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1.
Tumour Biol ; 42(10): 1010428320965284, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33028168

RESUMO

Glucose, as the main consuming nutrient of the body, faces different destinies in cancer cells. Glycolysis, oxidative phosphorylation, and pentose phosphate pathways produce different glucose-derived metabolites and thus affect cells' bioenergetics differently. Tumor cells' dependency to aerobic glycolysis and other cancer-specific metabolism changes are known as the cancer hallmarks, distinct cancer cells from normal cells. Therefore, these tumor-specific characteristics receive the limelight as targets for cancer therapy. Glutamine, serine, and fatty acid oxidation together with 5-lipoxygenase are main pathways that have attracted lots of attention for cancer therapy. In this review, we not only discuss different tumor metabolism aspects but also discuss the metabolism roles in the promotion of cancer cells at different stages and their difference with normal cells. Besides, we dissect the inhibitors potential in blocking the main metabolic pathways to introduce the effective and non-effective inhibitors in the field.


Assuntos
Antineoplásicos/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Medicina de Precisão , Antineoplásicos/farmacologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Metabolismo Energético/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/etiologia , Neoplasias/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Via de Pentose Fosfato/efeitos dos fármacos , Medicina de Precisão/métodos
2.
J Toxicol Sci ; 45(9): 515-537, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879252

RESUMO

The activities of the transaminases (aminotransferases) alanine aminotransferase and aspartate aminotransferase in the blood (serum or plasma) are widely used as sensitive markers of possible tissue damage and, in particular for liver toxicity. On the other hand, an increase in transaminase activities is not always accompanied by findings suggestive of hepatotoxicity. Transaminases are some of the key enzymes in the gluconeogenesis and glycolysis pathways and exist in many organs and tissues which have high activities of the gluconeogenesis and glycolysis. The activities of transaminases are altered not only in the liver but also in other organs by modification of gluconeogenesis by nutritional or hormonal factors and this phenomenon leads to alteration of transaminase activity in the blood. Drugs, which are considered to directly or secondarily modify gluconeogenesis through lowering blood glucose levels or activating lipid metabolism, such as α-glucosidase inhibitors and fibrates, slightly increase transaminase activities in the blood but there is little evidence that the phenomenon is related to drug-induced liver injury (DILI). This type of elevations can be called pharmacology-related elevation. The pharmacology-related elevation of transaminase activities sometimes makes it difficult to assess precisely the potential hepatotoxicity of new investigational drugs. Considering the characteristic of transaminases, concomitant use of new biomarkers more specific to hepatic injury is needed in the assessment of DILI both in non-clinical and clinical studies. In this review, we will discuss the specificity of transaminases to DILI and future perspectives for transaminases in the estimation of risk of DILI.


Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Gluconeogênese , Glicólise , Humanos , Fígado/metabolismo , Valor Preditivo dos Testes , Risco , Sensibilidade e Especificidade
3.
Nat Commun ; 11(1): 4509, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908151

RESUMO

Glycolysis is one of the primordial pathways of metabolism, playing a pivotal role in energy metabolism and biosynthesis. Glycolytic enzymes are known to form transient multi-enzyme assemblies. Here we examine the wider protein-protein interactions of plant glycolytic enzymes and reveal a moonlighting role for specific glycolytic enzymes in mediating the co-localization of mitochondria and chloroplasts. Knockout mutation of phosphoglycerate mutase or enolase resulted in a significantly reduced association of the two organelles. We provide evidence that phosphoglycerate mutase and enolase form a substrate-channelling metabolon which is part of a larger complex of proteins including pyruvate kinase. These results alongside a range of genetic complementation experiments are discussed in the context of our current understanding of chloroplast-mitochondrial interactions within photosynthetic eukaryotes.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Cloroplastos/enzimologia , Glicólise/fisiologia , Mitocôndrias/enzimologia , Arabidopsis/citologia , Proteínas de Arabidopsis/genética , Metabolismo Energético/fisiologia , Mutação , Fosfoglicerato Mutase/genética , Fosfoglicerato Mutase/metabolismo , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Fotossíntese/fisiologia , Plantas Geneticamente Modificadas , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/fisiologia , Piruvato Quinase/genética , Piruvato Quinase/metabolismo
4.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(6): 884-892, 2020 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895203

