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1.
Anticancer Res ; 41(9): 4271-4276, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475046

RESUMO

BACKGROUND/AIM: The anticancer mechanism of itraconazole remains unsolved; therefore, we studied itraconazole-induced alterations in specialized pro-resolving mediators (SPMs) in cancer cells. MATERIALS AND METHODS: The human cervical squamous carcinoma cell line CaSki was cultured with or without 1 µM itraconazole. Liquid chromatography/mass spectrometry analysis was conducted to identify SPMs that were influenced by itraconazole. Cell growth experiments were conducted using itraconazole and inhibitors targeting the metabolic pathways of candidate SPMs. RESULTS: Resolvin E3, resolvin E2, prostaglandin J2 (PGJ2), delta-12-PGJ2, and maresin 2 were identified as candidate SPMs. The 12/15-lipoxygenase inhibitor, which is involved in the conversion of 18-hydroxy-eicosapentaenoic acid to resolvin E3, attenuated the inhibitory effect of itraconazole. Inhibition of the PGJ2 metabolic pathway did not interfere with itraconazole treatment. CONCLUSION: The metabolic pathway of SPMs, including resolving E3, could be proposed as an anticancer target of itraconazole.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Ácidos Graxos Insaturados/metabolismo , Itraconazol/farmacologia , Inibidores de Lipoxigenase/farmacologia , Neoplasias do Colo do Útero/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Espectrometria de Massas , Redes e Vias Metabólicas/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico
2.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361761

RESUMO

Cocaine toxicity has been a subject of study because cocaine is one of the most common and potent drugs of abuse. In the current study the effect of cocaine on human liver cancer cell line (HepG2) was assessed. Cocaine toxicity (IC50) on HepG2 cells was experimentally calculated using an XTT assay at 2.428 mM. The metabolic profile of HepG2 cells was further evaluated to investigate the cytotoxic activity of cocaine at 2 mM at three different time points. Cell medium and intracellular material samples were analyzed with a validated HILIC-MS/MS method for targeted metabolomics on an ACQUITY Amide column in gradient mode with detection on a triple quadrupole mass spectrometer in multiple reaction monitoring. About 106 hydrophilic metabolites from different metabolic pathways were monitored. Multivariate analysis clearly separated the studied groups (cocaine-treated and control samples) and revealed potential biomarkers in the extracellular and intracellular samples. A predominant effect of cocaine administration on alanine, aspartate, and glutamate metabolic pathway was observed. Moreover, taurine and hypotaurine metabolism were found to be affected in cocaine-treated cells. Targeted metabolomics managed to reveal metabolic changes upon cocaine administration, however deciphering the exact cocaine cytotoxic mechanism is still challenging.


Assuntos
Alanina/metabolismo , Ácido Aspártico/metabolismo , Cocaína/toxicidade , Ácido Glutâmico/metabolismo , Metaboloma/efeitos dos fármacos , Biomarcadores/metabolismo , Cromatografia Líquida , Células Hep G2 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Redes e Vias Metabólicas , Metabolômica/métodos , Análise Multivariada , Espectrometria de Massas em Tandem , Taurina/análogos & derivados , Taurina/metabolismo
3.
Cells ; 10(7)2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34359932

RESUMO

MicroRNAs (miRNAs) are critical regulators of gene expression that may be used to identify the pathological pathways influenced by disease and cellular interactions. Viral miRNAs (v-miRNAs) encoded by both DNA and RNA viruses induce immune dysregulation, virus production, and disease pathogenesis. Given the absence of effective treatment and the prevalence of highly infective SARS-CoV-2 strains, improved understanding of viral-associated miRNAs could provide novel mechanistic insights into the pathogenesis of COVID-19. In this study, SARS-CoV-2 v-miRNAs were identified by deep sequencing in infected Calu-3 and Vero E6 cell lines. Among the ~0.1% small RNA sequences mapped to the SARS-CoV-2 genome, the top ten SARS-CoV-2 v-miRNAs (including three encoded by the N gene; v-miRNA-N) were selected. After initial screening of conserved v-miRNA-N-28612, which was identified in both SARS-CoV and SARS-CoV-2, its expression was shown to be positively associated with viral load in COVID-19 patients. Further in silico analysis and synthetic-mimic transfection of validated SARS-CoV-2 v-miRNAs revealed novel functional targets and associations with mechanisms of cellular metabolism and biosynthesis. Our findings support the development of v-miRNA-based biomarkers and therapeutic strategies based on improved understanding of the pathophysiology of COVID-19.


