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1.
Cell ; 181(2): 325-345.e28, 2020 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-32302571

RESUMEN

The mechanisms underlying ribonucleoprotein (RNP) granule assembly, including the basis for establishing and maintaining RNP granules with distinct composition, are unknown. One prominent type of RNP granule is the stress granule (SG), a dynamic and reversible cytoplasmic assembly formed in eukaryotic cells in response to stress. Here, we show that SGs assemble through liquid-liquid phase separation (LLPS) arising from interactions distributed unevenly across a core protein-RNA interaction network. The central node of this network is G3BP1, which functions as a molecular switch that triggers RNA-dependent LLPS in response to a rise in intracellular free RNA concentrations. Moreover, we show that interplay between three distinct intrinsically disordered regions (IDRs) in G3BP1 regulates its intrinsic propensity for LLPS, and this is fine-tuned by phosphorylation within the IDRs. Further regulation of SG assembly arises through positive or negative cooperativity by extrinsic G3BP1-binding factors that strengthen or weaken, respectively, the core SG network.


Asunto(s)
Gránulos Citoplasmáticos/metabolismo , ADN Helicasas/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , ARN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Ribonucleoproteínas/metabolismo , Línea Celular Tumoral , Citoplasma/metabolismo , Estructuras Citoplasmáticas/metabolismo , Células HEK293 , Humanos , Fosforilación , ARN/metabolismo
2.
Cell ; 167(3): 774-788.e17, 2016 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-27768896

RESUMEN

Expansion of a hexanucleotide repeat GGGGCC (G4C2) in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Transcripts carrying (G4C2) expansions undergo unconventional, non-ATG-dependent translation, generating toxic dipeptide repeat (DPR) proteins thought to contribute to disease. Here, we identify the interactome of all DPRs and find that arginine-containing DPRs, polyGly-Arg (GR) and polyPro-Arg (PR), interact with RNA-binding proteins and proteins with low complexity sequence domains (LCDs) that often mediate the assembly of membrane-less organelles. Indeed, most GR/PR interactors are components of membrane-less organelles such as nucleoli, the nuclear pore complex and stress granules. Genetic analysis in Drosophila demonstrated the functional relevance of these interactions to DPR toxicity. Furthermore, we show that GR and PR altered phase separation of LCD-containing proteins, insinuating into their liquid assemblies and changing their material properties, resulting in perturbed dynamics and/or functions of multiple membrane-less organelles.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Dipéptidos/metabolismo , Demencia Frontotemporal/metabolismo , Proteínas/metabolismo , Proteínas de Unión al ARN/metabolismo , Esclerosis Amiotrófica Lateral/genética , Animales , Proteína C9orf72 , Nucléolo Celular/metabolismo , Gránulos Citoplasmáticos/metabolismo , Expansión de las Repeticiones de ADN , Dipéptidos/genética , Drosophila melanogaster/genética , Demencia Frontotemporal/genética , Humanos , Membranas Intracelulares/metabolismo , Poro Nuclear/metabolismo , Péptidos/genética , Péptidos/metabolismo , Proteínas/genética
3.
Mol Cell ; 74(4): 713-728.e6, 2019 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-30981631

RESUMEN

Repeat expansion in the C9orf72 gene is the most common cause of the neurodegenerative disorder amyotrophic lateral sclerosis (C9-ALS) and is linked to the unconventional translation of five dipeptide-repeat polypeptides (DPRs). The two enriched in arginine, poly(GR) and poly(PR), infiltrate liquid-like nucleoli, co-localize with the nucleolar protein nucleophosmin (NPM1), and alter the phase separation behavior of NPM1 in vitro. Here, we show that poly(PR) DPRs bind tightly to a long acidic tract within the intrinsically disordered region of NPM1, altering its phase separation with nucleolar partners to the extreme of forming large, soluble complexes that cause droplet dissolution in vitro. In cells, poly(PR) DPRs disperse NPM1 from nucleoli and entrap rRNA in static condensates in a DPR-length-dependent manner. We propose that R-rich DPR toxicity involves disrupting the role of phase separation by NPM1 in organizing ribosomal proteins and RNAs within the nucleolus.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Proteínas Nucleares/genética , Secuencias Repetitivas de Aminoácido/genética , Esclerosis Amiotrófica Lateral/patología , Arginina/genética , Nucléolo Celular/química , Nucléolo Celular/genética , Dipéptidos/genética , Humanos , Nucleofosmina , Péptidos/genética , Poli A/genética , ARN Ribosómico/genética
4.
Proc Natl Acad Sci U S A ; 121(26): e2320572121, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38885380

