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1.
Adv Exp Med Biol ; 1269: 169-177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33966213

RESUMO

Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary and permanent consequence of dysfunctional mitochondria compensating for a poor ATP yield per mole glucose. Instead, the Warburg effect is an essential part of a "selfish" metabolic reprogramming, which results from the interplay between (normoxic or hypoxic) HIF-1 overexpression, oncogene activation (cMyc, Ras), loss of function of tumor suppressors (mutant p53, mutant PTEN, microRNAs and sirtuins with suppressor functions), activated (PI3K/Akt/mTORC1, Ras/Raf/Mek/Erk/c-Myc) or deactivated (AMPK) signaling pathways, components of the tumor microenvironment, and HIF-1 cooperations with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include (a) considerably accelerated glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, nonessential amino acids, lipids, and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate which stimulates tumor growth and suppression of antitumor immunity (in addition, lactate can serve as an energy source for normoxic cancer cells, contributes to extracellular acidosis, and thus drives malignant progression and resistances to conventional therapies); (f) maintenance of the cellular redox homeostasis and low ROS formation; and (g) HIF-1 overexpression, mutant p53, and mutant PTEN which inhibit mitochondrial biogenesis and functions, thus negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e., aerobic glycolysis in the presence of oxygen and - in principle - functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and - finally - poor patient outcome.


Assuntos
Neoplasias , Fosfatidilinositol 3-Quinases , Ciclo do Ácido Cítrico , Glicólise , Humanos , Neoplasias/genética , Microambiente Tumoral
2.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33803922

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by a sustained elevation of pulmonary artery (PA) pressure, right ventricular failure, and premature death. Enhanced proliferation and resistance to apoptosis (as seen in cancer cells) of PA smooth muscle cells (PASMCs) is a major pathological hallmark contributing to pulmonary vascular remodeling in PAH, for which current therapies have only limited effects. Emerging evidence points toward a critical role for Enhancer of Zeste Homolog 2 (EZH2) in cancer cell proliferation and survival. However, its role in PAH remains largely unknown. The aim of this study was to determine whether EZH2 represents a new factor critically involved in the abnormal phenotype of PAH-PASMCs. We found that EZH2 is overexpressed in human lung tissues and isolated PASMCs from PAH patients compared to controls as well as in two animal models mimicking the disease. Through loss- and gain-of-function approaches, we showed that EZH2 promotes PAH-PASMC proliferation and survival. By combining quantitative transcriptomic and proteomic approaches in PAH-PASMCs subjected or not to EZH2 knockdown, we found that inhibition of EZH2 downregulates many factors involved in cell-cycle progression, including E2F targets, and contributes to maintain energy production. Notably, we found that EZH2 promotes expression of several nuclear-encoded components of the mitochondrial translation machinery and tricarboxylic acid cycle genes. Overall, this study provides evidence that, by overexpressing EZH2, PAH-PASMCs remove the physiological breaks that normally restrain their proliferation and susceptibility to apoptosis and suggests that EZH2 or downstream factors may serve as therapeutic targets to combat pulmonary vascular remodeling.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteoma/genética , Hipertensão Arterial Pulmonar/genética , Transcriptoma/genética , Animais , Apoptose/genética , Proliferação de Células/genética , Ciclo do Ácido Cítrico/genética , Epigênese Genética/genética , Feminino , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/crescimento & desenvolvimento , Artéria Pulmonar/patologia , Ratos
3.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803109

RESUMO

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Regulação da Expressão Gênica , Mitocôndrias/metabolismo , Proteínas Mitocondriais/biossíntese , Mutação de Sentido Incorreto , Biossíntese de Proteínas , Proteínas Ribossômicas/biossíntese , Trifosfato de Adenosina/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Animais , Encéfalo/patologia , Ciclo do Ácido Cítrico/genética , Técnicas de Introdução de Genes , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Proteínas Ribossômicas/genética
4.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33804948