Assuntos
COVID-19/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/genética , Redes e Vias Metabólicas , MicroRNAs/genética , RNA Viral/genética , SARS-CoV-2/fisiologia , Animais , COVID-19/virologia , Linhagem Celular , Chlorocebus aethiops , Interações Hospedeiro-Patógeno , Humanos , Fosfoproteínas/genética , SARS-CoV-2/genética , Células Vero
4.
Nat Commun ; 12(1): 4976, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404790

RESUMO

To construct a superior microbial cell factory for chemical synthesis, a major challenge is to fully exploit cellular potential by identifying and engineering beneficial gene targets in sophisticated metabolic networks. Here, we take advantage of CRISPR interference (CRISPRi) and omics analyses to systematically identify beneficial genes that can be engineered to promote free fatty acids (FFAs) production in Escherichia coli. CRISPRi-mediated genetic perturbation enables the identification of 30 beneficial genes from 108 targets related to FFA metabolism. Then, omics analyses of the FFAs-overproducing strains and a control strain enable the identification of another 26 beneficial genes that are seemingly irrelevant to FFA metabolism. Combinatorial perturbation of four beneficial genes involving cellular stress responses results in a recombinant strain ihfAL--aidB+-ryfAM--gadAH-, producing 30.0 g L-1 FFAs in fed-batch fermentation, the maximum titer in E. coli reported to date. Our findings are of help in rewiring cellular metabolism and interwoven intracellular processes to facilitate high-titer production of biochemicals.


Assuntos
Escherichia coli/genética , Escherichia coli/isolamento & purificação , Escherichia coli/metabolismo , Ácidos Graxos não Esterificados/biossíntese , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Ácidos Graxos/metabolismo , Fermentação , Regulação Bacteriana da Expressão Gênica , Engenharia Metabólica , Redes e Vias Metabólicas/genética , Transcriptoma
5.
BMC Gastroenterol ; 21(1): 335, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454434

RESUMO

BACKGROUND: Although salt plays an important role in maintaining the normal physiological metabolism of the human body, many abnormalities in the liver caused by a high-salt diet, especially with normal pathological results, are not well characterized. METHODS: Eight-week-old female C57BL/6 mice were randomly divided into a normal group and a high salt group. These groups were then fed with normal or sodium-rich chow (containing 6% NaCl) for 6 weeks. Liver injury was evaluated, and the influences of a high-salt diet on the liver were analyzed by transcriptome sequencing at the end of week 6. RESULTS: We found that although no liver parenchymal injury could be found after high-salt feeding, many metabolic abnormalities had formed based on transcriptome sequencing results. GO and KEGG enrichment analyses of differentially expressed genes revealed that at least 15 enzymatic activities and the metabolism of multiple substances were affected by a high-salt diet. Moreover, a variety of signaling and metabolic pathways, as well as numerous biological functions, were involved in liver dysfunction due to a high-salt diet. This included some known pathways and many novel ones, such as retinol metabolism, linoleic acid metabolism, steroid hormone biosynthesis, and signaling pathways. CONCLUSIONS: A high-salt diet can induce serious abnormal liver metabolic activities in mice at the transcriptional level, although substantial physical damage may not yet be visible. This study, to our knowledge, was the first to reveal the impact of a high-salt diet on the liver at the omics level, and provides theoretical support for potential clinical risk evaluation, pathogenic mechanisms, and drug design for combating liver dysfunction. This study also provides a serious candidate direction for further research on the physiological impacts of high-salt diets.