RESUMEN

Although most known viruses infecting fungi pathogenic to higher eukaryotes are asymptomatic or reduce the virulence of their host fungi, those that confer hypervirulence to entomopathogenic fungus still need to be explored. Here, we identified and studied a novel mycovirus in Metarhizium flavoviride, isolated from small brown planthopper (Laodelphax striatellus). Based on molecular analysis, we tentatively designated the mycovirus as Metarhizium flavoviride partitivirus 1 (MfPV1), a species in genus Gammapartitivirus, family Partitiviridae. MfPV1 has two double-stranded RNAs as its genome, 1,775 and 1,575 bp in size respectively, encapsidated in isometric particles. When we transfected commercial strains of Metarhizium anisopliae and Metarhizium pingshaense with MfPV1, conidiation was significantly enhanced (t test; P-value < 0. 01), and the significantly higher mortality rates of the larvae of diamondback moth (Plutella xylostella) and fall armyworm (Spodoptera frugiperda), two important lepidopteran pests were found in virus-transfected strains (ANOVA; P-value < 0.05). Transcriptomic analysis showed that transcript levels of pathogenesis-related genes in MfPV1-infected M. anisopliae were obviously altered, suggesting increased production of metarhizium adhesin-like protein, hydrolyzed protein, and destruxin synthetase. Further studies are required to elucidate the mechanism whereby MfPV1 enhances the expression of pathogenesis-related genes and virulence of Metarhizium to lepidopteran pests. This study presents experimental evidence that the transfection of other entomopathogenic fungal species with a mycovirus can confer significant hypervirulence and provides a good example that mycoviruses could be used as a synergistic agent to enhance the biocontrol activity of entomopathogenic fungi.


Asunto(s)
Virus Fúngicos , Metarhizium , Metarhizium/patogenicidad , Metarhizium/genética , Animales , Virulencia/genética , Virus Fúngicos/genética , Control Biológico de Vectores/métodos , Mariposas Nocturnas/microbiología , Mariposas Nocturnas/virología , Genoma Viral , Filogenia
5.
PLoS Genet ; 20(1): e1011134, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38241355

RESUMEN

It has been well established that cancer cells can evade immune surveillance by mutating themselves. Understanding genetic alterations in cancer cells that contribute to immune regulation could lead to better immunotherapy patient stratification and identification of novel immune-oncology (IO) targets. In this report, we describe our effort of genome-wide association analyses across 22 TCGA cancer types to explore the associations between genetic alterations in cancer cells and 74 immune traits. Results showed that the tumor microenvironment (TME) is shaped by different gene mutations in different cancer types. Out of the key genes that drive multiple immune traits, top hit KEAP1 in lung adenocarcinoma (LUAD) was selected for validation. It was found that KEAP1 mutations can explain more than 10% of the variance for multiple immune traits in LUAD. Using public scRNA-seq data, further analysis confirmed that KEAP1 mutations activate the NRF2 pathway and promote a suppressive TME. The activation of the NRF2 pathway is negatively correlated with lower T cell infiltration and higher T cell exhaustion. Meanwhile, several immune check point genes, such as CD274 (PD-L1), are highly expressed in NRF2-activated cancer cells. By integrating multiple RNA-seq data, a NRF2 gene signature was curated, which predicts anti-PD1 therapy response better than CD274 gene alone in a mixed cohort of different subtypes of non-small cell lung cancer (NSCLC) including LUAD, highlighting the important role of KEAP1-NRF2 axis in shaping the TME in NSCLC. Finally, a list of overexpressed ligands in NRF2 pathway activated cancer cells were identified and could potentially be targeted for TME remodeling in LUAD.