RESUMO

OBJECTIVE: To observe the cell death pattern induced by gefitinib in non-small cell lung cancer A549 and H1975 cells and explore the possible mechanism in light of glycolysis. METHODS: The inhibitory effects of gefitinib at 20, 30, or 40 µmol/L in A549 cells and at 20, 40, or 80 µmol/L in H1975 cells were examined using MTT assay. The changes of lactic acid level in the cells were determined with a lactic acid kit, and the expression levels of glycolysis-related proteins (PKM2 and HK2) and the proteins in PI3K-Akt-mTOR signaling pathway were detected using Western blotting. 2-NBDG was used for detecting glucose uptake capacity of the cells, and ATP kit was used to detect the intracellular ATP level. The mitochondrial membrane potential of the cells was examined with the JC-1 kit, and cell apoptosis was analyzed with Annexin V-FITC/PI double staining. The relative expression levels of the apoptotic proteins Bax and Bcl-2 and the autophagy marker protein LC3B were detected with Western blotting. RESULTS: MTT assay showed that gefitinib inhibited the proliferation of A549 and H1975 cells in a time- and dose-dependent manner (P < 0.05). The IC50 of gefitinib at 24, 48 and 72 h was 48.6, 28.6 and 19.7 µmol/L in A549 cells and was 321.6, 49.1 and 14.6 µmol/L in H1975 cells, respectively. Gefitinib significantly lowered intracellular lactic acid level of the cells (P < 0.05) and down-regulated the expressions of PKM2 and HK2 proteins (P < 0.05) and PI3K-Akt-mTOR signaling pathway-associated proteins (P < 0.05). Gefitinib obviously inhibited glucose uptake and ATP levels in both A549 and H1975 cells (P < 0.05). Treatment with gefitinib induced obviously enhanced apoptosis in the cells, resulting in apoptosis rates of (10.77± 1.0)%, (14.5±0.4)%, (17.4±0.2)% and (32.1±0.6)% at 0, 20, 30 and 40 µmol/L in A549 cells (P < 0.05) and of (10.5±0.6)%, (13.2± 0.92)%, (18.9±0.98)% and (35.1±1.4)% at 0, 20, 40 and 80 µmol/L in H1975 cells, respectively (P < 0.05). The protein expression of Bax increased and that of Bcl-2 decreased following gefitinib treatment in the cells (P < 0.05). Gefitinib significantly increased autophagy in A549 and H1975 cells as shown by increased LC3B expressions following the treatment (P < 0.05). CONCLUSIONS: Gefitinib can inhibit the proliferation, induce apoptosis and increase autophagy in A549 and H1975 cells. Gefitinib induces apoptosis of the cells possibly by affecting glycolysis and PI3K-Akt-mTOR signaling pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Gefitinibe , Glicólise , Humanos , Fosfatidilinositol 3-Quinases
5.
Nat Commun ; 11(1): 3816, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732870

RESUMO

Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) on macrophages induces a robust pro-inflammatory response that is dependent on metabolic reprogramming. These innate metabolic changes have been compared to aerobic glycolysis in tumour cells. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming are unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, production of the central immune response metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.


Assuntos
Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Expressão Gênica , Glicólise/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Interleucina-1beta/genética , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição STAT3/genética , Serina/genética , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/genética
6.
Life Sci ; 258: 118196, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32763295

