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1.
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
2.
Curr Opin Pediatr ; 33(4): 423, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34138779
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
Anal Bioanal Chem ; 413(12): 3253-3268, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33791825

RESUMO

With the utilization of small-scale and highly parallelized cultivation platforms embedded in laboratory robotics, microbial phenotyping and bioprocess development have been substantially accelerated, thus generating a bottleneck in bioanalytical bioprocess sample analytics. While microscale cultivation platforms allow the monitoring of typical process parameters, only limited information about product and by-product formation is provided without comprehensive analytics. The use of liquid chromatography mass spectrometry can provide such a comprehensive and quantitative insight, but is often limited by analysis runtime and throughput. In this study, we developed and evaluated six methods for amino acid quantification based on two strong cation exchanger columns and a dilute and shoot approach in hyphenation with either a triple-quadrupole or a quadrupole time-of-flight mass spectrometer. Isotope dilution mass spectrometry with 13C15N labeled amino acids was used to correct for matrix effects. The versatility of the methods for metabolite profiling studies of microbial cultivation supernatants is confirmed by a detailed method validation study. The methods using chromatography columns showed a linear range of approx. 4 orders of magnitude, sufficient response factors, and low quantification limits (7-443 nM) for single analytes. Overall, relative standard deviation was comparable for all analytes, with < 8% and < 11% for unbuffered and buffered media, respectively. The dilute and shoot methods with an analysis time of 1 min provided similar performance but showed a factor of up to 35 times higher throughput. The performance and applicability of the dilute and shoot method are demonstrated using a library of Corynebacterium glutamicum strains producing L-histidine, obtained from random mutagenesis, which were cultivated in a microscale cultivation platform.


Assuntos
Espectrometria de Massas/métodos , Metabolismo , Aminoácidos/análise , Aminoácidos/normas , Proteínas de Bactérias/química , Cromatografia por Troca Iônica/métodos , Corynebacterium glutamicum/metabolismo , Análise de Injeção de Fluxo/métodos , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes
11.
Angew Chem Int Ed Engl ; 60(29): 16139-16148, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-33914416

RESUMO

Destruction of tumor metabolism symbiosis is an attractive cancer treatment method which targets tumor cells with little harm to normal cells. Yet, a single intervention strategy and poor penetration of the drug in tumor tissue result in limited effect. Herein, we propose a zero-waste zwitterion-based hydrogen sulfide (H2 S)-driven nanomotor based on the basic principle of reaction in human body. When loaded with monocarboxylic acid transporter inhibitor α-cyano-4-hydroxycinnamic acid (α-CHCA), the nanomotor can move in tumor microenvironment and induce multiple acidosis of tumor cells and inhibit tumor growth through the synergistic effect of motion effect, driving force H2 S and α-CHCA. Given the good biosafety of the substrate and driving gas of this kind of nanomotor, as well as the limited variety of nanomotors currently available to move in the tumor microenvironment, this kind of nanomotor may provide a competitive candidate for the active drug delivery system of cancer treatment.


Assuntos
Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Metabolismo/efeitos dos fármacos , Nanoestruturas , Linhagem Celular Tumoral , Humanos , Concentração de Íons de Hidrogênio , Microambiente Tumoral/efeitos dos fármacos
12.
Biomed Pharmacother ; 139: 111549, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33901876

RESUMO

The SIRT family of proteins constitutes highly conserved deacetylases with diverse and extensive functions. These proteins have specific biological functions, including regulation of transcription, cell cycle, cell differentiation, apoptosis, stress, metabolism, and genomic stability. Polydatin is a monocrystalline compound isolated from a Chinese herb, Polygonum cuspidatum. The pharmacological mechanisms of polydatin are mostly unclear but involve members of the SIRT protein family, among which SIRT1 plays a vital role. Polydatin is usually considered a potential SIRT1 activator. This review summarizes the signaling mechanism of polydatin involving SIRT1 and discusses the roles of related signal molecules such as PGC-1α, Nrf2, p38-MAPK, NLPR3 inflammasome, and p53. Further, we describe the metabolic regulation of related biological macromolecules and demonstrate that SIRT1, as a metabolic sensor, may act as a new pharmacological target for polydatin.