Asunto(s)
Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Estudio de Asociación del Genoma Completo , Factor 2 Relacionado con NF-E2/genética , Neoplasias Pulmonares/genética , Adenocarcinoma del Pulmón/genética , Microambiente Tumoral/genética , Pronóstico
6.
Am J Hum Genet ; 110(5): 762-773, 2023 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-37019109

RESUMEN

The ongoing release of large-scale sequencing data in the UK Biobank allows for the identification of associations between rare variants and complex traits. SAIGE-GENE+ is a valid approach to conducting set-based association tests for quantitative and binary traits. However, for ordinal categorical phenotypes, applying SAIGE-GENE+ with treating the trait as quantitative or binarizing the trait can cause inflated type I error rates or power loss. In this study, we propose a scalable and accurate method for rare-variant association tests, POLMM-GENE, in which we used a proportional odds logistic mixed model to characterize ordinal categorical phenotypes while adjusting for sample relatedness. POLMM-GENE fully utilizes the categorical nature of phenotypes and thus can well control type I error rates while remaining powerful. In the analyses of UK Biobank 450k whole-exome-sequencing data for five ordinal categorical traits, POLMM-GENE identified 54 gene-phenotype associations.


Asunto(s)
Exoma , Estudio de Asociación del Genoma Completo , Estudio de Asociación del Genoma Completo/métodos , Exoma/genética , Bancos de Muestras Biológicas , Fenotipo , Análisis de Datos , Reino Unido
7.
EMBO J ; 40(6): e105123, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33555074

RESUMEN

Similar to the brain, the eye is considered an immune-privileged organ where tissue-resident macrophages provide the major immune cell constituents. However, little is known about spatially restricted macrophage subsets within different eye compartments with regard to their origin, function, and fate during health and disease. Here, we combined single-cell analysis, fate mapping, parabiosis, and computational modeling to comprehensively examine myeloid subsets in distinct parts of the eye during homeostasis. This approach allowed us to identify myeloid subsets displaying diverse transcriptional states. During choroidal neovascularization, a typical hallmark of neovascular age-related macular degeneration (AMD), we recognized disease-specific macrophage subpopulations with distinct molecular signatures. Our results highlight the heterogeneity of myeloid subsets and their dynamics in the eye that provide new insights into the innate immune system in this organ which may offer new therapeutic targets for ophthalmological diseases.


Asunto(s)
Coroides/irrigación sanguínea , Ojo/inmunología , Macrófagos/inmunología , Células Mieloides/inmunología , Neovascularización Fisiológica/fisiología , Animales , Coroides/embriología , Biología Computacional , Simulación por Computador , Ojo/citología , Ojo/metabolismo , Femenino , Homeostasis/inmunología , Humanos , Inmunidad Innata/inmunología , Degeneración Macular/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/fisiología , Células Mieloides/metabolismo , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Transcripción Genética/genética
8.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35193978