RESUMO

Jerusalem artichokes are a perennial crop with high drought tolerance and high value as a raw material to produce biofuels, functional feed, and food. However, there are few comprehensive metabolomic studies on Jerusalem artichokes under drought conditions. METHODS: Ultra-performance liquid chromatography and tandem mass spectrometry were used to identify differential metabolites in Jerusalem artichoke seedling leaves under polyethylene glycol (PEG) 6000-simulated drought stress at 0, 18, 24, and 36 h. RESULTS: A total of 661 metabolites and 236 differential metabolites were identified at 0 vs. 18, 18 vs. 24, and 24 vs. 36 h. 146 differential metabolites and 56 common were identified and at 0 vs. 18, 24, and 36 h. Kyoto Encyclopedia of Genes and Genomes enrichment identified 236 differential metabolites involved in the biosynthesis of secondary metabolites and amino acids. Metabolites involved in glycolysis, phenolic metabolism, tricarboxylic cycle, glutamate-mediated proline biosynthesis, urea cycle, amino acid metabolism, unsaturated fatty acid biosynthesis, and the met salvage pathway responded to drought stress. CONCLUSION: A metabolic network in the leaves of Jerusalem artichokes under drought stress is proposed. These results will improve understanding of the metabolite response to drought stress in Jerusalem artichokes and develop a foundation for breeding drought-resistant varieties.


Assuntos
Helianthus/metabolismo , Metaboloma , Pressão Osmótica , Aminoácidos/metabolismo , Ciclo do Ácido Cítrico , Ácidos Graxos/metabolismo , Flavonoides/metabolismo , Glicólise , Plântula/metabolismo
5.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802822

RESUMO

Future space missions will include a return to the Moon and long duration deep space roundtrip missions to Mars. Leaving the protection that Low Earth Orbit provides will unavoidably expose astronauts to higher cumulative doses of space radiation, in addition to other stressors, e.g., microgravity. Immune regulation is known to be impacted by both radiation and spaceflight and it remains to be seen whether prolonged effects that will be encountered in deep space can have an adverse impact on health. In this study, we investigated the effects in the overall metabolism of three different low dose radiation exposures (γ-rays, 16O, and 56Fe) in spleens from male C57BL/6 mice at 1, 2, and 4 months after exposure. Forty metabolites were identified with significant enrichment in purine metabolism, tricarboxylic acid cycle, fatty acids, acylcarnitines, and amino acids. Early perturbations were more prominent in the γ irradiated samples, while later responses shifted towards more prominent responses in groups with high energy particle irradiations. Regression analysis showed a positive correlation of the abundance of identified fatty acids with time and a negative association with γ-rays, while the degradation pathway of purines was positively associated with time. Taken together, there is a strong suggestion of mitochondrial implication and the possibility of long-term effects on DNA repair and nucleotide pools following radiation exposure.


Assuntos
Radiação Cósmica , Metaboloma/efeitos da radiação , Exposição à Radiação , Baço/metabolismo , Baço/efeitos da radiação , Animais , Ciclo do Ácido Cítrico/efeitos da radiação , Relação Dose-Resposta à Radiação , Modelos Lineares , Masculino , Camundongos Endogâmicos C57BL , Análise Multivariada , Purinas/metabolismo
6.
Adv Exp Med Biol ; 1280: 261-276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791988

RESUMO

Metabolic reprogramming is an important characteristics of glioma, the most common form of malignant brain tumor. In this chapter, we aim to discuss some of the recently discovered metabolic alterations in glioma, including the dysregulated TCA cycle, amino acid, nucleotide, and lipid metabolism. We have also detailed some of the metabolomic applications in gliomas, particularly the analyses of body fluids and tissues of glioma patients. With new improvement of the technology, metabolomics will become a powerful tool to discover truly meaningful biomarkers for clinical applications in gliomas. Metabolomic studies of gliomas will also facilitate a better understanding of the molecular targets/pathways and the development of new therapeutic treatments for this devastating disease.


Assuntos
Neoplasias Encefálicas , Glioma , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Ciclo do Ácido Cítrico , Glioma/diagnóstico , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Metabolismo dos Lipídeos , Metabolômica , Mutação
7.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806730

RESUMO

Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.