RESUMO

AIM: The pharmacological properties of pentoxifylline have been re-evaluated, particularly in chronic kidney disease in diabetes, favored by its anti-inflammatory action. Definitive evidences of renal outcomes are lacking, which indicates the need for investigation of novel mechanisms of action of pentoxifylline. We postulated that components associated with the metabolism of advanced glycation end products (AGEs) may be modulated by pentoxifylline, which consequently decreases the detrimental effects of obesity on kidneys. MAIN METHODS: C57BL-6J mice were fed a high-fat diet for 14 weeks and treated with 50 mg/kg pentoxifylline during the last 7 weeks. Changes in the renal levels of AGE metabolism-associated components were investigated, with particular focus on the receptor for AGEs (RAGE), its downstream components, and components related to AGE detoxification, including glyoxalase 1 (GLO 1). KEY FINDINGS: Pentoxifylline reduced body weight gain, improved insulin sensitivity and glucose tolerance, downregulated biomarkers of glycoxidative stress, and enhanced plasma paraoxonase 1 activity. In the kidneys, pentoxifylline inhibited glomerular expansion, lipid deposition, reduced pro-inflammatory cytokine levels, and induced the activation of AMP-activated protein kinase. Pentoxifylline inhibited the renal accumulation of AGEs and reduced the levels of RAGE and its downstream components, and consequently mitigated oxidative stress and apoptosis. Pentoxifylline also increased the renal levels of GLO 1 and the activities of antioxidant enzymes. Urinary albumin levels were observed to be lowered, which reconfirmed the antialbuminuric effects of pentoxifylline. SIGNIFICANCE: The novel mechanisms of action help explain the renoprotective effects of pentoxifylline and the attenuation of obesity-associated renal complications related to glycoxidative stress.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Glicólise/efeitos dos fármacos , Rim/patologia , Lactoilglutationa Liase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pentoxifilina/farmacologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Rim/efeitos dos fármacos , Camundongos Obesos , Transdução de Sinais/efeitos dos fármacos
7.
Nat Commun ; 11(1): 4319, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859923

RESUMO

Disrupted energy metabolism drives cell dysfunction and disease, but approaches to increase or preserve ATP are lacking. To generate a comprehensive metabolic map of genes and pathways that regulate cellular ATP-the ATPome-we conducted a genome-wide CRISPR interference/activation screen integrated with an ATP biosensor. We show that ATP level is modulated by distinct mechanisms that promote energy production or inhibit consumption. In our system HK2 is the greatest ATP consumer, indicating energy failure may not be a general deficiency in producing ATP, but rather failure to recoup the ATP cost of glycolysis and diversion of glucose metabolites to the pentose phosphate pathway. We identify systems-level reciprocal inhibition between the HIF1 pathway and mitochondria; glycolysis-promoting enzymes inhibit respiration even when there is no glycolytic ATP production, and vice versa. Consequently, suppressing alternative metabolism modes paradoxically increases energy levels under substrate restriction. This work reveals mechanisms of metabolic control, and identifies therapeutic targets to correct energy failure.


Assuntos
Trifosfato de Adenosina/metabolismo , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Trifosfato de Adenosina/genética , Sistemas CRISPR-Cas , Linhagem Celular , Metabolismo Energético , Feminino , Fibroblastos , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Glicólise/fisiologia , Hexoquinase/genética , Hexoquinase/metabolismo , Humanos , Células K562 , Metabolômica , Mitocôndrias/metabolismo , Via de Pentose Fosfato , Mutação Puntual
8.
Life Sci ; 258: 118190, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32777299

RESUMO

AIMS: Glycolysis is an important process for cervical carcinoma development. Previous studies have indicated that stress-induced phosphoprotein 1 (STIP1) is associated with development of multiple tumors. Nevertheless, the role and mechanism of STIP1 in glycolysis of cervical carcinoma remain unclear. MAIN METHODS: The association between STIP1 and survival probability and the correlation between STIP1 expression and pyruvate kinase M2 (PKM2) as well as lactate dehydrogenase isoform A (LDHA) levels in cervical carcinoma were analyzed via The Cancer Genome Atlas (TCGA). The expression of STIP1, PKM2, LDHA, and cytochrome c (Cyt C) was measured via western blot or quantitative reverse transcription polymerase chain reaction. Cell viability and apoptosis were examined via cell counting kit 8 and flow cytometry, respectively. Glycolysis was assessed via detection of glucose consumption and lactate production. The protein involved in the Wnt/ß-catenin pathway was measured via western blot. KEY FINDINGS: STIP1 abundance was elevated in cervical carcinoma cells. High expression of STIP1 indicated poor survival probability. Knockdown of STIP1 inhibited cervical carcinoma cell viability and promoted apoptosis. STIP1 expression was positively correlated with PKM2 and LDHA levels in cervical carcinoma. Silence of STIP1 inhibited glycolysis and decreased PKM2 and LDHA expression. Down-regulation of STIP1 repressed the Wnt/ß-catenin pathway. Overexpression of ß-catenin reversed the effect of STIP1 silence on viability, apoptosis, glycolysis, and levels of PKM2 and LDHA. SIGNIFICANCE: STIP1 knockdown suppressed glycolysis in cervical carcinoma by inhibiting PKM2 and LDHA expression and activation of the Wnt/ß-catenin pathway.