RESUMEN

The architectural protein histone-like protein from Escherichia coli strain U93 (HU) is the most abundant bacterial DNA binding protein and highly conserved among bacteria and Apicomplexan parasites. It not only binds to double-stranded DNA (dsDNA) to maintain DNA stability but also, interacts with RNAs to regulate transcription and translation. Importantly, HU is essential to cell viability for many bacteria; hence, it is an important antibiotic target. Here, we report that Gp46 from bacteriophage SPO1 of Bacillus subtilis is an HU inhibitor whose expression prevents nucleoid segregation and causes filamentous morphology and growth defects in bacteria. We determined the solution structure of Gp46 and revealed a striking negatively charged surface. An NMR-derived structural model for the Gp46-HU complex shows that Gp46 occupies the DNA binding motif of the HU and therefore, occludes DNA binding, revealing a distinct strategy for HU inhibition. We identified the key residues responsible for the interaction that are conserved among HUs of bacteria and Apicomplexans, including clinically significant Mycobacterium tuberculosis, Acinetobacter baumannii, and Plasmodium falciparum, and confirm that Gp46 can also interact with these HUs. Our findings provide detailed insight into a mode of HU inhibition that provides a useful foundation for the development of antibacteria and antimalaria drugs.


Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Bacteriófagos/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Glicoproteínas/metabolismo , Proteínas Virales/metabolismo , Proteínas Bacterianas/metabolismo , ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Unión Proteica
9.
Am J Physiol Cell Physiol ; 326(1): C161-C176, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-38009195

RESUMEN

The relationship between gut microbiota and doxorubicin-induced cardiotoxicity (DIC) is becoming increasingly clear. Emodin (EMO), a naturally occurring anthraquinone, exerts cardioprotective effects and plays a protective role by regulating gut microbiota composition. Therefore, the protective effect of EMO against DIC injury and its underlying mechanisms are worth investigating. In this study, we analyzed the differences in the gut microbiota in recipient mice transplanted with different flora using 16S-rDNA sequencing, analyzed the differences in serum metabolites among groups of mice using a nontargeted gas chromatography-mass spectrometry coupling system, and assessed cardiac function based on cardiac morphological staining, cardiac injury markers, and ferroptosis indicator assays. We found EMO ameliorated DIC and ferroptosis, as evidenced by decreased myocardial fibrosis, cardiomyocyte hypertrophy, and myocardial disorganization; improved ferroptosis indicators; and the maintenance of normal mitochondrial morphology. The protective effect of EMO was eliminated by the scavenging effect of antibiotics on the gut microbiota. Through fecal microbiota transplantation (FMT), we found that EMO restored the gut microbiota disrupted by doxorubicin (DOX) to near-normal levels. This was evidenced by an increased proportion of Bacteroidota and a decreased proportion of Verrucomicrobiota. FMT resulted in changes in the composition of serum metabolites. Mice transplanted with EMO-improved gut microbiota showed better cardiac function and ferroptosis indices; however, these beneficial effects were not observed in Nrf2 (Nfe2l2)-/- mice. Overall, EMO exerted a protective effect against DIC by attenuating ferroptosis, and the above effects occurred by remodeling the composition of gut microbiota perturbed by DOX and required Nrf2 mediation.NEW & NOTEWORTHY This study demonstrated for the first time the protective effect of emodin against DIC and verified by FMT that its cardioprotective effect was achieved by remodeling gut microbiota composition, resulting in attenuation of ferroptosis. Furthermore, we demonstrated that these effects were mediated by the redox-related gene Nrf2.


Asunto(s)
Emodina , Ferroptosis , Microbioma Gastrointestinal , Animales , Ratones , Emodina/farmacología , Cardiotoxicidad , Factor 2 Relacionado con NF-E2/genética , Doxorrubicina/toxicidad , Miocitos Cardíacos
10.
Am J Physiol Cell Physiol ; 326(2): C331-C347, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38047307