Assuntos
Mitocôndrias/genética , Mitocôndrias/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Transporte Biológico , Proliferação de Células , Sobrevivência Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ciclo do Ácido Cítrico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético , Humanos , Redes e Vias Metabólicas , Microtúbulos/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral
8.
Nat Commun ; 12(1): 2261, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859194

RESUMO

Expanding the portfolio of products that can be made from lignin will be critical to enabling a viable bio-based economy. Here, we engineer Pseudomonas putida for high-yield production of the tricarboxylic acid cycle-derived building block chemical, itaconic acid, from model aromatic compounds and aromatics derived from lignin. We develop a nitrogen starvation-detecting biosensor for dynamic two-stage bioproduction in which itaconic acid is produced during a non-growth associated production phase. Through the use of two distinct itaconic acid production pathways, the tuning of TCA cycle gene expression, deletion of competing pathways, and dynamic regulation, we achieve an overall maximum yield of 56% (mol/mol) and titer of 1.3 g/L from p-coumarate, and 1.4 g/L titer from monomeric aromatic compounds produced from alkali-treated lignin. This work illustrates a proof-of-principle that using dynamic metabolic control to reroute carbon after it enters central metabolism enables production of valuable chemicals from lignin at high yields by relieving the burden of constitutively expressing toxic heterologous pathways.


Assuntos
Lignina/metabolismo , Engenharia Metabólica/métodos , Pseudomonas putida/metabolismo , Succinatos/metabolismo , Álcalis/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Basidiomycota/enzimologia , Basidiomycota/genética , Técnicas Biossensoriais , Burkholderia/enzimologia , Burkholderia/genética , Carbono/metabolismo , Ciclo do Ácido Cítrico/genética , Ácidos Cumáricos/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Microbiologia Industrial/métodos , Lignina/química , Estudo de Prova de Conceito , Pseudomonas putida/genética
9.
Adv Exp Med Biol ; 1286: 15-48, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33725343

RESUMO

Several studies have exploited the metabolic hallmarks that distinguish between normal and cancer cells, aiming at identifying specific targets of anti-cancer drugs. It has become apparent that metabolic flexibility allows cancer cells to survive during high anabolic demand or the depletion of nutrients and oxygen. Cancers can reprogram their metabolism to the microenvironments by increasing aerobic glycolysis to maximize ATP production, increasing glutaminolysis and anabolic pathways to support bioenergetic and biosynthetic demand during rapid proliferation. The increased key regulatory enzymes that support the relevant pathways allow us to design small molecules which can specifically block activities of these enzymes, preventing growth and metastasis of tumors. In this review, we discuss metabolic adaptation in cancers and highlight the crucial metabolic enzymes involved, specifically those involved in aerobic glycolysis, glutaminolysis, de novo fatty acid synthesis, and bioenergetic pathways. Furthermore, we also review the success and the pitfalls of the current anti-cancer drugs which have been applied in pre-clinical and clinical studies.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Ciclo do Ácido Cítrico , Metabolismo Energético , Glicólise , Humanos , Neoplasias/tratamento farmacológico , Microambiente Tumoral
10.
Nat Commun ; 12(1): 1876, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767183

RESUMO

Viruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface (ALI) cultures, and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes, SARS-CoV-2 infection increases the activity of mTORC1 in cell lines and lung ALI cultures. Lastly, we show evidence of mTORC1 activation in COVID-19 patient lung tissue, and that mTORC1 inhibitors reduce viral replication in kidney epithelial cells and lung ALI cultures. Our results suggest that targeting mTORC1 may be a feasible treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.


Assuntos
/patologia , Ciclo do Ácido Cítrico/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Benzamidas/farmacologia , Linhagem Celular , Chlorocebus aethiops , Glucose/metabolismo , Glutamina/metabolismo , Células HEK293 , Humanos , Pulmão/metabolismo , Pulmão/virologia , Morfolinas/farmacologia , Naftiridinas/farmacologia , Pirimidinas/farmacologia , Piruvato Carboxilase/biossíntese , Células Vero , Replicação Viral/efeitos dos fármacos
11.
Methods Mol Biol ; 2265: 91-110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33704708

RESUMO

Glutamine is a major substrate for biosynthesis. It contributes to multiple pathways required for cell proliferation, supports antioxidant defense via glutathione synthesis, and sustains the tricarboxylic acid (TCA) cycle through anaplerosis. Glutamine-fueled anaplerosis and related biosynthesis can be studied in detail in melanoma using stable isotope (13C) labeling followed by gas chromatography-mass spectrometry (GC-MS) analysis of metabolite amounts and labeling. Detailed protocols for the assay of polar metabolites (including amino acids, TCA cycle, and glycolysis metabolites) and fatty acids by these methods following cell treatment with 13C-glutamine or 13C-glucose are presented.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Glucose/metabolismo , Glutamina/metabolismo , Marcação por Isótopo/métodos , Melanoma/metabolismo , Aminoácidos/metabolismo , Isótopos de Carbono , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Ciclo do Ácido Cítrico/fisiologia , Glicólise/fisiologia , Humanos
12.
Artigo em Inglês | MEDLINE | ID: mdl-33572101

