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1.
Ecotoxicol Environ Saf ; 208: 111496, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33099137

RESUMO

Silica nanoparticles (SiNPs) have become one of the most widely studied nanoparticles in nanotechnology for environmental health and safety. Although many studies have devoted to evaluating the hepatotoxicity of SiNPs, it is currently impossible to predict the extent of liver lipid metabolism disorder by identifying changes in metabolites. In the present study, 40 male Sprague-Dawley (SD) rats were randomly divided into control group and 3 groups with different doses (1.8 mg/kg body weight (bw), 5.4 mg/kg bw, 16.2 mg/kg bw), receiving intratracheal instillation of SiNPs. Liver tissue was taken for lipid level analysis, and serum was used for blood biochemical analysis. Then, the metabolites changes of liver tissue in rats were systematically analyzed using 1H nuclear magnetic resonance (1H NMR) techniques in combination with multivariate statistical analysis. SiNPs induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride (TG) elevation in treated groups; TG and low-density lipoprotein cholesterol (LDL-C) were significantly higher in SiNPs-treated groups of high-dose, however high-density lipoprotein cholesterol (HDL-C) showed a declining trend in liver tissue. The orthogonal partial least squares discriminant analysis (OPLS-DA) scores plots revealed different metabolic profiles between control and high-dose group (Q2 =0.495, R2Y=0.802, p = 0.037), and a total of 11 differential metabolites. Pathway analysis indicated that SiNPs treatment mainly affected 10 metabolic pathways including purine metabolism, glucose-alanine cycle and metabolism of various amino acids such as glutamate, cysteine and aspartate (impact value>0.1, false discovery rate (FDR)< 0.05). The result indicated that exposure to SiNPs caused liver lipid metabolism disorder in rats, the biochemical criterions related to lipid metabolism changed significantly. The obviously changed metabolomics in SiNPs-treated rats mostly occurred in amino acids, organic acids and nucleosides.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Metaboloma/efeitos dos fármacos , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
2.
Cell ; 184(1): 120-132.e14, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33382968

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of over one million people worldwide. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a member of the Coronaviridae family of viruses that can cause respiratory infections of varying severity. The cellular host factors and pathways co-opted during SARS-CoV-2 and related coronavirus life cycles remain ill defined. To address this gap, we performed genome-scale CRISPR knockout screens during infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E). These screens uncovered host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, sterol regulatory element-binding protein (SREBP) signaling, bone morphogenetic protein (BMP) signaling, and glycosylphosphatidylinositol biosynthesis, as well as a requirement for several poorly characterized proteins. We identified an absolute requirement for the VMP1, TMEM41, and TMEM64 (VTT) domain-containing protein transmembrane protein 41B (TMEM41B) for infection by SARS-CoV-2 and three seasonal coronaviruses. This human coronavirus host factor compendium represents a rich resource to develop new therapeutic strategies for acute COVID-19 and potential future coronavirus pandemics.


Assuntos
Infecções por Coronavirus/genética , Estudo de Associação Genômica Ampla , /fisiologia , Células A549 , Linhagem Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Coronavirus Humano 229E/fisiologia , Infecções por Coronavirus/virologia , Coronavirus Humano NL63/fisiologia , Coronavirus Humano OC43/fisiologia , Técnicas de Inativação de Genes , Células HEK293 , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Proteínas de Membrana/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Mapeamento de Interação de Proteínas
3.
Gene ; 764: 145098, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32861881

RESUMO

Neocaridina denticulate sinensis is a small freshwater economic shrimp, as well as excellent laboratory model for their short life cycle and easy availability. However, the response of N. denticulate sinensis to pervasive copper pollution in aquatic environments has not been deeply investigated yet. Herein, we preformed Illumina sequencing technology to mine the alterations of cephalothorax transcriptome under 2.5 µmol/L of Cu2+ after 48 h. 122,512 unigenes were assembled and 219 unigenes were identified as significantly differentially expressed genes (DEGs) between control and Cu2+ treatment groups. Functional enrichment analysis revealed that DEGs were mostly associated with immune responses and molting, such as endocytosis, Fc gamma R-mediated phagocytosis and chitin metabolic process. Seven genes were chosen for qPCR verification, and the results showed that the transcriptome sequencing data were consistent with the qPCR results. This is the first report of transcriptome information about N. denticulate sinensis. These results provided a direction for the future research of resistance to Cu2+ in this shrimp, and simultaneously enriched gene information of N. denticulate sinensis.