Assuntos
Proteínas de Transporte/metabolismo , Regulação para Baixo/genética , Glicólise , Proteínas de Choque Térmico/metabolismo , Lactato Desidrogenase 5/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Neoplasias do Colo do Útero/genética , Via de Sinalização Wnt , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico/genética , Humanos , Modelos Biológicos , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt/genética
9.
Life Sci ; 258: 118236, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795537

RESUMO

Cancer cells exhibit distinct energy metabolic pathways due to multiple oncogenic events. In normoxia condition, the anaerobic glycolysis (Warburg effect) is highly observed in head and neck squamous cell carcinoma (HNSCC). HNSCC is associated with smoking, chewing tobacco, consumption of alcohol or Human Papillomavirus (HPV) infection primarily HPV16. In recent years, the correlation of HPV with HNSCC has significantly expanded. Despite the recent advancement in therapeutic approaches, the rate of HPV infected HNSCC has significantly increased in the last few years, specifically, in lower middle-income countries. The oncoproteins of High-risk Human Papillomavirus (HR-HPV), E6 and E7, alter the metabolic phenotype in HNSCC, which is distinct from non-HPV associated HNSCC. These oncoproteins, modulate the cell cycle and metabolic signalling through interacting with tumor suppressor proteins, p53 and pRb. Since, metabolic alteration represents a major hallmark for tumorigenesis, HPV acts as a source of biomarker linked to cancer progression in HNSCC. The dependency of cancer cells to specific nutrients and alteration of various metabolic associated genes may provide a unique opportunity for pharmacological intervention in HPV infected HNSCC. In this review, we have discussed the molecular mechanism (s) and metabolic regulation in HNSCC depending on the HPV status. We have also discussed the possible potential therapeutic approaches for HPV associated HNSCC through targeting metabolic pathways.


Assuntos
Metabolismo Energético/fisiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Papillomaviridae/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Glicólise/fisiologia , Humanos
10.
PLoS Pathog ; 16(8): e1008815, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32833996

RESUMO

Although therapeutics targeting viral metabolic processes have been considered as promising strategies to treat herpesvirus infection, the metabolic requirements of gallid alphaherpesvirus 1 (ILTV), which is economically important to the poultry industry worldwide, remain largely unknown. Using the ILTV-susceptible but nonpermissive chicken cell line DF-1 and the ILTV-permissive chicken cell line LMH as models, the present study explored the metabolic requirements of ILTV by global transcriptome analysis and metabolome assays of ILTV infected cell lines in combination with a set of functional validations. The extensive metabolic exploration demonstrated that ILTV infection tended to promote a metabolic shift from glycolysis to fatty acid (FA) and nucleotide biosynthesis and utilizes glutamine independently of glutaminolysis, without significant general effect on the TCA cycle. In addition, different metabolic pathways were found to be required for distinct stages of ILTV replication. Glucose and glutamine were required for the transcription of viral immediate early gene ICP4 and subsequent steps of viral replication. However, FA synthesis was essential for assembly but not required for other upstream steps of ILTV replication. Moreover, the metabolic requirements of ILTV infection revealed in chicken cell lines were further validated in chicken primary cells isolated from chicken embryo kidneys and chicken embryo livers. The present study, to the best of our knowledge, provides the first global metabolic profile of animal herpesviruses and illustrates the main characteristics of the metabolic program of ILTV.


