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1.
Molecules ; 26(7)2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33917533

RESUMEN

(1) Background: Data accuracy plays a key role in determining the model performances and the field of metabolism prediction suffers from the lack of truly reliable data. To enhance the accuracy of metabolic data, we recently proposed a manually curated database collected by a meta-analysis of the specialized literature (MetaQSAR). Here we aim to further increase data accuracy by focusing on publications reporting exhaustive metabolic trees. This selection should indeed reduce the number of false negative data. (2) Methods: A new metabolic database (MetaTREE) was thus collected and utilized to extract a dataset for metabolic data concerning glutathione conjugation (MT-dataset). After proper pre-processing, this dataset, along with the corresponding dataset extracted from MetaQSAR (MQ-dataset), was utilized to develop binary classification models using a random forest algorithm. (3) Results: The comparison of the models generated by the two collected datasets reveals the better performances reached by the MT-dataset (MCC raised from 0.63 to 0.67, sensitivity from 0.56 to 0.58). The analysis of the applicability domain also confirms that the model based on the MT-dataset shows a more robust predictive power with a larger applicability domain. (4) Conclusions: These results confirm that focusing on metabolic trees represents a convenient approach to increase data accuracy by reducing the false negative cases. The encouraging performances shown by the models developed by the MT-dataset invites to use of MetaTREE for predictive studies in the field of xenobiotic metabolism.


Asunto(s)
Bases de Datos Factuales , Glutatión/metabolismo , Redes y Vías Metabólicas , Análisis de Datos , Inactivación Metabólica , Análisis de Componente Principal , Programas Informáticos
2.
Bioresour Technol ; 332: 125047, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33839509

RESUMEN

Methanotrophs can oxidize methane as the sole carbon and energy, and the resulting intermediate products can be simultaneously utilized by coexistent denitrifying bacteria to remove the nitrogen, which named Aerobic Methane Oxidation Coupled to Denitrification (AME-D). In this paper, an AME-D system was built in an improved denitrification bio-filter, to analyze the nitrogen removal efficiency and mechanism. The maximum TN removal rate reached 95.05%. As shown in Raman spectroscopy, in the effluent wave crests generated by the symmetric expansion and contraction of NO3- disappeared, and the distortion of olefin CH2 and C-OH stretching of alcohols appeared. Metagenomics revealed Methylotenera and Methylobacter were the dominated methanotrophs. There was a completed methane and nitrogen metabolism pathway with the synergism of nxrAB, narGHI, nasAB, pmo-amoABC and mmo genes. Dissimilatory reduction pathway was the primary nitrate removal pathway. Moreover, Bradyrhizobium could participate in methane and nitrogen metabolism simultaneously.


Asunto(s)
Desnitrificación , Metano , Reactores Biológicos , Redes y Vías Metabólicas , Metagenómica , Nitrógeno , Oxidación-Reducción
3.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800748

RESUMEN

The plant hormone indole-3-acetic acid (IAA) is one of the main signals playing a role in the communication between host and endophytes. Endophytes can synthesize IAA de novo to influence the IAA homeostasis in plants. Although much is known about IAA biosynthesis in microorganisms, there is still less known about the pathway by which IAA is synthesized in fungal endophytes. The aim of this study is to examine a possible IAA biosynthesis pathway in Cyanodermella asteris. In vitro cultures of C. asteris were incubated with the IAA precursors tryptophan (Trp) and indole, as well as possible intermediates, and they were additionally treated with IAA biosynthesis inhibitors (2-mercaptobenzimidazole and yucasin DF) to elucidate possible IAA biosynthesis pathways. It was shown that (a) C. asteris synthesized IAA without adding precursors; (b) indole-3-acetonitrile (IAN), indole-3-acetamide (IAM), and indole-3-acetaldehyde (IAD) increased IAA biosynthesis; and (c) C. asteris synthesized IAA also by a Trp-independent pathway. Together with the genome information of C. asteris, the possible IAA biosynthesis pathways found can improve the understanding of IAA biosynthesis in fungal endophytes. The uptake of fungal IAA into Arabidopsis thaliana is necessary for the induction of lateral roots and other fungus-related growth phenotypes, since the application of the influx inhibitor 2-naphthoxyacetic acid (NOA) but not the efflux inhibitor N-1-naphtylphthalamic acid (NPA) were altering these parameters. In addition, the root phenotype of the mutation in an influx carrier, aux1, was partially rescued by C. asteris.