Assuntos
Cobre/toxicidade , Decápodes/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Frutos do Mar , Poluentes Químicos da Água/toxicidade , Animais , Quitina/metabolismo , Decápodes/efeitos dos fármacos , Decápodes/imunologia , Endocitose/efeitos dos fármacos , Endocitose/genética , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Anotação de Sequência Molecular , Muda/efeitos dos fármacos , Muda/genética , Fagocitose/efeitos dos fármacos , Fagocitose/genética , RNA-Seq , Transcriptoma/efeitos dos fármacos
4.
Chemosphere ; 262: 128058, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182140

RESUMO

Owing to the superlative properties, engineered nanomaterials (ENM) are being used in food, cosmetics, medicine, and electronics. Therefore, exogenous ENM can be housed into humans through a multitude of exposure routes, leading to compromise of the biomolecules' functionalities through structural deformations, and even at the metabolic level. Consequently, it is of great importance to understand the perturbations introduced at the metabolic level for the timely risk assessment (RA) of ENM. Current technological advancements in metabolomics empower us to visualize the metabolic dysregulations in biological cells, tissues, and living objects, instigated by the ENM. Given the fact, we propose multitiered untargeted metabolomics for the risk assessment of ENM. We propose largely validated experimental design principles that enable the well-organized and authentic identification of metabolic dysregulation connected with a newly engineered nanomaterial. Our scheme could participate in the enhanced transparency of the RA course of rapidly emerging ENM.


Assuntos
Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica/métodos , Nanoestruturas , Humanos , Nanoestruturas/química , Nanoestruturas/toxicidade , Nanotecnologia , Medição de Risco , Transdução de Sinais
5.
PLoS One ; 15(12): e0242986, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33301486

RESUMO

Cycloastragenol (CAG), a molecule isolated from 'Astragalus membranaceus', stimulates the telomerase activity and cell proliferation significantly. It has been proven that CAG has the ability to prevent some diseases in humans. In this study, we aimed to figure out the CAG effects on the different signaling mechanisms in plants and to broadly analyze the genome-wide transcriptional responses in order to demonstrate CAG as a new key molecule that can potentially help plants to overcome different environmental stresses. RNA-seq strategy was employed to assess the transcriptional profiles in A. thaliana calli. Our work primarily focused on an overall study on the transcriptomic responses of A. thaliana to CAG. A total of 22593 unigenes have been detected, among which 1045 unigenes associated with 213 GO terms were differentially expressed and were assigned to 118 KEGG pathways. The up-regulated genes are principally involved in cellular and metabolic processes in addition to the response to a stimulus. The data analysis revealed genes associated with defense signaling pathways such as cytochrome P450s transporter, antioxidant system genes, and stress-responsive protein families were significantly upregulated. The obtained results can potentially help in better understanding biotic and/or abiotic tolerance mechanisms in response to CAG.


Assuntos
Arabidopsis/crescimento & desenvolvimento , Perfilação da Expressão Gênica/métodos , Proteínas de Plantas/genética , Sapogeninas/farmacologia , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Análise de Sequência de RNA
6.
Nat Commun ; 11(1): 6343, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311467

RESUMO

D-mannose is a monosaccharide approximately a hundred times less abundant than glucose in human blood. Previous studies demonstrated that supraphysiological levels of D-mannose inhibit tumour growth and stimulate regulatory T cell differentiation. It is not known whether D-mannose metabolism affects the function of non-proliferative cells, such as inflammatory macrophages. Here, we show that D-mannose suppresses LPS-induced macrophage activation by impairing IL-1ß production. In vivo, mannose administration improves survival in a mouse model of LPS-induced endotoxemia as well as decreases progression in a mouse model of DSS-induced colitis. Phosphomannose isomerase controls response of LPS-activated macrophages to D-mannose, which impairs glucose metabolism by raising intracellular mannose-6-phosphate levels. Such alterations result in the suppression of succinate-mediated HIF-1α activation, imposing a consequent reduction of LPS-induced Il1b expression. Disclosing an unrecognized metabolic hijack of macrophage activation, our study points towards safe D-mannose utilization as an effective intervention against inflammatory conditions.