Assuntos
Infecções por Herpesviridae/metabolismo , Herpesvirus Galináceo 1/metabolismo , Metaboloma , Replicação Viral , Animais , Galinhas , Glicólise , Infecções por Herpesviridae/virologia
11.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(6): 765-768, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32684228

RESUMO

Macrophages are important innate immune cells that play essential roles in the inflammatory response. The phenotypic plasticity of macrophages enables them to be polarized into distinct gene phenotypes under different immune microenvironments to regulate the process of inflammation. The study of macrophage metabolic reprogramming aims to clarify the influence of key metabolic pathways on the regulation of different polarization states and related functions of macrophages. This review focuses on the relationship between the four key metabolic pathways [glycolysis, tricarboxylic acid (TCA) cycle, fatty acid metabolism and amino acid metabolism] and the distinct gene phenotypes of macrophages. It also reveals the metabolic regulation of the immune function of macrophage cells thus to provide new ideas and methods for the study of macrophage polarization-related process of inflammation.


Assuntos
Ativação de Macrófagos , Macrófagos , Glicólise , Humanos , Inflamação , Fenótipo
12.
Mol Med ; 26(1): 69, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641037

RESUMO

BACKGROUND: We previously showed that the autophagy inhibitor chloroquine (CQ) increases inflammatory cleaved caspase-1 activity in myocytes, and that caspase-1/11 is protective in sterile liver injury. However, the role of caspase-1/11 in the recovery of muscle from ischemia caused by peripheral arterial disease is unknown. We hypothesized that caspase-1/11 mediates recovery in muscle via effects on autophagy and this is modulated by CQ. METHODS: C57Bl/6 J (WT) and caspase-1/11 double-knockout (KO) mice underwent femoral artery ligation (a model of hind-limb ischemia) with or without CQ (50 mg/kg IP every 2nd day). CQ effects on autophagosome formation, microtubule associated protein 1A/1B-light chain 3 (LC3), and caspase-1 expression was measured using electron microscopy and immunofluorescence. Laser Doppler perfusion imaging documented perfusion every 7 days. After 21 days, in situ physiologic testing in tibialis anterior muscle assessed peak force contraction, and myocyte size and fibrosis was also measured. Muscle satellite cell (MuSC) oxygen consumption rate (OCR) and extracellular acidification rate was measured. Caspase-1 and glycolytic enzyme expression was detected by Western blot. RESULTS: CQ increased autophagosomes, LC3 consolidation, total caspase-1 expression and cleaved caspase-1 in muscle. Perfusion, fibrosis, myofiber regeneration, muscle contraction, MuSC fusion, OCR, ECAR and glycolytic enzyme expression was variably affected by CQ depending on presence of caspase-1/11. CQ decreased perfusion recovery, fibrosis and myofiber size in WT but not caspase-1/11KO mice. CQ diminished peak force in whole muscle, and myocyte fusion in MuSC and these effects were exacerbated in caspase-1/11KO mice. CQ reductions in maximal respiration and ATP production were reduced in caspase-1/11KO mice. Caspase-1/11KO MuSC had significant increases in protein kinase isoforms and aldolase with decreased ECAR. CONCLUSION: Caspase-1/11 signaling affects the response to ischemia in muscle and effects are variably modulated by CQ. This may be critically important for disease treated with CQ and its derivatives, including novel viral diseases (e.g. COVID-19) that are expected to affect patients with comorbidities like cardiovascular disease.


Assuntos
Caspase 1/metabolismo , Caspases Iniciadoras/metabolismo , Cloroquina/farmacologia , Infecções por Coronavirus/patologia , Isquemia/patologia , Músculo Esquelético/patologia , Pneumonia Viral/patologia , Animais , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Glicólise/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Células Musculares/metabolismo , Desenvolvimento Muscular , Músculo Esquelético/metabolismo , Neovascularização Fisiológica , Fosforilação Oxidativa , Pandemias , Doença Arterial Periférica/patologia , Pneumonia Viral/tratamento farmacológico , Regeneração , Transdução de Sinais
13.
Life Sci ; 257: 118028, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32615185