Assuntos
Cloreto de Sódio , Transcriptoma , Animais , Dieta , Feminino , Fígado/metabolismo , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos C57BL , Cloreto de Sódio/metabolismo
6.
Nat Commun ; 12(1): 4728, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354065

RESUMO

Understanding how diet and gut microbiota interact in the context of human health is a key question in personalized nutrition. Genome-scale metabolic networks and constraint-based modeling approaches are promising to systematically address this complex problem. However, when applied to nutritional questions, a major issue in existing reconstructions is the limited information about compounds in the diet that are metabolized by the gut microbiota. Here, we present AGREDA, an extended reconstruction of diet metabolism in the human gut microbiota. AGREDA adds the degradation pathways of 209 compounds present in the human diet, mainly phenolic compounds, a family of metabolites highly relevant for human health and nutrition. We show that AGREDA outperforms existing reconstructions in predicting diet-specific output metabolites from the gut microbiota. Using 16S rRNA gene sequencing data of faecal samples from Spanish children representing different clinical conditions, we illustrate the potential of AGREDA to establish relevant metabolic interactions between diet and gut microbiota.


Assuntos
Dieta , Microbioma Gastrointestinal/fisiologia , Redes e Vias Metabólicas , Modelos Biológicos , Algoritmos , Criança , Fenômenos Fisiológicos da Nutrição Infantil , Dieta Mediterrânea , Fermentação , Microbioma Gastrointestinal/genética , Humanos , Técnicas In Vitro , Lens (Planta)/química , Valor Nutritivo , RNA Ribossômico 16S/genética , Espanha
7.
Nat Commun ; 12(1): 4710, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354070

RESUMO

Cyanophage S-2L is known to profoundly alter the biophysical properties of its DNA by replacing all adenines (A) with 2-aminoadenines (Z), which still pair with thymines but with a triple hydrogen bond. It was recently demonstrated that a homologue of adenylosuccinate synthetase (PurZ) and a dATP triphosphohydrolase (DatZ) are two important pieces of the metabolism of 2-aminoadenine, participating in the synthesis of ZTGC-DNA. Here, we determine that S-2L PurZ can use either dATP or ATP as a source of energy, thereby also depleting the pool of nucleotides in dATP. Furthermore, we identify a conserved gene (mazZ) located between purZ and datZ genes in S-2L and related phage genomes. We show that it encodes a (d)GTP-specific diphosphohydrolase, thereby providing the substrate of PurZ in the 2-aminoadenine synthesis pathway. High-resolution crystal structures of S-2L PurZ and MazZ with their respective substrates provide a rationale for their specificities. The Z-cluster made of these three genes - datZ, mazZ and purZ - was expressed in E. coli, resulting in a successful incorporation of 2-aminoadenine in the bacterial chromosomal and plasmidic DNA. This work opens the possibility to study synthetic organisms containing ZTGC-DNA.


Assuntos
DNA Bacteriano/genética , Genes Virais , Siphoviridae/genética , 2-Aminopurina/análogos & derivados , 2-Aminopurina/metabolismo , Adenilossuccinato Sintase/química , Adenilossuccinato Sintase/genética , Adenilossuccinato Sintase/metabolismo , Bacteriófagos , Pareamento de Bases , Cristalografia por Raios X , DNA Bacteriano/metabolismo , DNA Viral/genética , DNA Viral/metabolismo , Desoxiadenosinas/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Genoma Viral , Redes e Vias Metabólicas , Modelos Moleculares , Monoéster Fosfórico Hidrolases/química , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Podoviridae/classificação , Podoviridae/genética , Conformação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Siphoviridae/classificação , Eletricidade Estática , Proteínas Virais/química , Proteínas Virais/genética , Proteínas Virais/metabolismo
8.
Nat Commun ; 12(1): 4845, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381036

RESUMO

The human gut microbiota is increasingly recognized as an important factor in modulating innate and adaptive immunity through release of ligands and metabolites that translocate into circulation. Urbanizing African populations harbor large intestinal diversity due to a range of lifestyles, providing the necessary variation to gauge immunomodulatory factors. Here, we uncover a gradient of intestinal microbial compositions from rural through urban Tanzanian, towards European samples, manifested both in relative abundance and genomic variation observed in stool metagenomics. The rural population shows increased Bacteroidetes, led by Prevotella copri, but also presence of fungi. Measured ex vivo cytokine responses were significantly associated with 34 immunomodulatory microbes, which have a larger impact on circulating metabolites than non-significant microbes. Pathway effects on cytokines, notably TNF-α and IFN-γ, differential metabolome analysis and enzyme copy number enrichment converge on histidine and arginine metabolism as potential immunomodulatory pathways mediated by Bifidobacterium longum and Akkermansia muciniphila.