Assuntos
Interleucina-1beta/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Manose/metabolismo , Manose/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Colite/metabolismo , Colite/patologia , Regulação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/metabolismo , Interleucina-1beta/genética , Lipopolissacarídeos/efeitos adversos , Manosefosfatos/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Monócitos/metabolismo
7.
Nat Commun ; 11(1): 5773, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188211

RESUMO

Beneficial modulation of the gut microbiome has high-impact implications not only in humans, but also in livestock that sustain our current societal needs. In this context, we have tailored an acetylated galactoglucomannan (AcGGM) fibre to match unique enzymatic capabilities of Roseburia and Faecalibacterium species, both renowned butyrate-producing gut commensals. Here, we test the accuracy of AcGGM within the complex endogenous gut microbiome of pigs, wherein we resolve 355 metagenome-assembled genomes together with quantitative metaproteomes. In AcGGM-fed pigs, both target populations differentially express AcGGM-specific polysaccharide utilization loci, including novel, mannan-specific esterases that are critical to its deconstruction. However, AcGGM-inclusion also manifests a "butterfly effect", whereby numerous metabolic changes and interdependent cross-feeding pathways occur in neighboring non-mannanolytic populations that produce short-chain fatty acids. Our findings show how intricate structural features and acetylation patterns of dietary fibre can be customized to specific bacterial populations, with potential to create greater modulatory effects at large.


Assuntos
Fibras na Dieta/farmacologia , Microbioma Gastrointestinal , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Metabolismo Secundário , Acetilação/efeitos dos fármacos , Animais , Butiratos/metabolismo , Ceco/metabolismo , Dieta , Comportamento Alimentar/efeitos dos fármacos , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Genoma , Masculino , Mananas/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metagenômica , Análise de Componente Principal , Proteoma/metabolismo , RNA Ribossômico 16S/genética , Metabolismo Secundário/efeitos dos fármacos , Suínos , Madeira/química
8.
Aquat Toxicol ; 229: 105669, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33142158

RESUMO

Polybrominated diphenyl ethers (PBDEs) are ubiquitously distributed persistent organic pollutants (POPs) in marine environments. Phytoplankton are the entrance of PBDEs entering to biotic environments from abiotic environments, while the responding mechanisms of phytoplankton to PBDEs have not been full established. Therefore, we chose the model diatom Thalassiosira pseudonana in this study, by integrating whole transcriptome analysis with physiological-biochemical data, to reveal the molecular responding mechanisms of T. pseudonana to the toxicity of BDE-47. Our results indicated the changes of genes expressions correlated to the physiological-biochemical changes, and there were multiple molecular mechanisms of T. pseudonana responding to the toxicity of BDE-47: Gene expressions evidence explained the suppression of light reaction and proved the occurrence of cellular oxidative stress; In the meanwhile, up-regulations of genes in pathways involving carbon metabolisms happened, including the Calvin cycle, glycolysis, TCA cycle, fatty acid synthesis, and triacylglycerol synthesis; Lastly, DNA damage was found and three outcome including DNA repair, cell cycle arrest and programmed cell death (PCD) happened, which could finally inhibit the cell division and population growth of T. pseudonana. This study presented the most complete molecular responding mechanisms of phytoplankton cells to PBDEs, and provided valuable information of various PBDEs-sensitive genes with multiple functions for further research involving organic pollutants and phytoplankton.