RESUMO

AIMS: Sertoli cells (SCs) play an important role in the process of spermatogenesis. SCs provide energy for germ cells (GCs) and themselves through glycolysis and fatty acid oxidation (FAO) respectively. High fat diet (HFD) impairs spermatogenesis by damaging function of SCs, however whether HFD disrupts energy metabolism in SCs remains unclear. MAIN METHODS: To explore this hypothesis, we built male Wistar rat model fed on HFD and cultured rats' primary SCs with palmitic acid (PA). Rats' fertility and sperm quality were evaluated in vivo. Glycolysis, lactate production and mitochondrial respiration were assessed by using extracellular flux analyzer, and the expression of enzymes involved in glucose and FAO was analyzed by Real-Time PCR or Western Blotting. KEY FINDINGS: The showed that the sperm concentration and pups per litter significantly decreased in rats fed on HFD compared to those rats fed on normal diet. There was an elevation of lactate levels in testicular tissue of rats fed on HFD and primary SCs exposed to PA. In vitro, PA increased glycolytic flux, and lactate production, and the levels of carnitine palmitoyltransferase I (CPT1) and long chain acyl-CoA dehydrogenase (LCAD) which were two key enzymes for fatty acid ß oxidation. Further analysis showed that mitochondrial respiration was impaired by PA, followed by the decrease in ATP turnover, maximal respiration and the increase in proton leak. SIGNIFICANCE: Taken together, the elevated lactate level, lipid metabolism disorder and mitochondrial dysfunction caused by HFD lead to SCs dysfunction, which ultimately leads to decreased sperm quality.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Células de Sertoli/metabolismo , Espermatogênese/fisiologia , Animais , Metabolismo Energético , Ácidos Graxos/metabolismo , Glucose/metabolismo , Glicólise , Insulina/metabolismo , Metabolismo dos Lipídeos/fisiologia , Masculino , Oxirredução , Ácido Palmítico , Ratos , Ratos Wistar , Triglicerídeos/metabolismo
14.
PLoS One ; 15(7): e0236038, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658933

RESUMO

The attenuation of hyper-inflammation in sepsis with the administration of anti-inflammatory macrophages is an interesting adjuvant therapy for sepsis. Because the induction of anti-inflammatory macrophages by microRNA (miR), a regulator of mRNA, has been mentioned, the exploration on miR-induced anti-inflammatory macrophages was performed. The over-expression of miR-223 and miR-146a in RAW264.7 induced M2 macrophage-polarization (anti-inflammatory macrophages) as evaluated by the enhanced expression of Arginase-1 and Fizz. However, miR-223 over-expressed cells demonstrated the more potent anti-inflammatory property against LPS stimulation as lesser iNOS expression, lower supernatant IL-6 and higher supernatant IL-10 compared with miR-146a over-expressed cells. Interestingly, LPS stimulation in miR-223 over-expressed cells, compared with LPS-stimulated control cells, demonstrated lower activity of glycolysis pathway and higher mitochondrial respiration, as evaluated by the extracellular flux analysis, and also down-regulated HIF-1α, an important enzyme of glycolysis pathway. In addition, the administration of miR-223 over-expressed macrophages with IL-4 pre-conditioning, but not IL-4 stimulated control cells, attenuated sepsis severity in LPS injected mice as evaluated by serum creatinine, liver enzymes, lung histology and serum cytokines. In conclusion, miR-223 interfered with the glycolysis pathway through the down-regulation of HIF-1α, resulting in the anti-inflammatory status. The over-expression of miR-223 in macrophages prevented the conversion into M1 macrophage polarization after LPS stimulation. The administration of miR-223 over-expressed macrophages, with IL-4 preconditioning, attenuated sepsis severity in LPS model. Hence, a proof of concept in the induction of anti-inflammatory macrophages through the cell-energy interference for sepsis treatment was proposed as a basis of cell-based therapy in sepsis.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Glicólise , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Macrófagos/transplante , MicroRNAs/genética , Sepse/prevenção & controle , Animais , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Ativação de Macrófagos , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/induzido quimicamente , Sepse/metabolismo , Sepse/patologia
15.
Life Sci ; 257: 118076, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32659371