Assuntos
Citocinas/imunologia , Microbioma Gastrointestinal/fisiologia , População Rural , População Urbana , Adulto , Arginina/metabolismo , Bactérias/imunologia , Bactérias/isolamento & purificação , Bactérias/metabolismo , Dieta , Feminino , Microbioma Gastrointestinal/imunologia , Histidina/metabolismo , Humanos , Imunomodulação , Masculino , Redes e Vias Metabólicas , Metaboloma/imunologia , Fatores Socioeconômicos , Tanzânia , Urbanização
9.
Adv Exp Med Biol ; 1331: 31-48, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453291

RESUMO

Recent research has demonstrated that degeneration of the basal forebrain cholinergic system, far from being a mere downstream mediator of Alzheimer's disease (AD) symptoms, may play a disease-aggravating role in the continuum of AD pathology. The search for novel biomarkers of the cholinergic deficit in AD and novel therapeutic targets for the sustenance of the basal forebrain cholinergic system has therefore taken on more urgency. A novel model that explains the preferential vulnerability of basal forebrain cholinergic neurons in AD as the result of pathological alterations to nerve growth factor (NGF) metabolism offers an integrated investigative platform for the development of such biomarkers and therapeutics. By positing a reciprocal trophic interaction between the basal forebrain and its target tissues, this model can also explain the disease-modifying nature of the cholinergic deficit in AD and can incorporate other key factors in basal forebrain cholinergic degeneration, including NGF receptor changes and retrograde transport deficits in AD. This chapter will focus on the potential of NGF metabolic pathway biomarkers in AD as well as therapeutic targets to correct NGF metabolic deficits, aiding the development of novel pro-cholinergic therapeutics.


Assuntos
Doença de Alzheimer , Preparações Farmacêuticas , Doença de Alzheimer/tratamento farmacológico , Biomarcadores , Humanos , Redes e Vias Metabólicas , Fator de Crescimento Neural/metabolismo
10.
Gene ; 802: 145870, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34363886

RESUMO

Leydig cells (LCs) are testosterone-generating endocrine cells that are located outside the seminiferous tubules in the testis, and testosterone is fundamental for retaining spermatogenesis and male fertility. In buffalo, adult Leydig cells (ALCs) are developed by immature Leydig cells (ILCs) in the postnatal testes. However, the genes/pathways associated to the regulation of testosterone secretion function during the development of postnatal LCs remains comprehensively unidentified. The present study comparatively analyzed the transcriptome profiles of ILC and ALC in buffalo with significant differences in testosterone secretion. Differentially expressed genes (DEGs) analysis identified 972 and 1,091 annotated genes that were significantly up- and down-regulated in buffalo ALC. Functional enrichment analysis showed that cAMP signaling being the most significantly enriched pathway, and testosterone synthesis and lipid transport-related genes/pathways were upregulated in ALC. Furthermore, gene set enrichment analysis (GSEA) shows that cAMP signaling and steroid hormone biosynthesis were activated in ALC, demonstrating that cAMP signaling may serve as a positive regulatory pathway in the maintenance of testosterone function during postnatal development of LCs. Protein-protein interaction (PPI) networks analysis highlighted that ADCY8, ADCY2, POMC, CHRM2, SST, PTGER3, SSTR2, SSTR1, NPY1R, and HTR1D as hub genes in the cAMP signaling pathway. In conclusion, this study identified key genes and pathways associated in the regulation of testosterone secretion function during the ILC-ALC transition in buffalo based on bioinformatics analysis, and these key genes might be deeply involved in cAMP generation to influencing testosterone levels in LCs. The results suggest that ALCs might increase testosterone levels by enhancing cAMP production than ILCs. Our data will enhance the understanding of developmental mechanism studies related to testosterone function and provide preliminary evidence for molecular mechanisms of LCs regulating spermatogenesis.