Assuntos
Diatomáceas/genética , Perfilação da Expressão Gênica , Éteres Difenil Halogenados/toxicidade , Testes de Toxicidade , Apoptose/efeitos dos fármacos , Carbono/metabolismo , Dano ao DNA , Diatomáceas/efeitos dos fármacos , Diatomáceas/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Éteres Difenil Halogenados/metabolismo , Complexos de Proteínas Captadores de Luz/genética , Complexos de Proteínas Captadores de Luz/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Nitrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , Fotossíntese/efeitos dos fármacos , Complexo de Proteína do Fotossistema II/genética , Complexo de Proteína do Fotossistema II/metabolismo , Fitoplâncton/efeitos dos fármacos , Fitoplâncton/genética , Transcriptoma/genética , Poluentes Químicos da Água/toxicidade
9.
Life Sci ; 260: 118472, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971106

RESUMO

AIMS: Testicular torsion/detorsion (T/D) is a critical medical condition that necessitates prompt surgical intervention to avoid testicular atrophy and infertility. The use of natural compounds may protect against the associated detrimental oxidative stress and inflammatory responses. Interestingly, acetyl-11-keto-ß-boswellic acid (AKBA), the main active constituent of Boswellia resin, has shown potent inhibitory effect on 5-lipoxygenase enzyme which converts arachidonic acid into inflammatory mediators. Therefore, this study was conducted to assess the protective mechanisms by which AKBA may protect against testicular T/D injury in rats. MAIN METHODS: Male rats were randomly distributed into five groups: Sham, AKBA (50 mg/kg, p.o.), unilateral testicular T/D, AKBA at two dose levels (25 or 50 mg/kg for 15 successive days) followed by T/D. Histological examination and Johnsen's score were performed to assess testicular injury and perturbations in spermatogenesis. Biochemical parameters included markers of testicular function (serum testosterone), oxidant/antioxidant status (malondialdehyde, glutathione), inflammation (5-lipoxygenase, leukotriene-B4, myeloperoxidase, interleukin-1ß, interleukin-6), apoptosis (Bax, Bcl2, caspase-3), DNA integrity (quantitative DNA fragmentation, DNA laddering, PARP-1), energy production (ATP), in addition to p38 MAPK and JNK protein expression. KEY FINDINGS: In a dose dependent manner, AKBA significantly inhibited testicular T/D-induced upregulation of 5-LOX/LTB4 and p38-MAPK/JNK/Bax pathways and their associated downstream inflammatory and apoptotic cascades. These effects were accompanied with ATP replenishment and DNA preservation, resulting ultimately in salvage of the testis. SIGNIFICANCE: Unprecedentedly, the present mechanistic study revealed the pathways by which AKBA may inhibit testicular T/D injury and offered a novel protective approach that may attenuate the severity of this condition.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Torção do Cordão Espermático/metabolismo , Torção do Cordão Espermático/prevenção & controle , Testículo/efeitos dos fármacos , Triterpenos/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Caspase 3/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Leucotrieno B4/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ratos Wistar , Testículo/metabolismo , Testículo/patologia , Testosterona/metabolismo , Triterpenos/administração & dosagem , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
10.
Phytomedicine ; 79: 153322, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32920286