Asunto(s)
Arabidopsis/microbiología , Ascomicetos/metabolismo , Endófitos/metabolismo , Ácidos Indolacéticos/metabolismo , Indoles/farmacología , Raíces de Plantas/microbiología , Triptófano/farmacología , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Ascomicetos/efectos de los fármacos , Ascomicetos/genética , Bencimidazoles/farmacología , Medios de Cultivo Condicionados , Genoma Fúngico , Glicolatos/farmacología , Especificidad del Huésped , Ácidos Indolacéticos/farmacología , Indoles/metabolismo , Redes y Vías Metabólicas/genética , Ftalimidas/farmacología , Raíces de Plantas/efectos de los fármacos , Raíces de Plantas/genética , Triazoles/farmacología , Triptófano/metabolismo
4.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800857

RESUMEN

Fusarium wilt of flax is an aggressive disease caused by the soil-borne fungal pathogen Fusarium oxysporum f. sp. lini. It is a challenging pathogen presenting a constant threat to flax production industry worldwide. Previously, we reported chromosome-level assemblies of 5 highly pathogenic F. oxysporum f. sp. lini strains. We sought to characterize the genomic architecture of the fungus and outline evolutionary mechanisms shaping the pathogen genome. Here, we reveal the complex multi-compartmentalized genome organization and uncover its diverse evolutionary dynamics, which boosts genetic diversity and facilitates host adaptation. In addition, our results suggest that host of functions implicated in the life cycle of mobile genetic elements are main contributors to dissimilarity between proteomes of different Fusaria. Finally, our experiments demonstrate that mobile genetics elements are expressed in planta upon infection, alluding to their role in pathogenicity. On the whole, these results pave the way for further in-depth studies of evolutionary forces shaping the host-pathogen interaction.


Asunto(s)
Lino/microbiología , Fusarium/genética , Genoma Fúngico , Enfermedades de las Plantas/microbiología , Cromosomas Fúngicos/genética , Evolución Molecular , Proteínas Fúngicas/genética , Interacciones Huésped-Patógeno/genética , Redes y Vías Metabólicas/genética , Anotación de Secuencia Molecular , Filogenia , Proteoma , Especificidad de la Especie , Virulencia/genética
5.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800878

RESUMEN

Uveal melanoma (UM) is a malignant tumor that arises in the melanocytes of the uveal tract. It is the most frequent eye cancer, and despite new therapeutic approaches, prognosis is still poor, with up to 50% of patients developing metastasis with no efficient treatment options available. In contrast to cutaneous melanoma, UM is considered an "immune-cold" tumor due to the low mutational burden and the unique immunosuppressive microenvironment. To gain insight into the role of the UM microenvironment in regard to prognosis and metastatic progression, we have performed a pool analysis characterizing the UM microenvironment by using a bioinformatic approach. A variety of scores based on gene expression measuring stromal infiltration were calculated and used to assess association with prognosis. As a result, the highest immune and stromal scores were associated with poor prognosis. Specifically, stromal cells (fibroblasts and endothelial cells), T cells CD8+, natural killer (NK) cells, and macrophages M1 and M2 infiltration were associated with poor prognosis. Contrary to other tumors, lymphocytic infiltration is related to poor prognosis. Only B cells were associated with more favorable prognosis. UM samples scoring high in both angiogenesis (Angio) and antigen presentation (AP) pathways showed a poor prognosis suggesting an additive role of both functions. Almost all these tumors exhibited a chromosome 3 monosomy. Finally, an enrichment analysis showed that tumors classified as high Angio-high AP also activated metabolic pathways such as glycolysis or PI3K-AKT-MTOR. In summary, our pool analysis identified a cluster of samples with angiogenic and inflammatory phenotypes exhibiting poor prognosis and metabolic activation. Our analysis showed robust results replicated in a pool analysis merging different datasets from different analytic platforms.