Assuntos
Búfalos/genética , Células Intersticiais do Testículo/fisiologia , Testículo/citologia , Testosterona/fisiologia , Animais , Búfalos/fisiologia , Separação Celular/veterinária , AMP Cíclico/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Redes e Vias Metabólicas , RNA-Seq/veterinária , Transdução de Sinais , Espermatogênese/genética , Esteroides/biossíntese , Testosterona/metabolismo , Transcriptoma
11.
Theriogenology ; 173: 221-229, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34399386

RESUMO

Glucocorticoids (GCs) are known to play an important role in maintaining basal and stress-related homeostasis by interacting with endocrine mediators and prostaglandins (PGs). Although a growing body of evidence shows that GCs exert their regulatory action at a multitude of sites in the reproductive axis through corticosteroid receptors, little is known about the direct role of cortisol, an active form of GCs, in the equine endometrium. Thus, the study aimed to determine the effect of cortisol on PGF2α synthesis in the endometrial tissue and cells in vitro. In Exp.1, the immunolocalization and the expression of the glucocorticoid receptor (GCR) in the endometrium throughout the estrous cycle were established. In Exp. 2 and 3, the effects of cortisol on PGF2α secretion and transcripts associated with the arachidonic acid (AA) cascade in endometrial tissues, and cells were defined. Endometrial tissues obtained from the early, mid, and late luteal phases and the follicular phase of the estrous cycle were exposed to cortisol (100, 200, and 400 nM) for 24 h. Endometrial epithelial and stromal cells (early phase of estrous cycle) were exposed to cortisol (100 nM) for 24 h. Then, PGF2α secretion and transcripts associated with the AA cascade (PLA2G2A, PLA2G4A, PTGS2, and PGFS) were assessed. GCR was expressed in the cytoplasm and the nucleus in the luminal and glandular epithelium as well as in the stroma. Endometrial GCR protein abundance was up-regulated at the late luteal phase compared to the mid-luteal phase of the estrous cycle. Cortisol dose-dependently decreased PGF2α secretion, PLA2G2A and PLA2G4A transcripts in endometrial tissues. Additionally, cortisol treatment decreased PGF2α secretion from endometrial epithelial and stromal cells. Moreover, it affected PLA2G2A, PLA2G4A, and PTGS2 transcripts in endometrial stromal cells. These findings suggest that cortisol suppresses the synthesis of PGF2α by affecting the AA cascade in the equine endometrium during the estrous cycle.


Assuntos
Dinoprosta , Hidrocortisona , Animais , Ácido Araquidônico/metabolismo , Ácido Araquidônico/farmacologia , Dinoprosta/metabolismo , Dinoprosta/farmacologia , Dinoprostona/metabolismo , Endométrio/metabolismo , Feminino , Cavalos , Hidrocortisona/metabolismo , Redes e Vias Metabólicas
12.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34360674

RESUMO

Population aging has been a global trend for the last decades, which increases the pressure to develop new cell-based or drug-based therapies, including those that may cure bone diseases. To understand molecular processes that underlie bone development and turnover, we followed osteogenic differentiation of human dental pulp stem cells (DPSCs) using a specific induction medium. The differentiation process imitating in vivo osteogenesis is triggered by various signaling pathways and is associated with massive proteome and metabolome changes. Proteome was profiled by ultrahigh-performance liquid chromatography and comprehensively quantified by ion mobility-enhanced mass spectrometry. From 2667 reproducibly quantified and identified proteins, 432 were differentially abundant by strict statistic criteria. Metabolome profiling was carried out by nuclear magnetic resonance. From 27 detected metabolites, 8 were differentially accumulated. KEGG and MetaboAnalyst hinted metabolic pathways that may be involved in the osteogenic process. Enrichment analysis of differentially abundant proteins highlighted PPAR, FoxO, JAK-STAT, IL-17 signaling pathways, biosynthesis of thyroid hormones and steroids, mineral absorption, and fatty acid metabolism as processes with prominent impact on osteoinduction. In parallel, metabolomic data showed that aminoacyl-tRNA biosynthesis, as well as specific amino acids, likely promote osteodifferentiation. Targeted immunoassays validated and complemented omic results. Our data underlined the complexity of the osteogenic mechanism. Finally, we proposed promising targets for future validation in patient samples, a step toward the treatment of bone defects.