RESUMO

Impaired bioenergetics have been reported in veterans with Gulf War illness (VGWIs), including prolonged post-exercise recovery of phosphocreatine (PCr-R) assessed with 31Phosphorus magnetic resonance spectroscopy. The citric acid cycle (CAC) is considered the most important metabolic pathway for supplying energy, with relationships among CAC markers reported to shift in some but not all impaired bioenergetic settings. We sought to assess relations of CAC markers to one another and to PCr-R. Participants were 33 VGWIs and 33 healthy controls 1:1 matched on age-sex-ethnicity. We assessed seven CAC intermediates, and evaluated PCr-R in a subset of matched case-control pairs (N = 14). CAC markers did not significantly differ between cases and controls. Relationships of alpha-ketoglutarate to malate, isocitrate, and succinate were strongly significant in cases with materially weaker relationships in controls, suggesting possible shifts in these markers in concert in VGWIs. PCr-R correlated strongly with five of seven CAC markers in controls (succinate, malate, fumarate, citrate, isocitrate, range r = -0.74 to -0.88), but bore no relationship in VGWIs. In summary, PCr-R related significantly to CAC markers in healthy controls, but not VGWIs. In contrast, relations of CAC markers to one another appeared to shift (often strengthen) in VGWIs.


Assuntos
Ciclo do Ácido Cítrico , Guerra do Golfo , Metabolismo Energético , Humanos , Fosfocreatina , Projetos Piloto
13.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540894

RESUMO

Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more research is necessary to understand the underlying mechanisms of this process. In this review, we give a detailed overview of the contribution of impaired mitochondrial dynamics and energy homeostasis during heart failure progression. In particular, we focus on the regulation of fatty acid metabolism and the effects of fatty acid accumulation on mitochondrial structural and functional homeostasis.


Assuntos
Ácidos Graxos/metabolismo , Insuficiência Cardíaca/metabolismo , Mitocôndrias Cardíacas/metabolismo , Dinâmica Mitocondrial , Tecido Adiposo/metabolismo , Sinalização do Cálcio , Cardiomiopatias/metabolismo , Ceramidas/biossíntese , Ciclo do Ácido Cítrico , Progressão da Doença , Ácidos Graxos/efeitos adversos , Homeostase , Humanos , Corpos Cetônicos/metabolismo , Doenças Mitocondriais/metabolismo , Mitofagia , NAD/metabolismo , Pericárdio/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Espécies Reativas de Oxigênio/metabolismo
14.
Biotechnol Adv ; 48: 107710, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33582180

RESUMO

Dicarboxylic acids (DCAs) are important commodity chemicals which have been widely applied in polymer, food and pharmaceutical industries. Biosynthesis of DCAs from renewable carbon sources represents a promising alternative to chemical synthesis. Over the years, the recombinant strains have been constructed to produce an increasing number of DCAs. In this review, recent advances on the microbial synthesis of various DCAs have been summarized and categorized into three groups: the tricarboxylic acid cycle-derived, lysine metabolism-related, and aromatic compounds degradation-derived DCAs. We focused mainly on the metabolic engineering and synthetic biology strategies for improving the production efficiency, including metabolic flux analysis, fine-tuning of gene expression, cofactor balancing, metabolic compartmentalization, dynamic regulation and co-culture to regulate the production at multiple levels. The current challenges and perspectives have also been discussed.


Assuntos
Ácidos Dicarboxílicos , Engenharia Metabólica , Ciclo do Ácido Cítrico , Compostos Orgânicos
15.
Nat Commun ; 12(1): 1209, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619282

RESUMO

Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1ß after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.