Asunto(s)
Linfocitos Infiltrantes de Tumor/patología , Melanoma/patología , Neovascularización Patológica/fisiopatología , Neoplasias de la Úvea/patología , Anciano , Animales , Presentación de Antígeno , Análisis por Conglomerados , Conjuntos de Datos como Asunto , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , Estimación de Kaplan-Meier , Subgrupos Linfocitarios/patología , Macrófagos/patología , Masculino , Melanoma/irrigación sanguínea , Melanoma/genética , Melanoma/inmunología , Redes y Vías Metabólicas , Persona de Mediana Edad , Neovascularización Patológica/genética , Pronóstico , Transducción de Señal , Células del Estroma/patología , Microambiente Tumoral , Neoplasias de la Úvea/irrigación sanguínea , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/inmunología
6.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806862

RESUMEN

Considering the widespread occurrence of oxalate in nature and its broad impact on a host of organisms, it is surprising that so little is known about the turnover of this important acid. In plants, oxalate oxidase is the most well-studied enzyme capable of degrading oxalate, but not all plants possess this activity. Recently, acyl-activating enzyme 3 (AAE3), encoding an oxalyl-CoA synthetase, was identified in Arabidopsis. This enzyme has been proposed to catalyze the first step in an alternative pathway of oxalate degradation. Since this initial discovery, this enzyme and proposed pathway have been found to be important to other plants and yeast as well. In this study, we identify, in Arabidopsis, an oxalyl-CoA decarboxylase (AtOXC) that is capable of catalyzing the second step in this proposed pathway of oxalate catabolism. This enzyme breaks down oxalyl-CoA, the product of AtAAE3, into formyl-CoA and CO2. AtOXC:GFP localization suggested that this enzyme functions within the cytosol of the cell. An Atoxc knock-down mutant showed a reduction in the ability to degrade oxalate into CO2. This reduction in AtOXC activity resulted in an increase in the accumulation of oxalate and the enzyme substrate, oxalyl-CoA. Size exclusion studies suggest that the enzyme functions as a dimer. Computer modeling of the AtOXC enzyme structure identified amino acids of predicted importance in co-factor binding and catalysis. Overall, these results suggest that AtOXC catalyzes the second step in this alternative pathway of oxalate catabolism.


Asunto(s)
Arabidopsis/fisiología , Carboxiliasas/metabolismo , Oxalatos/metabolismo , Fenómenos Fisiológicos de las Plantas , Secuencia de Aminoácidos , Carboxiliasas/química , Carboxiliasas/genética , Cromatografía Líquida de Alta Presión , Clonación Molecular , Activación Enzimática , Regulación de la Expresión Génica de las Plantas , Redes y Vías Metabólicas , Modelos Moleculares , Oxidación-Reducción , Desarrollo de la Planta/genética , Conformación Proteica , Transporte de Proteínas
7.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33809928

RESUMEN

Based on their nutrient composition, soybeans and related foods have been considered to be nutritious and healthy for humans. Particularly, the biological activity and subsequent benefits of soy products may be associated with the presence of isoflavone in soybeans. As an alternative treatment for menopause-related symptoms, isoflavone has gained much popularity for postmenopausal women who have concerns related to undergoing hormone replacement therapy. However, current research has still not reached a consensus on the effects of isoflavone on humans. This overview is a summary of the current literature about the processing of soybeans and isoflavone types (daidzein, genistein, and S-equol) and supplements and their extraction and analysis as well as information about the utilization of isoflavones in soybeans. The processes of preparation (cleaning, drying, crushing and dehulling) and extraction of soybeans are implemented to produce refined soy oil, soy lecithin, free fatty acids, glycerol and soybean meal. The remaining components consist of inorganic constituents (minerals) and the minor components of biologically interesting small molecules. Regarding the preventive effects on diseases or cancers, a higher intake of isoflavones is associated with a moderately lower risk of developing coronary heart disease. It may also reduce the risks of breast and colorectal cancer as well as the incidence of breast cancer recurrence. Consumption of isoflavones or soy foods is associated with reduced risks of endometrial and bladder cancer. Regarding the therapeutic effects on menopausal syndrome or other diseases, isoflavones have been found to alleviate vasomotor syndromes even after considering placebo effects, reduce bone loss in the spine and ameliorate hypertension and in vitro glycemic control. They may also alleviate depressive symptoms during pregnancy. On the other hand, isoflavones have not shown definitive effects regarding improving cognition and urogenital symptoms. Because of lacking standardization in the study designs, such as the ingredients and doses of isoflavones and the durations and outcomes of trials, it currently remains difficult to draw overall conclusions for all aspects of isoflavones. These limitations warrant further investigations of isoflavone use for women's health.