RESUMO

BACKGROUND: Gut-heart axis has emerged as a novel concept to provide new insights into the complex mechanisms of heart failure (HF) and offer new therapeutic targets. Cardiac hypertrophy (CH) is one of the etiological agents contributing to the development of HF. Baoyuan Decoction (BYD), a traditional Chinese medicine (TCM) formula, exhibits unambiguous effects on treating CH and preventing HF. Previously, we have reported that BYD-targeted endogenous metabolites are potentially linked to gut microbiota metabolism, but the contribution of gut microbiota and metabolic interaction to the cardioprotective efficacy of BYD remains to be elucidated. PURPOSE: To investigate whether the gut microbiota plays a key role in anti-CH effects of BYD. STUDY DESIGN: A comprehensive strategy via incorporating pharmacodynamics, microbiomics, metabolomics, and microflora suppression model was adopted to investigate the links between the microbiota-host metabolic interaction and BYD efficacy in CH rats. METHOD: Firstly, the efficacy evaluation of BYD in treating chronic isoproterenol (ISO)-induced CH rats was performed by using multiple pharmacodynamic approaches. Then, the fecal metabolomics and 16S rRNA sequencing techniques were used to obtain the microbial and metabolic features of BYD against CH. After that, the potential gut-heart axis-based mechanism of BYD against CH was predicted by bioinformatic network analysis and validated by multiple molecular biology approaches. Finally, the antibiotics (AB)-induced gut microbiota suppression was employed to investigate whether the anti-CH effects of BYD is associated with the gut microflora. RESULTS: The fecal microbial communities and metabolic compositions were significantly altered in ISO-induced CH rats, while BYD effectively ameliorated the CH-associated gut microbiota dysbiosis, especially of Firmicutes and Bacteroidetes, and time-dependently alleviated the disturbance of fecal metabolome and reversed the changes of key CH and gut microbiota-related metabolites, such as short/medium chain fatty acids, primary/secondary bile acids, and amino acids. The mechanism study showed that the anti-CH effect of BYD was related to inhibition of the derivatives of arginine and tryptophan and their downstream pro-hypertrophic, pro-inflammatory, and pro-oxidant signaling pathways. The following microflora suppression test showed that BYD-mediated myocardial protection was decreased either in pharmacodynamics or in metabolic modulation. CONCLUSION: This study demonstrates that the protection of BYD against CH is partially gut microbiota dependent, and the regulatory effects of gut metabolism-related tryptophan and arginine derivatives is an important cardioprotection mechanism of BYD.


Assuntos
Cardiomegalia/tratamento farmacológico , Cardiomegalia/microbiologia , Cardiotônicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Cardiomegalia/patologia , Disbiose/tratamento farmacológico , Disbiose/etiologia , Disbiose/microbiologia , Fezes/química , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Coração/efeitos dos fármacos , Isoproterenol/toxicidade , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Miocárdio/metabolismo , Miocárdio/patologia , RNA Ribossômico 16S/análise , RNA Ribossômico 16S/genética , Ratos Sprague-Dawley
11.
PLoS One ; 15(9): e0239843, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32997725

RESUMO

Banxia Houpu decoction (BXHPD) has been used to treat depression in clinical practice for centuries. However, the pharmacological mechanisms of BXHPD still remain unclear. Network Pharmacology (NP) approach was used to explore the potential molecular mechanisms of BXHPD in treating depression. Potential active compounds of BXHPD were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform Database. STRING database was used to build a interaction network between the active compounds and target genes associated with depression. The topological features of nodes were visualized and calculated. Significant pathways and biological functions were identified using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. A total of 44 active compounds were obtained from BXHPD, and 121 potential target genes were considered to be therapeutically relevant. Pathway analysis indicated that MAPK signaling pathway, ErbB signaling pathway, HIF-1 signaling pathway and PI3K-Akt pathway were significant pathways in depression. They were mainly involved in promoting nerve growth and nutrition and alleviating neuroinflammatory conditions. The result provided some potential ways for modern medicine in the treatment of depression.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Bases de Dados Factuais , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/patologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Medicina Tradicional Chinesa , Redes e Vias Metabólicas/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos
12.
Adv Exp Med Biol ; 1274: 101-135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894509

RESUMO

Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.


Assuntos
Redes e Vias Metabólicas/efeitos dos fármacos , Modelos Biológicos , Terapia de Alvo Molecular , Esfingolipídeos/metabolismo , Ceramidas/metabolismo , Humanos , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo
13.
PLoS Biol ; 18(8): e3000757, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32833957

RESUMO

In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation ("nutrient-growth dysregulation") can lead to rapid cell death. Here, we demonstrate that cells can adapt to nutrient-growth dysregulation by evolving major metabolic defects. Specifically, when yeast lysine-auxotrophic mutant lys- encountered lysine limitation, an evolutionarily novel stress, cells suffered nutrient-growth dysregulation. A subpopulation repeatedly evolved to lose the ability to synthesize organosulfurs (lys-orgS-). Organosulfurs, mainly reduced glutathione (GSH) and GSH conjugates, were released by lys- cells during lysine limitation when growth was dysregulated, but not during glucose limitation when growth was regulated. Limiting organosulfurs conferred a frequency-dependent fitness advantage to lys-orgS- by eliciting a proper slow growth program, including autophagy. Thus, nutrient-growth dysregulation is associated with rapid organosulfur release, which enables the selection of organosulfur auxotrophy to better tune cell growth to the metabolic environment. We speculate that evolutionarily novel stresses can trigger atypical release of certain metabolites, setting the stage for the evolution of new ecological interactions.