RESUMEN

Diabetic cardiomyopathy (dCM) is a major complication of diabetes; however, specific treatments for dCM are currently lacking. RTA 408, a semisynthetic triterpenoid, has shown therapeutic potential against various diseases by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. We established in vitro and in vivo models using high glucose toxicity and db/db mice, respectively, to simulate dCM. Our results demonstrated that RTA 408 activated Nrf2 and alleviated various dCM-related cardiac dysfunctions, both in vivo and in vitro. Additionally, it was found that silencing the Nrf2 gene eliminated the cardioprotective effect of RTA 408. RTA 408 ameliorated oxidative stress in dCM mice and high glucose-exposed H9C2 cells by activating Nrf2, inhibiting mitochondrial fission, exerting anti-inflammatory effects through the Nrf2/NF-κB axis, and ultimately suppressing apoptosis, thereby providing cardiac protection against dCM. These findings provide valuable insights for potential dCM treatments.NEW & NOTEWORTHY We demonstrated first that the nuclear factor erythroid 2-related factor 2 (Nrf2) activator RTA 408 has a protective effect against diabetic cardiomyopathy. We found that RTA 408 could stimulate the nuclear entry of Nrf2 protein, regulate the mitochondrial fission-fusion balance, and redistribute p65, which significantly alleviated the oxidative stress level in cardiomyocytes, thereby reducing apoptosis and inflammation, and protecting the systolic and diastolic functions of the heart.


Asunto(s)
Diabetes Mellitus , Cardiomiopatías Diabéticas , Triterpenos , Ratones , Animales , FN-kappa B/genética , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Dinámicas Mitocondriales , Estrés Oxidativo , Inflamación/metabolismo , Triterpenos/metabolismo , Triterpenos/farmacología , Triterpenos/uso terapéutico , Miocitos Cardíacos/metabolismo , Glucosa/metabolismo , Diabetes Mellitus/metabolismo
11.
Am J Physiol Cell Physiol ; 326(3): C724-C741, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38223927

RESUMEN

Diabetic cardiomyopathy (DCM) is closely related to ferroptosis, a new type of cell death that mainly manifests as intracellular iron accumulation and lipid peroxidation. Paeoniflorin (PA) helps to improve impaired glucose tolerance, influences the distribution of the intestinal flora, and induces significant resistance to ferroptosis in several models. In this study, we found that PA improved cardiac dysfunction in mice with DCM by alleviating myocardial damage, resisting oxidative stress and ferroptosis, and changing the community composition and structure of the intestinal microbiota. Metabolomics analysis revealed that PA-treated fecal microbiota transplantation affected metabolites in DCM mice. Based on in vivo and in vitro experiments, 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor that mediates the cardioprotective and antiferroptotic effects of PA-treated fecal microbiota transplantation (FMT) in DCM mice.NEW & NOTEWORTHY This study demonstrated for the first time that paeoniflorin (PA) exerts protective effects in diabetic cardiomyopathy mice by alleviating myocardial damage, resisting ferroptosis, and changing the community composition and structure of the intestinal microbiota, and 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor in its therapeutic efficacy.


Asunto(s)
Diabetes Mellitus , Cardiomiopatías Diabéticas , Ferroptosis , Microbioma Gastrointestinal , Glucósidos , Monoterpenos , Animales , Ratones , Cardiomiopatías Diabéticas/tratamiento farmacológico , Miocardio
12.
BMC Genomics ; 25(1): 32, 2024 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-38177998