RESUMO

AIMS: Huntington's disease is a rare neurodegenerative disorder which is associated with defected glucose metabolism with consequent behavioral disturbance including memory and locomotion. 3-nitropropionic acid (3-NP) can cause, in high single dose, an acute striatal injury/Huntington's disease. Dapagliflozin, which is one of the longest duration of action of SGLTIs family, may be able to diminish that injury and its resultant behavioral disturbances. MATERIAL AND METHODS: Forty rats were divided into four groups (n = 10 in each group): normal control group (CTRL), dapagliflozin (CTRL + DAPA) group, 3-nitropropionic acid (3-NP) group, and dapagliflozin plus 3-nitropropionic acid (DAPA + 3-NP) group. Behavioral tests (beam walking test, hanging wire test, limb withdrawal test, Y-maze spontaneous alteration, elevated plus maze) were performed with evaluating neurological scoring. In striatum, neurotransmitters (glutamate, aspartate, GABA, ACh and AChE activity) were measured. In addition, apoptosis and glycolysis markers (NF-κB, Cyt-c, lactate, HK-II activity, P53, calpain, PEA15 and TIGAR) were determined. Inflammation (IL-1ß, IL-6, IL-8 and TNF-α) and autophagy (beclin-1, LC3 and DRAM) indicators were measured. Additionally, histopathological screening was conducted. KEY FINDINGS: 3-Nitropropionic acid had the ability to perturb the neurotransmission which was reflected in impaired behavioral outcome. All of glycolysis, apoptosis and inflammation markers were elevated after 3-NP acute intoxication but autophagy parameters, except DRAM, were reduced. However, DAPA markedly reversed the abovementioned parameters. SIGNIFICANCE: Dapagliflozin demonstrated anti-glycolytic, anti-apoptotic, anti-inflammatory and autophagic effects on 3-NP-damaged striatal cells and promoted the behavioral outcome.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Glicólise/efeitos dos fármacos , Doença de Huntington/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Animais , Autofagia/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Doença de Huntington/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar
16.
Nature ; 583(7817): 603-608, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32641832

RESUMO

Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses1-5. By contrast, astrocytes are under neuronal control through specific neurotransmitter receptors5-7. However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB1) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB1 receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB1 receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice.


Assuntos
Astrócitos/metabolismo , Metabolismo Energético , Glucose/metabolismo , Mitocôndrias/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Células Cultivadas , Dronabinol/farmacologia , Complexo I de Transporte de Elétrons/química , Complexo I de Transporte de Elétrons/metabolismo , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Ácido Láctico/metabolismo , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Oxirredução , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Receptor CB1 de Canabinoide/agonistas , Comportamento Social
17.
Nat Commun ; 11(1): 3427, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647171

RESUMO

The contribution of inflammation to the chronic joint disease osteoarthritis (OA) is unclear, and this lack of clarity is detrimental to efforts to identify therapeutic targets. Here we show that chondrocytes under inflammatory conditions undergo a metabolic shift that is regulated by NF-κB activation, leading to reprogramming of cell metabolism towards glycolysis and lactate dehydrogenase A (LDHA). Inflammation and metabolism can reciprocally modulate each other to regulate cartilage degradation. LDHA binds to NADH and promotes reactive oxygen species (ROS) to induce catabolic changes through stabilization of IκB-ζ, a critical pro-inflammatory mediator in chondrocytes. IκB-ζ is regulated bi-modally at the stages of transcription and protein degradation. Overall, this work highlights the function of NF-κB activity in the OA joint as well as a ROS promoting function for LDHA and identifies LDHA as a potential therapeutic target for OA treatment.


Assuntos
Condrócitos/metabolismo , Lactato Desidrogenase 5/metabolismo , Terapia de Alvo Molecular , Osteoartrite/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aerobiose , Animais , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Citoproteção/efeitos dos fármacos , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/farmacologia , Articulação do Joelho/patologia , Meniscos Tibiais/cirurgia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos Endogâmicos C57BL , NAD/metabolismo , NF-kappa B/metabolismo , Osteoartrite/genética , Osteoartrite/patologia
18.
Ann Surg ; 272(2): 311-318, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32675544