Assuntos
Adaptação Fisiológica/genética , Lisina/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Nutrientes/farmacologia , Saccharomyces cerevisiae/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Evolução Biológica , Glucose/metabolismo , Glucose/farmacologia , Lisina/deficiência , Redes e Vias Metabólicas/genética , Nitrogênio/metabolismo , Nitrogênio/farmacologia , Nutrientes/metabolismo , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Sirolimo/farmacologia , Estresse Fisiológico
14.
Biochim Biophys Acta Bioenerg ; 1861(12): 148300, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32858000

RESUMO

Alteration in metabolic repertoire is associated with resistance phenotype. Although a common phenotype, not much efforts have been undertaken to design effective strategies to target the metabolic drift in cancerous cells with drug resistant properties. Here, we identified that drug resistant AML cell line HL-60/MX2 did not follow classical Warburg effect, instead these cells exhibited drastically low levels of aerobic glycolysis. Biochemical analysis confirmed reduced glucose consumption and lactic acid production by resistant population with no differences in glutamine consumption. Raman spectroscopy revealed increased lipid and cytochrome content in resistant cells which were also visualized as lipid droplets by Raman mapping, electron microscopy and lipid specific staining. Gene set enrichment analysis data from sensitive and resistant cell lines revealed significant enrichment of lipid metabolic pathways in HL-60/MX2 cells. Further, HL-60/MX2 possessed higher mitochondrial activity and increased OXPHOS suggesting the role of fatty acid metabolism as energy source which was confirmed by increased rate of fatty acid oxidation. Accordingly, OXPHOS inhibitor increased sensitivity of resistant cells to chemotherapeutic drug and fatty acid oxidation inhibitor Etomoxir reduced colony formation ability of resistant cells demonstrating the requirement of fatty acid metabolism and dependency on OXPHOS by resistant leukemic cells for survival and tumorigenicity.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético , Ácidos Graxos/metabolismo , Fosforilação Oxidativa , Proliferação de Células/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Células HL-60 , Humanos , Lipídeos/análise , Redes e Vias Metabólicas/efeitos dos fármacos , Mitoxantrona/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Células THP-1
15.
J Cell Biol ; 219(10)2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32785687

RESUMO

With the rapid global spread of SARS-CoV-2, we have become acutely aware of the inadequacies of our ability to respond to viral epidemics. Although disrupting the viral life cycle is critical for limiting viral spread and disease, it has proven challenging to develop targeted and selective therapeutics. Synthetic lethality offers a promising but largely unexploited strategy against infectious viral disease; as viruses infect cells, they abnormally alter the cell state, unwittingly exposing new vulnerabilities in the infected cell. Therefore, we propose that effective therapies can be developed to selectively target the virally reconfigured host cell networks that accompany altered cellular states to cripple the host cell that has been converted into a virus factory, thus disrupting the viral life cycle.


Assuntos
Antivirais/farmacologia , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Viroses/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Descoberta de Drogas , Humanos , Fatores Imunológicos/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Mapas de Interação de Proteínas , Proteólise , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/fisiologia , Viroses/genética
16.
Nat Commun ; 11(1): 3978, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770044

RESUMO

Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, represses cancer growth and improves cancer therapy. However, the response of different cancer cells to this nutritional manipulation is highly variable, and the molecular determinants of this heterogeneity remain poorly understood. Here we report that hepatocyte nuclear factor 4α (HNF4α) dictates the sensitivity of liver cancer to methionine restriction. We show that hepatic sulfur amino acid (SAA) metabolism is under transcriptional control of HNF4α. Knocking down HNF4α or SAA enzymes in HNF4α-positive epithelial liver cancer lines impairs SAA metabolism, increases resistance to methionine restriction or sorafenib, promotes epithelial-mesenchymal transition, and induces cell migration. Conversely, genetic or metabolic restoration of the transsulfuration pathway in SAA metabolism significantly alleviates the outcomes induced by HNF4α deficiency in liver cancer cells. Our study identifies HNF4α as a regulator of hepatic SAA metabolism that regulates the sensitivity of liver cancer to methionine restriction.


