue when the availability of fruit is low. We assess variation in muscle mass by examining the relationship between urinary creatinine and specific gravity and use the residuals as a non-invasive measure of estimated lean body mass (ELBM). Despite orangutans having a suite of adaptations to buffer them from fruit scarcity and associated caloric deficits, ELBM was lower during low fruit periods in all age-sex classes. As predicted, adult male orangutans had higher ELBM than adult females and immatures. Contrary to expectation, flanged and unflanged males did not differ significantly in ELBM. These findings highlight the precarity of orangutan health in the face of rapid environmental change and add to a growing body of evidence that orangutans are characterized by unique metabolic traits shaped by their unpredictable forest environment.


Assuntos
Creatina/análise , Músculo Esquelético/metabolismo , Pongo pygmaeus/metabolismo , Animais , Comportamento Animal/fisiologia , Creatina/urina , Ecossistema , Comportamento Alimentar/fisiologia , Feminino , Insegurança Alimentar , Florestas , Frutas , Masculino , Metabolismo/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Pongo/fisiologia , Pongo pygmaeus/fisiologia
20.
Rev. Eugenio Espejo ; 15(2): 115-136, 20210516.
Artigo em Espanhol | LILACS | ID: biblio-1252504

RESUMO

Blastocystis es un stramenopile o cromista, pleomórfico no móvil. Se han identificado diecinue-ve subtipos de este organismo (ST1-ST19). Tiene una presencia a nivel mundial. Este microor-ganismo tiene un metabolismo intermediario anaeróbico. Un aspecto interesante de la bioquími-ca de este stramenopile está dado por la presencia de organelas similares a mitocondrias con un conjunto de rutas: cadena de fosforilación oxidativa incompleta, ciclo de Krebs parcial, metabo-lismo de ácidos grasos (anabolismo y catabolismo), metabolismo de aminoácidos y ensamblaje de proteínas con centros hierro/azufre. El tratamiento se ha basado tradicionalmente en metroni-dazol y otros imidazoles. Sin embargo, hay un número creciente de cepas resistentes a esos medicamentos. La reciente obtención del genoma nuclear y los estudios bioquímicos, proteómi-cos, metabolómicos, interactómicos permitirán el desarrollo racional de nuevos fármacos curati-vos. El objetivo de esta revisión es describir el metabolismo de Blastocystis spp


Blastocystis is a stramenopile or chromist, nonmobile pleomorphic. Nineteen subtypes of this organism (ST1-ST19) have been identified worldwide. This microorganism has an intermediate anaerobic metabolism. An interesting aspect of the biochemistry of this stramenopile is given by the presence of mitochondrial-like organelles with a set of pathways: incomplete oxidative phos-phorylation chain, partial Krebs cycle, fatty acid metabolism (anabolism and catabolism), amino acid metabolism and protein assembly with iron / sulfur centers. Treatment has traditionally been based on metronidazole and other imidazoles. However, there are a growing number of strains resistant to these drugs. The recent obtaining of the nuclear genome and the biochemical, proteomic, metabolomic and interactomic studies will allow the rational development of new curative drugs. The objective of this review is to describe the metabolism of Blastocystis spp.


Assuntos
Humanos , Masculino , Feminino , Doenças Parasitárias , Blastocystis , Metabolismo , Anaerobiose , Metronidazol , Antígenos de Protozoários
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