RESUMEN

BACKGROUND: γ-glutamylcyclotransferase (GGCT), an enzyme to maintain glutathione homeostasis, plays a vital role in the response to plant growth and development as well as the adaptation to various stresses. Although the GGCT gene family analysis has been conducted in Arabidopsis and rice, the family genes have not yet been well identified and analyzed at the genome-wide level in wheat (Triticum aestivum L.). RESULTS: In the present study, 20 TaGGCT genes were identified in the wheat genome and widely distributed on chromosomes 2A, 2B, 2D, 3A, 4A, 5A, 5B, 5D, 6A, 6B, 6D, 7A, 7B, and 7D. Phylogenetic and structural analyses showed that these TaGGCT genes could be classified into three subfamilies: ChaC, GGGACT, and GGCT-PS. They exhibited similar motif compositions and distribution patterns in the same subgroup. Gene duplication analysis suggested that the expansion of TaGGCT family genes was facilitated by segmental duplications and tandem repeats in the wheat evolutionary events. Identification of diverse cis-acting response elements in TaGGCT promoters indicated their potential fundamental roles in response to plant development and abiotic stresses. The analysis of transcriptome data combined with RT-qPCR results revealed that the TaGGCTs genes exhibited ubiquitous expression across plant organs, with highly expressed in roots, stems, and developing grains. Most TaGGCT genes were up-regulated after 6 h under 20% PEG6000 and ABA treatments. Association analysis revealed that two haplotypes of TaGGCT20 gene displayed significantly different Thousand-kernel weight (TKW), Kernel length (KL), and Kernel width (KW) in wheat. The geographical and annual distribution of the two haplotypes of TaGGCT20 gene further revealed that the frequency of the favorable haplotype TaGGCT20-Hap-I was positively selected in the historical breeding process of wheat. CONCLUSION: This study investigated the genome-wide identification, structure, evolution, and expression analysis of TaGGCT genes in wheat. The motifs of TaGGCTs were highly conserved throughout the evolutionary history of wheat. Most TaGGCT genes were highly expressed in roots, stems, and developing grains, and involved in the response to drought stresses. Two haplotypes were developed in the TaGGCT20 gene, where TaGGCT20-Hap-I, as a favorable haplotype, was significantly associated with higher TKW, KL, and KW in wheat, suggesting that the haplotype is used as a function marker for the selection in grain yield in wheat breeding.


Asunto(s)
Triticum , gamma-Glutamilciclotransferasa , gamma-Glutamilciclotransferasa/genética , Filogenia , Fitomejoramiento , Regiones Promotoras Genéticas , Regulación de la Expresión Génica de las Plantas , Genoma de Planta , Proteínas de Plantas/genética
13.
BMC Genomics ; 25(1): 791, 2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39160492

RESUMEN

Acinetobacter baumannii is a gram-negative bacillus prevalent in nature, capable of thriving under various environmental conditions. As an opportunistic pathogen, it frequently causes nosocomial infections such as urinary tract infections, bacteremia, and pneumonia, contributing to increased morbidity and mortality in clinical settings. Consequently, developing novel vaccines against Acinetobacter baumannii is of utmost importance. In our study, we identified 10 highly conserved antigenic proteins from the NCBI and UniProt databases for epitope mapping. We subsequently screened and selected 8 CTL, HTL, and LBL epitopes, integrating them into three distinct vaccines constructed with adjuvants. Following comprehensive evaluations of immunological and physicochemical parameters, we conducted molecular docking and molecular dynamics simulations to assess the efficacy and stability of these vaccines. Our findings indicate that all three multi-epitope mRNA vaccines designed against Acinetobacter baumannii are promising; however, further animal studies are required to confirm their reliability and effectiveness.


Asunto(s)
Acinetobacter baumannii , Vacunas Bacterianas , Biología Computacional , Acinetobacter baumannii/inmunología , Acinetobacter baumannii/genética , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/genética , Biología Computacional/métodos , Epítopos/inmunología , Epítopos/química , Simulación del Acoplamiento Molecular , Infecciones por Acinetobacter/prevención & control , Infecciones por Acinetobacter/inmunología , Mapeo Epitopo , Vacunas de ARNm , Simulación de Dinámica Molecular , Humanos , ARN Mensajero/genética , ARN Mensajero/inmunología , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/genética , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/genética , Proteínas Bacterianas/química
14.
Biochem Biophys Res Commun ; 739: 150568, 2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39178797