Assuntos
Frutose/farmacologia , Glutamina/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Ácidos/metabolismo , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Glucose/farmacologia , Glicólise/efeitos dos fármacos , Marcação por Isótopo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Análise do Fluxo Metabólico , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Oxirredução , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Fenótipo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
16.
Science ; 371(6531)2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33602825

RESUMO

Although metabolism plays an active role in antibiotic lethality, antibiotic resistance is generally associated with drug target modification, enzymatic inactivation, and/or transport rather than metabolic processes. Evolution experiments of Escherichia coli rely on growth-dependent selection, which may provide a limited view of the antibiotic resistance landscape. We sequenced and analyzed E. coli adapted to representative antibiotics at increasingly heightened metabolic states. This revealed various underappreciated noncanonical genes, such as those related to central carbon and energy metabolism, which are implicated in antibiotic resistance. These metabolic alterations lead to lower basal respiration, which prevents antibiotic-mediated induction of tricarboxylic acid cycle activity, thus avoiding metabolic toxicity and minimizing drug lethality. Several of the identified metabolism-specific mutations are overrepresented in the genomes of >3500 clinical E. coli pathogens, indicating clinical relevance.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Genes Bacterianos , Mutação , Adaptação Fisiológica , Carbenicilina/farmacologia , Ciprofloxacino/farmacologia , Ciclo do Ácido Cítrico/genética , Evolução Molecular Direcionada , Metabolismo Energético/genética , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/genética , Técnicas de Silenciamento de Genes , Genoma Bacteriano , Complexo Cetoglutarato Desidrogenase/genética , Testes de Sensibilidade Microbiana , Análise de Sequência de DNA , Estreptomicina/farmacologia
17.
Sci Total Environ ; 772: 144957, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578161

RESUMO

Short-chain chlorinated paraffins (SCCPs) could disrupt fatty acid metabolism in male rat liver through activating rat PPARα signaling. However, whether this mode of action can translate to humans remained largely unclear. In this study, based on luciferase assays, C10-13-CPs (56.5% Cl) at concentrations greater than 1 µM (i.e., 362 µg/L) showed weak agonistic activity toward human PPARα (hPPARα) signaling. But in HepG2 cells, exposure to C10-13-CPs (56.5% Cl) at the human internal exposure level (100 µg/L) down-regulated expressions of most of the tested hPPARα target genes, which encode for enzymes that oxidize fatty acids. In line with the gene expression data, metabolomics further confirmed that exposure to four SCCP standards with varying chlorine contents at 100 µg/L significantly suppressed oxidation of fatty acids in HepG2 cells, mainly evidenced by elevations in both total fatty acids and long-chain acylcarnitines. In addition, exposure to these SCCPs also caused a shift in carbohydrate metabolism from the tricarboxylic acid cycle (TCA cycle) to aerobic glycolysis. Overall, the results revealed that SCCPs could inhibit hPPARα-mediated fatty acid oxidation, and stimulated aerobic glycolysis in HepG2 cells.


Assuntos
Hidrocarbonetos Clorados , Parafina , Animais , China , Ciclo do Ácido Cítrico , Monitoramento Ambiental , Ácidos Graxos , Glicólise , Humanos , Hidrocarbonetos Clorados/análise , Masculino , PPAR alfa/genética , Parafina/análise , Ratos
18.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33495822

RESUMO

It is generally considered that there is an increase in glycolysis in the hypertrophied right ventricle (RV) during pulmonary hypertension (PH), which leads to a decrease in glucose oxidation through the tricarboxylic acid (TCA) cycle. Although recent studies have demonstrated that fatty acid (FA) and glucose accumulated in the RV of patients with PH, the details of this remain to be elucidated. The purpose of the current study was to assess the metabolic remodeling in the RV of rats with PH using a metabolic analysis. Male rats were treated with the vascular endothelial growth factor receptor blocker SU5416 followed by 3 weeks of hypoxic conditions and 5 weeks of normoxic conditions (Su/Hx rats). Hemodynamic measurements were conducted, and the RV was harvested for the measurement of metabolites. A metabolomics analysis revealed a decreasing trend in the levels of alanine, argininosuccinic acid and downstream TCA cycle intermediates, including fumaric and malic acid and an increasing trend in branched­chain amino acids (BCAAs) in Su/Hx rats compared with the controls; however, no trends in glycolysis were indicated. The FA metabolomics analysis also revealed a decreasing trend in the levels of long­chain acylcarnitines, which transport FA from the cytosol to the mitochondria and are essential for beta­oxidation. The current study demonstrated that the TCA cycle was less activated because of a decreasing trend in the expression of fumaric acid and malic acid, which might be attributable to the expression of adenylosuccinic acid and argininosuccinic acid. These results suggest that dysregulated BCAA metabolism and a decrease in FA oxidation might contribute to the reduction of the TCA cycle reactions.