Assuntos
Osteoblastos/metabolismo , Osteogênese , Transdução de Sinais , Células-Tronco/fisiologia , Diferenciação Celular , Linhagem Celular , Polpa Dentária/citologia , Humanos , Redes e Vias Metabólicas , Metabolômica , Proteômica
13.
Nat Commun ; 12(1): 4790, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373465

RESUMO

Eukaryotic organisms play an important role in industrial biotechnology, from the production of fuels and commodity chemicals to therapeutic proteins. To optimize these industrial systems, a mathematical approach can be used to integrate the description of multiple biological networks into a single model for cell analysis and engineering. One of the most accurate models of biological systems include Expression and Thermodynamics FLux (ETFL), which efficiently integrates RNA and protein synthesis with traditional genome-scale metabolic models. However, ETFL is so far only applicable for E. coli. To adapt this model for Saccharomyces cerevisiae, we developed yETFL, in which we augmented the original formulation with additional considerations for biomass composition, the compartmentalized cellular expression system, and the energetic costs of biological processes. We demonstrated the ability of yETFL to predict maximum growth rate, essential genes, and the phenotype of overflow metabolism. We envision that the presented formulation can be extended to a wide range of eukaryotic organisms to the benefit of academic and industrial research.


Assuntos
Genoma , Engenharia Metabólica , Redes e Vias Metabólicas , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Biomassa , Biotecnologia , Simulação por Computador , Escherichia coli/genética , Regulação Fúngica da Expressão Gênica , Glucose , Modelos Biológicos , Fenótipo , Termodinâmica
14.
Nutrients ; 13(7)2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34371961

RESUMO

Here we present an extensive narrative review of the broadly understood modifications to the lifestyles of women with polycystic ovary syndrome (PCOS). The PubMed database was analyzed, combining PCOS entries with causes, diseases, diet supplementation, lifestyle, physical activity, and use of herbs. The metabolic pathways leading to disturbances in lipid, carbohydrate, and hormonal metabolism in targeted patients are described. The article refers to sleep disorders, changes in mental health parameters, and causes of oxidative stress and inflammation. These conditions consistently lead to the occurrence of severe diseases in patients suffering from diabetes, the fatty degeneration of internal organs, infertility, atherosclerosis, cardiovascular diseases, dysbiosis, and cancer. The modification of lifestyles, diet patterns and proper selection of nutrients, pharmacological and natural supplementation in the form of herbs, and physical activity have been proposed. The progress and consequences of PCOS are largely modifiable and depend on the patient's approach, although we have to take into account also the genetic determinants.


Assuntos
Dieta , Exercício Físico , Estilo de Vida , Síndrome do Ovário Policístico/terapia , Suplementos Nutricionais , Disbiose/complicações , Feminino , Microbioma Gastrointestinal , Humanos , Redes e Vias Metabólicas , Plantas Medicinais , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/fisiopatologia , Sono
16.
Viruses ; 13(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34452405

RESUMO

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.


Assuntos
Antivirais/uso terapêutico , Dengue/tratamento farmacológico , Transcriptoma , Adenosina Trifosfatases/antagonistas & inibidores , Antagonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/uso terapêutico , Antivirais/farmacologia , Encéfalo/metabolismo , Simulação por Computador , Dengue/sangue , Dengue/genética , Dengue/metabolismo , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Humanos , Fígado/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , NF-kappa B/metabolismo , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Dengue Grave/sangue , Dengue Grave/tratamento farmacológico , Dengue Grave/genética , Dengue Grave/metabolismo , Baço/metabolismo
17.
Nutrients ; 13(7)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34371816