Assuntos
Glucosídeos/farmacologia , Metabolismo/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Sirtuína 1/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Glucosídeos/uso terapêutico , Humanos , Inflamassomos , Inibidores da Agregação Plaquetária/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Estilbenos/uso terapêutico
13.
mBio ; 12(2)2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849974

RESUMO

Antimicrobial treatment of bacteria often results in a small population of surviving tolerant cells, or persisters, that may contribute to recurrent infection. Antibiotic persisters are metabolically dormant, but the basis of their persistence in the presence of membrane-disrupting biological compounds is less well understood. We previously found that the model plant pathogen Pseudomonas syringae pv. phaseolicola 1448A (Pph) exhibits persistence to tailocin, a membrane-disrupting biocontrol compound with potential for sustainable disease control. Here, we compared physiological traits associated with persistence to tailocin and to the antibiotic streptomycin and established that both treatments leave similar frequencies of persisters. Microscopic profiling of treated populations revealed that while tailocin rapidly permeabilizes most cells, streptomycin treatment results in a heterogeneous population in the redox and membrane permeability state. Intact cells were sorted into three fractions according to metabolic activity, as indicated by a redox-sensing reporter dye. Streptomycin persisters were cultured from the fraction associated with the lowest metabolic activity, but tailocin persisters were cultured from a fraction associated with an active metabolic signal. Cells from culturable fractions were able to infect host plants, while the nonculturable fractions were not. Tailocin and streptomycin were effective in eliminating all persisters when applied sequentially, in addition to eliminating cells in other viable states. This study identifies distinct metabolic states associated with antibiotic persistence, tailocin persistence, and loss of virulence and demonstrates that tailocin is highly effective in eliminating dormant cells.IMPORTANCE Populations of genetically identical bacteria encompass heterogeneous physiological states. The small fraction of bacteria that are dormant can help the population survive exposure to antibiotics and other stresses, potentially contributing to recurring infection cycles in animal or plant hosts. Membrane-disrupting biological control treatments are effective in killing dormant bacteria, but these treatments also leave persister-like survivors. The current work demonstrates that in Pph, persisters surviving treatment with membrane-disrupting tailocin proteins have an elevated redox state compared to that of dormant streptomycin persisters. Combination treatment was effective in killing both persister types. Culturable persisters corresponded closely with infectious cells in each treated population, whereas the high-redox and unculturable fractions were not infectious. In linking redox states to heterogeneous phenotypes of tailocin persistence, streptomycin persistence, and infection capability, this work will inform the search for mechanisms and markers for each phenotype.


Assuntos
Antibacterianos/farmacologia , Bacteriocinas/farmacologia , Viabilidade Microbiana/efeitos dos fármacos , Pseudomonas syringae/efeitos dos fármacos , Pseudomonas syringae/metabolismo , Estreptomicina/farmacologia , Metabolismo/efeitos dos fármacos , Oxirredução , Fenótipo , Pseudomonas syringae/crescimento & desenvolvimento
14.
Nutrients ; 13(4)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918804

RESUMO

Short-chain fatty acids (SCFAs), as products of intestinal bacterial metabolism, are particularly relevant in the diagnosis of intestinal dysbiosis. The most common studies of microbiome metabolites include butyric acid, propionic acid and acetic acid, which occur in varying proportions depending on diet, age, coexisting disease and other factors. During pregnancy, metabolic changes related to the protection of energy homeostasis are of fundamental importance for the developing fetus, its future metabolic fate and the mother's health. SCFAs act as signaling molecules that regulate the body's energy balance through G-protein receptors. GPR41 receptors affect metabolism through the microflora, while GPR43 receptors are recognized as a molecular link between diet, microflora, gastrointestinal tract, immunity and the inflammatory response. The possible mechanism by which the gut microflora may contribute to fat storage, as well as the occurrence of gestational insulin resistance, is blocking the expression of the fasting-induced adipose factor. SCFAs, in particular propionic acid via GPR, determine the development and metabolic programming of the fetus in pregnant women. The mechanisms regulating lipid metabolism during pregnancy are similar to those found in obese people and those with impaired microbiome and its metabolites. The implications of SCFAs and metabolic disorders during pregnancy are therefore critical to maternal health and neonatal development. In this review paper, we summarize the current knowledge about SCFAs, their potential impact and possible mechanisms of action in relation to maternal metabolism during pregnancy. Therefore, they constitute a contemporary challenge to practical nutritional therapy. Material and methods: The PubMed database were searched for "pregnancy", "lipids", "SCFA" in conjunction with "diabetes", "hypertension", and "microbiota", and searches were limited to work published for a period not exceeding 20 years in the past. Out of 2927 publication items, 2778 papers were excluded from the analysis, due to being unrelated to the main topic, conference summaries and/or articles written in a language other than English, while the remaining 126 publications were included in the analysis.