Asunto(s)
Isoflavonas/administración & dosificación , Menopausia/efectos de los fármacos , Fitoestrógenos/administración & dosificación , Extractos Vegetales/administración & dosificación , Soja/química , Animales , Fraccionamiento Químico , Suplementos Dietéticos , Evaluación Preclínica de Medicamentos , Sofocos/tratamiento farmacológico , Humanos , Isoflavonas/química , Isoflavonas/aislamiento & purificación , Isoflavonas/metabolismo , Redes y Vías Metabólicas , Fitoestrógenos/química , Fitoestrógenos/aislamiento & purificación , Fitoestrógenos/metabolismo , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Soja/metabolismo , Análisis Espectral , Relación Estructura-Actividad , Síndrome
8.
BMC Bioinformatics ; 22(Suppl 2): 78, 2021 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-33902438

RESUMEN

BACKGROUND: Genome-wide reconstructions of metabolism opened the way to thorough investigations of cell metabolism for health care and industrial purposes. However, the predictions offered by Flux Balance Analysis (FBA) can be strongly affected by the choice of flux boundaries, with particular regard to the flux of reactions that sink nutrients into the system. To mitigate possible errors introduced by a poor selection of such boundaries, a rational approach suggests to focus the modeling efforts on the pivotal ones. METHODS: In this work, we present a methodology for the automatic identification of the key fluxes in genome-wide constraint-based models, by means of variance-based sensitivity analysis. The goal is to identify the parameters for which a small perturbation entails a large variation of the model outcomes, also referred to as sensitive parameters. Due to the high number of FBA simulations that are necessary to assess sensitivity coefficients on genome-wide models, our method exploits a master-slave methodology that distributes the computation on massively multi-core architectures. We performed the following steps: (1) we determined the putative parameterizations of the genome-wide metabolic constraint-based model, using Saltelli's method; (2) we applied FBA to each parameterized model, distributing the massive amount of calculations over multiple nodes by means of MPI; (3) we then recollected and exploited the results of all FBA runs to assess a global sensitivity analysis. RESULTS: We show a proof-of-concept of our approach on latest genome-wide reconstructions of human metabolism Recon2.2 and Recon3D. We report that most sensitive parameters are mainly associated with the intake of essential amino acids in Recon2.2, whereas in Recon 3D they are associated largely with phospholipids. We also illustrate that in most cases there is a significant contribution of higher order effects. CONCLUSION: Our results indicate that interaction effects between different model parameters exist, which should be taken into account especially at the stage of calibration of genome-wide models, supporting the importance of a global strategy of sensitivity analysis.


Asunto(s)
Redes y Vías Metabólicas , Modelos Biológicos , Genoma , Humanos , Análisis de Flujos Metabólicos
9.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809459

RESUMEN

Forensic toxicology and forensic medicine are unique among all other medical fields because of their essential legal impact, especially in civil and criminal cases. New high-throughput technologies, borrowed from chemistry and physics, have proven that metabolomics, the youngest of the "omics sciences", could be one of the most powerful tools for monitoring changes in forensic disciplines. Metabolomics is a particular method that allows for the measurement of metabolic changes in a multicellular system using two different approaches: targeted and untargeted. Targeted studies are focused on a known number of defined metabolites. Untargeted metabolomics aims to capture all metabolites present in a sample. Different statistical approaches (e.g., uni- or multivariate statistics, machine learning) can be applied to extract useful and important information in both cases. This review aims to describe the role of metabolomics in forensic toxicology and in forensic medicine.