Assuntos
Fator 4 Nuclear de Hepatócito/metabolismo , Neoplasias Hepáticas/metabolismo , Metionina/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Cisteína/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/genética , Fígado/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Mesoderma/efeitos dos fármacos , Mesoderma/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Camundongos , Sorafenibe/farmacologia , Transcrição Genética/efeitos dos fármacos
17.
Ecotoxicol Environ Saf ; 202: 110944, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800225

RESUMO

Bisphenol A (BPA), a weak estrogenic endocrine disruptor and a well-known plasticizer, has the potential to perturb diverse physiological functions; however, its impact on immune and metabolic function in aquatic vertebrates is relatively less understood. The present study aims to investigate the impact of BPA on hepatotoxicity, metabolic and immune parameters vis-à-vis estrogen receptor expression modulation in a freshwater teleost, Labeo bata (Cyprinidae, Cypriniformes). The 96-h median lethal concentration of BPA in L. bata has been determined as 4.79 mg/L. Our data demonstrate that congruent with induction of plasma vitellogenin (VTG), chronic exposure to sub-lethal BPA (2 and 4 µM/L) attenuates erythrocyte count, hemoglobin concentration, packed cell volume, mean corpuscular hemoglobin, but not leukocyte number. Further, a significant increase in MDA, concomitant with diminished catalase and heightened GST activity corroborates well with hepatic dystrophic changes, appearance of fatty liver (macrovesicular steatosis) and elevated serum lipids (triglyceride, cholesterol, LDL, VLDL) in BPA-treated groups. Interestingly, a differential regulation of estrogen receptor (ER) subtypes at transcript and protein level signifies negative influence of BPA on hepatic ERα/ERß homeostasis in this species. While at a lower dose it promotes Akt phosphorylation (activation), BPA at the higher dose attenuates ERK1/2 phosphorylation (activation), suggesting potential alteration in insulin sensitivity. Importantly, dose-dependent decrease in hepatic TNF-α, IL-1ß, iNOS (NOS2) expression and nitric oxide (NO) level corresponds well with progressive decline in p-NF-κB, p-p38 MAPK, albeit with differential sensitivity, in BPA-exposed groups. Collectively, BPA exposure has wide-spread negative influence on hematological, biochemical and hepatic events in this species.


Assuntos
Compostos Benzidrílicos/toxicidade , Cyprinidae/metabolismo , Disruptores Endócrinos/toxicidade , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Receptores Estrogênicos/genética , Animais , Cyprinidae/imunologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Água Doce/química , Expressão Gênica/efeitos dos fármacos , Homeostase , Inflamação , Fígado/imunologia , Fígado/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Vitelogeninas/metabolismo
18.
Ecotoxicol Environ Saf ; 205: 111126, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32823070

RESUMO

Triphenyl phosphate (TPP) has been found in various environmental media and in biota suggesting widespread human exposure. However, there is still insufficient information on the hepatotoxicity mechanisms of health risk exposed to TPP. In this study, TPP could induce human normal liver cell (L02) apoptosis, injury cell ultrastructure and elevate the levels of reactive oxygen species (ROS). The integrated multi-omic (transcriptomic, proteomic, and metabolomic) analysis was used to further investigate the mechanisms. Transcriptomic analysis revealed that TPP exposure markedly affected cell apoptosis, oncogene activation, REDOX homeostasis, DNA damage and repair. Additionally, proteomic analysis found that the related proteins associated with apoptosis, oxidative stress, metabolism and membrane structure were affected. And metabolomic analysis verified that the related metabolic pathways, such as glycolysis, citrate cycle, oxidative phosphorylation, lipid and protein metabolism, were also significantly disrupted. Based on the multi-omic results, a hypothesized network was constructed to discover the key molecular events in response to TPP and illustrate the mechanism of TPP-induced hepatotoxicity in L02 cells. Therefore, molecular responses could be elucidated at multiple biological levels, and multi-omic analysis could provide scientific tools for exploring potential mechanisms of toxicity and chemical risk assessment.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Poluentes Ambientais/toxicidade , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Organofosfatos/toxicidade , Transcriptoma/efeitos dos fármacos , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Perfilação da Expressão Gênica , Humanos , Metabolômica , Estresse Oxidativo/efeitos dos fármacos , Proteômica , Espécies Reativas de Oxigênio/metabolismo
19.
Commun Biol ; 3(1): 466, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811894