Assuntos
Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal , Metabolismo , Animais , Feminino , Humanos , Metabolismo dos Lipídeos , Obesidade/metabolismo , Gravidez , Complicações na Gravidez/metabolismo
15.
Nutrients ; 13(5)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922358

RESUMO

Binge-eating disorder, recently accepted as a diagnostic category, is differentiated from bulimia nervosa in that the former shows the presence of binge-eating episodes and the absence of compensatory behavior. Epigenetics is a conjunct of mechanisms (like DNA methylation) that regulate gene expression, which are dependent on environmental changes. Analysis of DNA methylation in eating disorders shows that it is reduced. The present study aimed to analyze the genome-wide DNA methylation differences between individuals diagnosed with BED and BN. A total of 46 individuals were analyzed using the Infinium Methylation EPIC array. We found 11 differentially methylated sites between BED- and BN-diagnosed individuals, with genome-wide significance. Most of the associations were found in genes related to metabolic processes (ST3GAL4, PRKAG2, and FRK), which are hypomethylated genes in BED. Cg04781532, located in the body of the PRKAG2 gene (protein kinase AMP-activated non-catalytic subunit gamma 2), was hypomethylated in individuals with BED. Agonists of PRKAG2, which is the subunit of AMPK (AMP-activated protein kinase), are proposed to treat obesity, BED, and BN. The present study contributes important insights into the effect that BED could have on PRKAG2 activation.


Assuntos
Transtorno da Compulsão Alimentar/diagnóstico , Transtorno da Compulsão Alimentar/genética , Metilação de DNA/genética , Metabolismo/genética , Adolescente , Anorexia Nervosa/diagnóstico , Anorexia Nervosa/genética , Feminino , Humanos , Masculino , Projetos Piloto
16.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33805128

RESUMO

Chronic heart failure (CHF) is a disease with important clinical and socio-economic ramifications. Malnutrition and severe alteration of the protein components of the body (protein disarrangements), common conditions in CHF patients, are independent correlates of heart dysfunction, disease progression, and mortality. Autophagy, a prominent occurrence in the heart of patients with advanced CHF, is a self-digestive process that prolongs myocardial cell lifespan by the removal of cytosolic components, such as aging organelles and proteins, and recycles the constituent elements for new protein synthesis. However, in specific conditions, excessive activation of autophagy can lead to the destruction of molecules and organelles essential to cell survival, ultimately leading to organ failure and patient death. In this review, we aim to describe the experimental and clinical evidence supporting a pathophysiological role of nutrition and autophagy in the progression of CHF. The understanding of the mechanisms underlying the interplay between nutrition and autophagy may have important clinical implications by providing molecular targets for innovative therapeutic strategies in CHF patients.


Assuntos
Autofagia , Insuficiência Cardíaca/fisiopatologia , Coração/fisiologia , Desnutrição/fisiopatologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Sobrevivência Celular , Doença Crônica , Citosol/metabolismo , Progressão da Doença , Insuficiência Cardíaca/complicações , Humanos , Desnutrição/complicações , Metabolismo , Camundongos , Músculo Esquelético/metabolismo , Contração Miocárdica , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Ratos , Medição de Risco
17.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921398

RESUMO

The intervertebral disc is the largest avascular organ. Autophagy is an important cell survival mechanism by self-digestion and recycling damaged components under stress, primarily nutrient deprivation. Resident cells would utilize autophagy to cope with the harsh disc environment. Our objective was to elucidate the roles of human disc cellular autophagy. In human disc cells, serum deprivation and pro-inflammatory interleukin-1ß (IL-1ß) stimulation increased autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II and decreased autophagy substrate p62/sequestosome 1 (p62/SQSTM1), indicating enhanced autophagy. Then, RNA interference (RNAi) of autophagy-related gene 5 (ATG5), essential for autophagy, showed decreases in ATG5 protein (26.8%-27.4%, p < 0.0001), which suppressed early-stage autophagy with decreased LC3-II and increased p62/SQSTM1. Cell viability was maintained by ATG5 RNAi in serum-supplemented media (95.5%, p = 0.28) but reduced in serum-free media (80.4%, p = 0.0013) with IL-1ß (69.9%, p = 0.0008). Moreover, ATG5 RNAi accelerated IL-1ß-induced changes in apoptosis and senescence. Meanwhile, ATG5 RNAi unaffected IL-1ß-induced catabolic matrix metalloproteinase release, down-regulated anabolic gene expression, and mitogen-activated protein kinase pathway activation. Lysosomotropic chloroquine supplementation presented late-stage autophagy inhibition with apoptosis and senescence induction, while catabolic enzyme production was modest. Disc-tissue analysis detected age-related changes in ATG5, LC3-II, and p62/SQSTM1. In summary, autophagy protects against human disc cellular apoptosis and senescence rather than extracellular matrix catabolism.