RESUMO

(1) Background: Type-2-diabetes-mellitus (DM) is one the most important cardiovascular-risk-factors. Among many molecules regulating vascular tone, nitric oxide appears to be the most pivotal. Although micro- and macrovascular-abnormalities are extensively studied, the alterations in the nitric-oxide-metabolic-pathway require further investigations. Additionally, the role of erythrocytes in the vascular tone regulation has not been extensively explored. The aim of this study was to evaluate the endothelial-function and the nitric-oxide-metabolic-pathway in erythrocytes and plasma of diabetic individuals. (2) Methods: A total of 80 subjects were enrolled in this cross-sectional study, including 35 patients with DM and 45 healthy individuals. The endothelial-function was evaluated in response to different stimuli. (3) Results: In the DM group, decreased Arginine and citrulline concentrations in the plasma compartment with reduced Arginine/ADMA and ADMA/DMA-ratios were observed. Preserved nitric-oxide-metabolism in erythrocytes with reduced citrulline level and significantly higher NO-bioavailability were noted. Significant endothelial dysfunction in DM individuals was proved in response to the heat-stimulus. (4) Conclusions: DM patients at an early stage of disease show significant differences in the nitric-oxide-metabolic-pathway, which are more pronounced in the plasma compartment. Erythrocytes constitute a buffer with a higher nitric-oxide-bioavailability, less affected by the DM-related deviations. Patients at an early-stage of DM reveal endothelial-dysfunction, which could be diagnosed earlier using the laser-Doppler-flowmetry.


Assuntos
Arginina/análogos & derivados , Arginina/sangue , Diabetes Mellitus Tipo 2/sangue , Endotélio Vascular/metabolismo , Eritrócitos/metabolismo , Óxido Nítrico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Citrulina/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade
18.
J Agric Food Chem ; 69(35): 10311-10320, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34431666

RESUMO

Based on hydrophilic interaction liquid chromatography (HILIC) liquid chromatography-mass spectrometry (LC-MS), untargeted differential metabolomics analysis was performed on the pear wine samples before and after browning to determine the key compounds that affect the browning of Dangshan pear wine. A total of 196 significantly differential metabolites were found, 22 of which might be related to the browning of Dangshan pear wine. d-(+)-glucose, l-phenylalanine, l-norleucine, methionine, d-(+)-proline, aloin, and rutin were the key differential metabolites in pear wine before and after browning. The Maillard reaction of d-(+)-glucose, l-norleucine, methionine, and the oxidation of aloin played critical roles in the browning of Dangshan pear wine. The reaction of aloin and glucose to form 5-hydroxyaloin A, 7-hydroxyaloin B, and elgonica-dimer A was one of the important metabolic pathways in which the phenolic compounds formed anthraquinone during the browning process of Dangshan pear wine.


Assuntos
Pyrus , Vinho , Frutas , Reação de Maillard , Redes e Vias Metabólicas , Vinho/análise
19.
J Theor Biol ; 529: 110860, 2021 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-34389361

RESUMO

Autocatalytic Sets are reaction networks theorised as networks at the basis of life. Their main feature is the ability of spontaneously emerging and self-reproducing. The Reflexively and Food-generated theory provides a formal definition of Autocatalytic Sets in terms of graphs with peculiar topological properties. This formalisation has been proved to be a powerful tool for the study of the chemical networks underlying life, and it was able to identify autocatalytic structures in real metabolic networks. However, the dynamical behaviour of such networks has not been yet complitely clarified. In this work, I present a first attempt to connect the topology of an Autocatalytic Set with its dynamics. For this purpose, I represent Autocatalytic Sets in terms of Chemical Reaction Networks, and I use the Chemical Reaction Network theory to detect motifs in the networks'structure, that allow to determine the long-term behaviour of the system.


Assuntos
Redes e Vias Metabólicas , Origem da Vida , Catálise
20.
Sci Signal ; 14(690)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230210

RESUMO

Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.


Assuntos
COVID-19/imunologia , Ácido Cinurênico/imunologia , SARS-CoV-2 , Adulto , Idoso , COVID-19/sangue , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Ácido Cinurênico/sangue , Modelos Logísticos , Masculino , Redes e Vias Metabólicas/imunologia , Metabolômica , Pessoa de Meia-Idade , Análise Multivariada , Índice de Gravidade de Doença , Fatores Sexuais , Transdução de Sinais/imunologia , Triptofano/metabolismo
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