Assuntos
Ácidos Graxos/metabolismo , Hipertrofia Ventricular Direita/tratamento farmacológico , Indóis/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Pirróis/farmacologia , Animais , Ciclo do Ácido Cítrico/genética , Glucose/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Hipertrofia Ventricular Direita/genética , Hipertrofia Ventricular Direita/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Hipóxia/patologia , Oxirredução/efeitos dos fármacos , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/genética
19.
J Agric Food Chem ; 69(2): 824-835, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33410682

RESUMO

Understanding the metabolic modulation of major quality traits during ripening is critical for fruit quality improvement in kiwifruits. Here, integrated proteomic and metabolomic profiling was undertaken to comprehensively examine the dynamics of kiwifruit ripening. This data set presents a global view of the critical pathways involved in fruit ripening, and the contributions of key events to the regulation of kiwifruit ripening and softening, amino acid metabolism, balance in sugar accumulation and organic acid metabolism, glycolysis, and tricarboxylic acid (TCA) pathways were discussed. We suggested key enzymes for starch synthesis and degradation, including AGPase, SS, and SBE, especially for BMY, which was considered a key enzyme for starch degradation. In addition, our analysis implicated the key enzymes ACO4 and ACS9 in ethylene synthesis and the aspartate aminotransferase ASP3 in the conversion of amino acids. These results provide new insights into the modulation of fruit ripening, metabolism, and quality in post-harvest kiwifruits.


Assuntos
Actinidia/metabolismo , Frutas/crescimento & desenvolvimento , Proteínas de Plantas/metabolismo , Actinidia/enzimologia , Actinidia/genética , Actinidia/crescimento & desenvolvimento , Ciclo do Ácido Cítrico , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica de Plantas , Metabolômica , Proteínas de Plantas/genética , Proteômica , Controle de Qualidade
20.
Am J Physiol Regul Integr Comp Physiol ; 320(4): R393-R403, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33407018

RESUMO

The postweaning fast of northern elephant seal pups is characterized by a lipid-dependent metabolism and associated with a decrease in plasma glucagon-like peptide-1 (GLP-1), insulin, and glucose and increased gluconeogenesis (GNG) and ketogenesis. We have also demonstrated that exogenous GLP-1 infusion increased plasma insulin despite simultaneous increases in cortisol and glucagon, which collectively present contradictory regulatory stimuli of GNG, ketogenesis, and glycolysis. To assess the effects of GLP-1 on metabolism using primary carbon metabolite profiles in late-fasted seal pups, we dose-dependently infused late-fasted seals with low (LDG; 10 pM/kg; n = 3) or high (HDG; 100 pM/kg; n = 4) GLP-1 immediately following a glucose bolus (0.5 g/kg), using glucose without GLP-1 as control (n = 5). Infusions were performed in similarly aged animals 6-8 wk into their postweaning fast. The plasma metabolome was measured from samples collected at five time points just prior to and during the infusions, and network maps constructed to robustly evaluate the effects of GLP-1 on primary carbon metabolism. HDG increased key tricarboxylic acid (TCA) cycle metabolites, and decreased phosphoenolpyruvate and acetoacetate (P < 0.05) suggesting that elevated levels of GLP-1 promote glycolysis and suppress GNG and ketogenesis, which collectively increase glucose clearance. These GLP-1-mediated effects on cellular metabolism help to explain why plasma GLP-1 concentrations decrease naturally in fasting pups as an evolved mechanism to help conserve glucose during the late-fasting period.


Assuntos
Glicemia/efeitos dos fármacos , Ciclo do Ácido Cítrico/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Gluconeogênese/efeitos dos fármacos , Corpos Cetônicos/metabolismo , Focas Verdadeiras/metabolismo , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Relação Dose-Resposta a Droga , Jejum/sangue , Infusões Intravenosas , Masculino , Metaboloma , Metabolômica , Focas Verdadeiras/sangue , Fatores de Tempo , Desmame
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