Asunto(s)
Medicina Legal , Toxicología Forense , Metabolómica , Biomarcadores/metabolismo , Humanos , Redes y Vías Metabólicas , Metaboloma
10.
BMC Bioinformatics ; 22(1): 208, 2021 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-33882841

RESUMEN

BACKGROUND: The Metabolic Network Explorer is a new addition to the BioCyc.org website and the Pathway Tools software suite that supports the interactive exploration of metabolic networks. Any metabolic network visualization tool must by necessity show only a subset of all possible metabolite connections, or the results will be visually overwhelming. Existing tools, even those that purport to show an organism's full metabolic network, limit the set of displayed connections based on predefined pathways or other preselected criteria. We sought instead to provide a tool that would give the user dynamic control over which connections to follow. RESULTS: The Metabolic Network Explorer is an easy-to-use, web-based software tool that allows the user to specify a starting metabolite of interest and interactively explore its immediate metabolic neighborhood in either or both directions to any desired depth, letting the user select from the full set of connected reactions. Although, as for other tools, only a small portion of the metabolic network is visible at a time, that portion is selected by the user, based on the full reaction complement, and it is easy to switch among alternate paths of interest. The display is intuitive, customizable, and provides copious links to more detailed information pages. CONCLUSIONS: The Metabolic Network Explorer fills a gap in the set of metabolic network visualization tools and complements other modes of exploration. Its primary strengths are its ease of use, diagrams that are intuitive to biologists, and its integration with the broader corpus of data provided by a BioCyc Pathway/Genome Database.


Asunto(s)
Redes y Vías Metabólicas , Programas Informáticos , Internet
11.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809189

RESUMEN

Plant specialized metabolites (SMs) play an important role in the interaction with the environment and are part of the plant defense response. These natural products are volatile, semi-volatile and non-volatile compounds produced from common building blocks deriving from primary metabolic pathways and rapidly evolved to allow a better adaptation of plants to environmental cues. Specialized metabolites include terpenes, flavonoids, alkaloids, glucosinolates, tannins, resins, etc. that can be used as phytochemicals, food additives, flavoring agents and pharmaceutical compounds. This review will be focused on Mediterranean crop plants as a source of SMs, with a special attention on the strategies that can be used to modulate their production, including abiotic stresses, interaction with beneficial soil microorganisms and novel genetic approaches.


Asunto(s)
Productos Biológicos/metabolismo , Productos Agrícolas/metabolismo , Resistencia a la Enfermedad/genética , Metabolismo Secundario/genética , Productos Agrícolas/crecimiento & desarrollo , Flavonoides/metabolismo , Humanos , Región Mediterránea , Redes y Vías Metabólicas/genética , Fitoquímicos/metabolismo , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/microbiología , Estrés Fisiológico/efectos de los fármacos , Terpenos/metabolismo
12.
PLoS Comput Biol ; 17(4): e1008860, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33835998

RESUMEN

The COVID-19 pandemic is posing an unprecedented threat to the whole world. In this regard, it is absolutely imperative to understand the mechanism of metabolic reprogramming of host human cells by SARS-CoV-2. A better understanding of the metabolic alterations would aid in design of better therapeutics to deal with COVID-19 pandemic. We developed an integrated genome-scale metabolic model of normal human bronchial epithelial cells (NHBE) infected with SARS-CoV-2 using gene-expression and macromolecular make-up of the virus. The reconstructed model predicts growth rates of the virus in high agreement with the experimental measured values. Furthermore, we report a method for conducting genome-scale differential flux analysis (GS-DFA) in context-specific metabolic models. We apply the method to the context-specific model and identify severely affected metabolic modules predominantly comprising of lipid metabolism. We conduct an integrated analysis of the flux-altered reactions, host-virus protein-protein interaction network and phospho-proteomics data to understand the mechanism of flux alteration in host cells. We show that several enzymes driving the altered reactions inferred by our method to be directly interacting with viral proteins and also undergoing differential phosphorylation under diseased state. In case of SARS-CoV-2 infection, lipid metabolism particularly fatty acid oxidation, cholesterol biosynthesis and beta-oxidation cycle along with arachidonic acid metabolism are predicted to be most affected which confirms with clinical metabolomics studies. GS-DFA can be applied to existing repertoire of high-throughput proteomic or transcriptomic data in diseased condition to understand metabolic deregulation at the level of flux.