RESUMO

OBJECTIVE: We aimed to determine whether tumor metabolism could be prognostic of cure in L-EAC patients who receive definitive chemoradiation. SUMMARY BACKGROUND DATA: Patients with inoperable localized esophageal adenocarcinoma (L-EAC) often receive definitive chemoradiation; however, biomarkers and/or imaging variables to prognosticate cure are missing. METHODS: Two hundred sixty-six patients with L-EAC who had chemoradiation but not surgery were analyzed from the prospectively maintained EAC databases in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center (Texas, USA) between March 2002 and April 2015. Maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) from the positron emission tomography data were evaluated. RESULTS: Of 266 patients, 253 (95%) were men; the median age was 67 years (range 20-91 yrs) and 153 had poorly differentiated L-EAC. The median SUVmax was 10.3 (range 0-87) and the median TLG was 85.7 (range 0-3227). Both SUVmax and TLG were higher among those with: tumors >5 cm in length, high clinical stage, and high tumor and node categories by TNM staging (all P < 0.0001). Of 234 patients evaluable for cure, 60 (25.6%) achieved cure. In the multivariable logistic regression model, low TLG (but not low SUVmax) was associated with cure (continuous TLG value: odds ratio 0.70, 95% confidence interval (CI) 0.54-0.92). TLG was quantified into 4 quartile categorical variables; first quartile (Q1; <32), second quartile (Q2; 32.0-85.6), third quartile (Q3; 85.6-228.4), and fourth quartile (Q4; >228.4); the cure rate was only 10.3% in Q4 and 5.1% in Q3 but increased to 28.8% in Q2, and 58.6% in Q1. The cross-validation resulted in an average accuracy of prediction score of 0.81 (95% CI, 0.75-0.86). CONCLUSIONS: In this cross-validated model, 59% of patients in the 1st quartile were cured following definitive chemoradiation. Baseline TLG could be pursued as one of the tools for esophageal preservation.


Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/terapia , Quimiorradioterapia/métodos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Institutos de Câncer , Estudos de Coortes , Bases de Dados Factuais , Intervalo Livre de Doença , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/mortalidade , Feminino , Seguimentos , Glicólise/efeitos dos fármacos , Glicólise/efeitos da radiação , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Medição de Risco , Estatísticas não Paramétricas , Análise de Sobrevida , Texas , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação
19.
Cell Metab ; 32(3): 437-446.e5, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32697943

RESUMO

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.


Assuntos
Betacoronavirus/fisiologia , Glicemia/metabolismo , Infecções por Coronavirus/complicações , Complicações do Diabetes/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Monócitos/metabolismo , Pneumonia Viral/complicações , Adulto , Linhagem Celular , Infecções por Coronavirus/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Feminino , Glicólise , Humanos , Inflamação/complicações , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/virologia , Pandemias , Pneumonia Viral/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
20.
Nature ; 584(7821): 470-474, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32669712

RESUMO

The rate of cell growth is crucial for bacterial fitness and drives the allocation of bacterial resources, affecting, for example, the expression levels of proteins dedicated to metabolism and biosynthesis1,2. It is unclear, however, what ultimately determines growth rates in different environmental conditions. Moreover, increasing evidence suggests that other objectives are also important3-7, such as the rate of physiological adaptation to changing environments8,9. A common challenge for cells is that these objectives cannot be independently optimized, and maximizing one often reduces another. Many such trade-offs have indeed been hypothesized on the basis of qualitative correlative studies8-11. Here we report a trade-off between steady-state growth rate and physiological adaptability in Escherichia coli, observed when a growing culture is abruptly shifted from a preferred carbon source such as glucose to fermentation products such as acetate. These metabolic transitions, common for enteric bacteria, are often accompanied by multi-hour lags before growth resumes. Metabolomic analysis reveals that long lags result from the depletion of key metabolites that follows the sudden reversal in the central carbon flux owing to the imposed nutrient shifts. A model of sequential flux limitation not only explains the observed trade-off between growth and adaptability, but also allows quantitative predictions regarding the universal occurrence of such tradeoffs, based on the opposing enzyme requirements of glycolysis versus gluconeogenesis. We validate these predictions experimentally for many different nutrient shifts in E. coli, as well as for other respiro-fermentative microorganisms, including Bacillus subtilis and Saccharomyces cerevisiae.


Assuntos
Adaptação Fisiológica , Meio Ambiente , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/metabolismo , Acetatos/metabolismo , Bacillus subtilis/citologia , Bacillus subtilis/crescimento & desenvolvimento , Bacillus subtilis/metabolismo , Divisão Celular , Escherichia coli/enzimologia , Escherichia coli/genética , Fermentação , Gluconeogênese , Glucose/metabolismo , Glicólise , Metabolômica , Modelos Biológicos , Mutação , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo
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