RESUMO

Chinese herbal formulas including the lung-cleaning and toxicity-excluding (LCTE) soup have played an important role in treating the ongoing COVID-19 pandemic (caused by SARS-CoV-2) in China. Applying LCTE outside of China may prove challenging due to the unfamiliar rationale behind its application in terms of Traditional Chinese Medicine. To overcome this barrier, a biochemical understanding of the clinical effects of LCTE is needed. Here, we explore the chemical compounds present in the reported LCTE ingredients and the proteins targeted by these compounds via a network pharmacology analysis. Our results indicate that LCTE contains compounds with the potential to directly inhibit SARS-CoV-2 and inflammation, and that the compound targets proteins highly related to COVID-19's main symptoms. We predict the general effect of LCTE is to affect the pathways involved in viral and other microbial infections, inflammation/cytokine response, and lung diseases. Our work provides a biochemical basis for using LCTE to treat COVID-19 and its main symptoms.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Pandemias , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/análise , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antivirais/química , Antivirais/uso terapêutico , Sulfato de Cálcio , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Sistemas de Liberação de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Fitoterapia , Plantas Medicinais/química , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Sistema Respiratório/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores
20.
Phytomedicine ; 77: 153266, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32629383

RESUMO

BACKGROUND: Yunnan Baiyao (YNBY) is a traditional Chinese medicine formulae, which has the functions of hemostasis, activating blood circulation and removing blood stasis, anti-inflammation, etc. Although the presence of Caowu (CW, Aconiti Kusnezoffii Radix), the detoxification mechanism of YNBY is still unclear. PURPOSE: In current study, network pharmacology, toxicological methods and metabolomics technique were applied to explore YNBY in attenuating toxicity of CW. METHODS: Prediction of targets and pathways of CW were carried out by commonly used network pharmacological method. Simultaneously, SD rats were orally administrated with CW, processed CW (ZCW), YNBY, and YNBY which lack of CW (QCW) for 15 days. Tissue samples were observed with histopathology. Urine samples were analyzed with ultra-performance liquid chromatography-mass spectrometry to screen differential metabolites and related metabolic pathways associated with toxicity of CW. Furthermore, by comparing the changes of the metabolite contents, focused the attenuated metabolic pathway. Finally, the network pharmacological and experimental data were integrated to investigate detoxification mechanism of YNBY. RESULTS: A total of 44 potential toxicity biomarkers were identified and 14 related pathways were involved in the toxicity of CW. Furthermore, 5 core toxicity biomarkers (2-keto-6-acetamidocaproate, γ-glutamylleucine, prostaglandin E3, 4-hydroxy-5-(3'-hydroxyphenyl)-valeric acid-3'-O-sulphate, and 3,4-dihydroxy- phenylglycol O-sulfate) were regulated to normal condition in YNBY group. Lysine degradation was locked as the core metabolic pathway of detoxification of YNBY. Integrating the predicted results of network pharmacology, ACHE, SLC6A3, SLC6A4 might be the target of protective role of other herbs in YNBY. CONCLUSION: Network pharmacology combined with metabolomics exhibited a powerful mean to investigate the herbal toxicity and probed into the detoxification mechanism of formulae, which contributes to its safety evaluation.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Aconitum/química , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , China , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Metabólica , Lisina/metabolismo , Masculino , Espectrometria de Massas/métodos , Metabolômica/métodos , Ratos Sprague-Dawley
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