Asunto(s)
/metabolismo , Pulmón/metabolismo , Modelos Biológicos , Algoritmos , Biomasa , Bronquios/metabolismo , Bronquios/virología , /virología , Células Cultivadas , Biología Computacional , Células Epiteliales/metabolismo , Células Epiteliales/virología , Perfilación de la Expresión Génica , Humanos , Pulmón/patología , Pulmón/virología , Análisis de Flujos Metabólicos/estadística & datos numéricos , Redes y Vías Metabólicas/genética , Metabolómica , Pandemias , Fosforilación , Mapas de Interacción de Proteínas , /patogenicidad , Transcriptoma
13.
Nat Commun ; 12(1): 1980, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33790300

RESUMEN

The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these 'SLE-like' conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Perfilación de la Expresión Génica/métodos , Interferón Tipo I/inmunología , Lupus Eritematoso Sistémico/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Femenino , Humanos , Interferón Tipo I/metabolismo , Interferón Tipo I/farmacología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Redes y Vías Metabólicas/genética , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Adulto Joven
14.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806362

RESUMEN

Date palm (Phoenix dactylifera) is one of the most widespread fruit crop species and can tolerate drastic environmental conditions that may not be suitable for other fruit species. Excess UV-B stress is one of the greatest concerns for date palm trees and can cause genotoxic effects. Date palm responds to UV-B irradiation through increased DEG expression levels and elaborates upon regulatory metabolic mechanisms that assist the plants in adjusting to this exertion. Sixty-day-old Khalas date palm seedlings (first true-leaf stage) were treated with UV-B (wavelength, 253.7 nm; intensity, 75 µW cm-2 for 72 h (16 h of UV light and 8 h of darkness). Transcriptome analysis revealed 10,249 and 12,426 genes whose expressions were upregulated and downregulated, respectively, compared to the genes in the control. Furthermore, the differentially expressed genes included transcription factor-encoding genes and chloroplast- and photosystem-related genes. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect metabolite variations. Fifty metabolites, including amino acids and flavonoids, showed changes in levels after UV-B excess. Amino acid metabolism was changed by UV-B irradiation, and some amino acids interacted with precursors of different pathways that were used to synthesize secondary metabolites, i.e., flavonoids and phenylpropanoids. The metabolite content response to UV-B irradiation according to hierarchical clustering analysis showed changes in amino acids and flavonoids compared with those of the control. Amino acids might increase the function of scavengers of reactive oxygen species by synthesizing flavonoids that increase in response to UV-B treatment. This study enriches the annotated date palm unigene sequences and enhances the understanding of the mechanisms underlying UV-B stress through genetic manipulation. Moreover, this study provides a sequence resource for genetic, genomic and metabolic studies of date palm.


Asunto(s)
Phoeniceae/metabolismo , Phoeniceae/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Regulación de la Expresión Génica de las Plantas/efectos de la radiación , Genes del Cloroplasto/efectos de la radiación , Genes de Plantas/efectos de la radiación , Redes y Vías Metabólicas/genética , Redes y Vías Metabólicas/efectos de la radiación , Anotación de Secuencia Molecular , Fosforilación Oxidativa/efectos de la radiación , Phoeniceae/genética , Fotosíntesis/efectos de la radiación , Hojas de la Planta/genética , Hojas de la Planta/metabolismo , Hojas de la Planta/efectos de la radiación , Proteínas de Plantas/genética , RNA-Seq , Estrés Fisiológico/efectos de la radiación , Factores de Transcripción/genética , Transcriptoma/efectos de la radiación
15.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805647

RESUMEN

Plants continually monitor their innate developmental status and external environment and make adjustments to balance growth, differentiation and stress responses using a complex and highly interconnected regulatory network composed of various signaling molecules and regulatory proteins. Phytohormones are an essential group of signaling molecules that work through a variety of different pathways conferring plasticity to adapt to the everchanging developmental and environmental cues. Of these, jasmonic acid (JA), a lipid-derived molecule, plays an essential function in controlling many different plant developmental and stress responses. In the past decades, significant progress has been made in our understanding of the molecular mechanisms that underlie JA metabolism, perception, signal transduction and its crosstalk with other phytohormone signaling pathways. In this review, we discuss the JA signaling pathways starting from its biosynthesis to JA-responsive gene expression, highlighting recent advances made in defining the key transcription factors and transcriptional regulatory proteins involved. We also discuss the nature and degree of crosstalk between JA and other phytohormone signaling pathways, highlighting recent breakthroughs that broaden our knowledge of the molecular bases underlying JA-regulated processes during plant development and biotic stress responses.