Assuntos
Proteína 5 Relacionada à Autofagia/genética , Disco Intervertebral/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteína Sequestossoma-1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Autofagia/genética , Linhagem Celular , Sobrevivência Celular/genética , Senescência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/patologia , Masculino , Metabolismo/efeitos dos fármacos , Pessoa de Meia-Idade
18.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921428

RESUMO

A hyper-specialization characterizes modern medicine with the consequence of classifying the various diseases of the body into unrelated categories. Such a broad diversification of medicine goes in the opposite direction of physics, which eagerly looks for unification. We argue that unification should also apply to medicine. In accordance with the second principle of thermodynamics, the cell must release its entropy either in the form of heat (catabolism) or biomass (anabolism). There is a decreased flow of entropy outside the body due to an age-related reduction in mitochondrial entropy yield resulting in increased release of entropy in the form of biomass. This shift toward anabolism has been known in oncology as Warburg-effect. The shift toward anabolism has been reported in most diseases. This quest for a single framework is reinforced by the fact that inflammation (also called the immune response) is involved in nearly every disease. This strongly suggests that despite their apparent disparity, there is an underlying unity in the diseases. This also offers guidelines for the repurposing of old drugs.


Assuntos
Imunidade/fisiologia , Medicina/classificação , Metabolismo/fisiologia , Especialização/normas , Reposicionamento de Medicamentos , Entropia , Guias como Assunto , Humanos
19.
Nutrients ; 13(5)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922631

RESUMO

Glycerol monocaprylate (GMC) is a glycerol derivative of medium-chain fatty acids (MCFAs) and is widely used as a preservative in food processing. However, GMC and its hydrolytic acid (octylic acid) have antibacterial properties that may affect the physiology and intestinal microecology of the human body. Therefore, in this study, the effects of two different dosages of GMC (150 and 1600 mg kg-1) on glucose, lipid metabolism, inflammation, and intestinal microecology of normal diet-fed C57BL/6 mice were comprehensively investigated. The obtained results showed that the level of triglycerides (TGs) in the low-dose group down-regulated significantly, and the anti-inflammatory cytokine interleukin 10 (IL-10) significantly increased, while the pro-inflammatory cytokines monocyte chemotactic protein 1 (MCP-1) and interleukin 1beta (IL-1ß) in the high-dose group were significantly decreased. Importantly, GMC promoted the α-diversity of gut microbiota in normal-diet-fed mice, regardless of dosages. Additionally, it was found that the low-dose treatment of GMC significantly increased the abundance of Lactobacillus, while the high-dose treatment of GMC significantly increased the abundance of SCFA-producers such as Clostridiales, Lachnospiraceae, and Ruminococcus. Moreover, the content of short-chain fatty acids (SCFAs) was significantly increased by GMC supplementation. Thus, our research provides a novel insight into the effects of GMC on gut microbiota and physiological characteristics.


Assuntos
Ácidos Graxos Voláteis/biossíntese , Microbioma Gastrointestinal/efeitos dos fármacos , Glicerol/farmacologia , Inflamação/microbiologia , Metabolismo/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Citocinas/sangue , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Hormônios/sangue , Inflamação/sangue , Inflamação/genética , Inflamação/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL
20.
Nat Cell Biol ; 23(4): 413-423, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33795871

RESUMO

Endothelial cells (ECs) adapt their metabolism to enable the growth of new blood vessels, but little is known how ECs regulate metabolism to adopt a quiescent state. Here, we show that the metabolite S-2-hydroxyglutarate (S-2HG) plays a crucial role in the regulation of endothelial quiescence. We find that S-2HG is produced in ECs after activation of the transcription factor forkhead box O1 (FOXO1), where it limits cell cycle progression, metabolic activity and vascular expansion. FOXO1 stimulates S-2HG production by inhibiting the mitochondrial enzyme 2-oxoglutarate dehydrogenase. This inhibition relies on branched-chain amino acid catabolites such as 3-methyl-2-oxovalerate, which increase in ECs with activated FOXO1. Treatment of ECs with 3-methyl-2-oxovalerate elicits S-2HG production and suppresses proliferation, causing vascular rarefaction in mice. Our findings identify a metabolic programme that promotes the acquisition of a quiescent endothelial state and highlight the role of metabolites as signalling molecules in the endothelium.


Assuntos
Proliferação de Células/genética , Células Endoteliais/metabolismo , Proteína Forkhead Box O1/genética , Neovascularização Fisiológica/genética , Animais , Regulação da Expressão Gênica/genética , Glutaratos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Metabolismo/genética , Camundongos , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais/genética , Valeratos/metabolismo
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