Asunto(s)
Ciclopentanos/metabolismo , Regulación de la Expresión Génica de las Plantas , Oxilipinas/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Proteínas de Plantas/genética , Plantas/genética , Transducción de Señal/genética , Adaptación Fisiológica/genética , Núcleo Celular/metabolismo , Cloroplastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Giberelinas/metabolismo , Ácidos Indolacéticos/metabolismo , Redes y Vías Metabólicas/genética , Peroxisomas/metabolismo , Células Vegetales/metabolismo , Proteínas de Plantas/metabolismo , Plantas/metabolismo , Estrés Fisiológico , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
16.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805833

RESUMEN

A large British study, with almost 3000 patients, identified diabetes as main risk factor for delayed and nonunion fracture healing, the treatment of which causes large costs for the health system. In the past years, much progress has been made to treat common complications in diabetics. However, there is still a lack of advanced strategies to treat diabetic bone diseases. To develop such therapeutic strategies, mechanisms leading to massive bone alterations in diabetics have to be well understood. We herein describe an in vitro model displaying bone metabolism frequently observed in diabetics. The model is based on osteoblastic SaOS-2 cells, which in direct coculture, stimulate THP-1 cells to form osteoclasts. While in conventional 2D cocultures formation of mineralized matrix is decreased under pre-/diabetic conditions, formation of mineralized matrix is increased in 3D cocultures. Furthermore, we demonstrate a matrix stability of the 3D carrier that is decreased under pre-/diabetic conditions, resembling the in vivo situation in type 2 diabetics. In summary, our results show that a 3D environment is required in this in vitro model to mimic alterations in bone metabolism characteristic for pre-/diabetes. The ability to measure both osteoblast and osteoclast function, and their effect on mineralization and stability of the 3D carrier offers the possibility to use this model also for other purposes, e.g., drug screenings.


Asunto(s)
Huesos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Redes y Vías Metabólicas/genética , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Resorción Ósea/genética , Resorción Ósea/metabolismo , Resorción Ósea/patología , Huesos/patología , Calcificación Fisiológica/genética , Anhidrasa Carbónica II/genética , Anhidrasa Carbónica II/metabolismo , Catepsina K/genética , Catepsina K/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Técnicas de Cocultivo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Regulación de la Expresión Génica , Humanos , Modelos Biológicos , Osteoblastos/patología , Osteoclastos/patología , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligando RANK/genética , Ligando RANK/metabolismo , Células THP-1 , Fosfatasa Ácida Tartratorresistente/genética , Fosfatasa Ácida Tartratorresistente/metabolismo , Andamios del Tejido
17.
Adv Exp Med Biol ; 1280: 243-260, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33791987

RESUMEN

Oxygen is directly involved in many key pathophysiological processes. Oxygen deficiency, also known as hypoxia, could have adverse effects on mammalian cells, with ischemia in vital tissues being the most significant (Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol 164(6): 1875-1882, 2004); therefore, timely adaptive responses to variations in oxygen availability are essential for cellular homeostasis and survival. The most critical molecular event in hypoxic response is the activation and stabilization of a transcriptional factor termed hypoxia-induced factor-1 (HIF-1) that is responsible for the upregulation of many downstream effector genes, collectively known as hypoxia-responsive genes. Multiple key biological pathways such as proliferation, energy metabolism, invasion, and metastasis are governed by these genes; thus, HIF-1-mediated pathways are equally pivotal in both physiology and pathology.As we gain knowledge on the molecular mechanisms underlying the regulation of HIF-1, a great focus has been placed on elucidating the cellular function of HIF-1, particularly the role of HIF-1 in cancer pathogenesis pathways such as proliferation, invasion, angiogenesis, and metastasis. In cancer, HIF-1 is directly involved in the shift of cancer tissues from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the Warburg effect. Although targeting HIF-1 as a cancer therapy seems like an extremely rational approach, owing to the complex network of its downstream effector genes, the development of specific HIF-1 inhibitors with fewer side effects and more specificity has not been achieved. Therefore, in this review, we provide a brief background about the function of HIF proteins in hypoxia response with a special emphasis on the unique role played by HIF-1α in cancer growth and invasiveness, in the hypoxia response context.


Asunto(s)
Neoplasias , Animales , Hipoxia de la Célula , Humanos , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Redes y Vías Metabólicas , Neoplasias/genética , Neovascularización Patológica/genética
18.
Adv Exp Med Biol ; 1280: 131-147, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33791979

RESUMEN

Cancer cells exhibit different metabolic patterns compared to their normal counterparts. Although the reprogrammed metabolism has been indicated as strong biomarkers of cancer initiation and progression, increasing evidences suggest that metabolic alteration tuned by oncogenic drivers contributes to the occurrence and development of cancers rather than just being a hallmark of cancer. With this notion, targeting cancer metabolism holds promise as a novel anticancer strategy and is embracing its renaissance during the past two decades. Herein we have summarized the most recent developments in omics technology, including both metabolomics and proteomics, and how the combined use of these analytical tools significantly impacts this field by comprehensively and systematically recording the metabolic changes in cancer and hence reveals potential therapeutic targets that function by modulating the disrupted metabolic pathways.


Asunto(s)
Metabolómica , Neoplasias , Biomarcadores , Humanos , Redes y Vías Metabólicas , Neoplasias/tratamiento farmacológico , Proteómica
19.
Adv Exp Med Biol ; 1280: 291-301, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33791990

RESUMEN

Gastric cancer is the fourth most common malignancy worldwide and the third leading cause of cancer deaths. Recent metabolomics research has advanced our understanding of the relationship between metabolic reprogramming and gastric cancer progression and led to the discovery of metabolic targets for potential clinical applications and therapeutic interventions. As a powerful tool for metabolite and flux measurement, metabolomics not only allows a comprehensive analysis of metabolites and related metabolic pathways but also can investigate the interactions between gastric cancer cells and tumour microenvironment as well as between the cancer cells and gastric microbiome. In this chapter, we aim to summarize the recent advances in gastric cancer metabolism and discuss the applications of metabolomics for target discovery in gastric cancer.


Asunto(s)
Neoplasias Gástricas , Humanos , Redes y Vías Metabólicas , Metabolómica , Microambiente Tumoral
20.
J Plant Res ; 134(3): 625-639, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33829347

RESUMEN

Valeriana officinalis is a medicinal plant, a source of bioactive chemical compounds and secondary metabolites which are applied in pharmaceutical industries. The advent of ethnomedicine has provided alternatives for disease treatment and has increased demands for natural products and bioactive compounds. A set of preliminary steps to answers for such demands can include integrative omics for systems metabolic engineering, as an approach that contributes to the understanding of cellular metabolic status. There is a growing trend of this approach for genetically engineering metabolic pathways in plant systems, by which natural and synthetic compounds can be produced. As in the case of most medicinal plants, there are no sufficient information about molecular mechanisms involved in the regulation of metabolic pathways in V. officinalis. In this research, systems biology was performed on the RNA-seq transcriptome and metabolome data to find key genes that contribute to the synthesis of major secondary metabolites in V. officinalis. The R Package Weighted Gene Co-Expression Network Analysis (WGCNA) was employed to analyze the data. Based on the results, some major modules and hub genes were identified to be associated with the valuable secondary metabolites. In addition, some TF-encoding genes, including AP2/ERF-ERF, WRKY and NAC TF families, as well as some regulatory factors including protein kinases and transporters were identified. The results showed that several novel hub genes, such as PCMP-H24, RPS24B, ANX1 and PXL1, may play crucial roles in metabolic pathways. The current findings provide an overall insight into the metabolic pathways of V. officinalis and can expand the potential for engineering genome-scale pathways and systems metabolic engineering to increase the production of bioactive compounds by plants.


Asunto(s)
Valeriana , Regulación de la Expresión Génica de las Plantas , Redes y Vías Metabólicas , Transcriptoma , Valeriana/genética
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