RESUMEN

Doxorubicin (DOX), as a first-line anticancer drug, is widely used in the treatment of various cancers. However, its clinical application is restricted due to its severe cardiac toxicity. Previous studies have indicated exercise training can alleviate the DOX-induced cardiotoxicity (DIC), but the underlying mechanism remains unclear. Our research has discovered, post-exercise, an elevated expression level of mir-17-3p, but in DIC its level decreases. Therefore, we further studied the effect of exercise mir-17-3p axis on DIC. In vivo, we simulated DIC mouse model, followed by an intervention using swimming and adenovirus to inhibit mir-17-3p. We found that inhibition of mir-17-3p can weaken the protection of exercise against DIC, presenting as weakened heart function. Besides, the levels of Malondialdehyde and Fe2+ in the cardiac tissue increased, along with diminished glutathione peroxidase 4 and Solute Carrier Family 7 Member 11 levels, and a decline in the concentration of glutathione, causing an increase in ferroptosis. Moreover, in vitro, we used dual-luciferase assay to confirm that Kelch Like ECH Associated Protein 1 (KEAP1) can be a target gene of mir-17-3p. We used Keap1/NFE2 Like BZIP Transcription Factor 2 (NRF2) inhibitor brusatol and Stimulator of Interferon Response CGAMP Interactor 1 (STING) agonist SR-717 to verify the mir-17-3p/KEAP1 axis can affect the Cyclic GMP-AMP Synthase (CGAS)/STING pathway, leading to further ferroptosis in DIC. This manifested as a reduction in ferroptosis. In summary, our research suggests swimming training enhances the levels of mir-17-3p, thereby activating the KEAP1/NRF2 pathway, and weakening the CGAS/STING pathway, improving ferroptosis in DIC.

15.
BMC Plant Biol ; 24(1): 341, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38671351

RESUMEN

BACKGROUND: Ubiquitination is an important regulatory step of selective protein degradation in the plant UPS (ubiquitin-proteasome system), which is involved in various biological processes in eukaryotes. Ubiquitin-conjugating enzymes play an intermediate role in the process of protein ubiquitination reactions and thus play an essential role in regulating plant growth and response to adverse environmental conditions. However, a genome-wide analysis of the UBC gene family in wheat (Triticum aestivum L.) has not yet been performed. RESULTS: In this study, the number, physiochemical properties, gene structure, collinearity, and phylogenetic relationships of TaUBC family members in wheat were analyzed using bioinformatics methods. The expression pattern of TaUBC genes in different tissues/organs and developmental periods, as well as the transcript levels under abiotic stress treatment, were analyzed using RNA-Seq data and qRT-PCR. Meanwhile, favorable haplotypes of TaUBC25 were investigated based on wheat resequencing data of 681 wheat cultivars from the Wheat Union Database. The analyses identified a total of 93 TaUBC family members containing a UBC domain in wheat genome. These genes were unevenly distributed across 21 chromosomes, and numerous duplication events were observed between gene members. Based on phylogenetic analysis, the TaUBC family was divided into 13 E2 groups and a separate UEV group. We investigated the expression of TaUBC family genes under different tissue/organ and stress conditions by quantitative real-time PCR (qRT-PCR) analysis. The results showed that some TaUBC genes were specifically expressed in certain tissues/organs and that most TaUBC genes responded to NaCl, PEG6000, and ABA treatment with different levels of expression. In addition, we performed association analysis for the two haplotypes based on key agronomic traits such as thousand-kernel weight (TKW), kernel length (KL), kernel weight (KW), and kernel thickness (KT), examining 122 wheat accessions at three environmental sites. The results showed that TaUBC25-Hap II had significantly higher TKW, KL, KW, and KT than TaUBC25-Hap I. The distribution analysis of haplotypes showed that TaUBC25-Hap II was preferred in the natural population of wheat. CONCLUSION: Our results identified 93 members of the TaUBC family in wheat, and several genes involved in grain development and abiotic stress response. Based on the SNPs detected in the TaUBC sequence, two haplotypes, TaUBC25-Hap I and TaUBC25-Hap II, were identified among wheat cultivars, and their potential value for wheat breeding was validated by association analysis. The above results provide a theoretical basis for elucidating the evolutionary relationships of the TaUBC gene family and lay the foundation for studying the functions of family members in the future.


Asunto(s)
Familia de Multigenes , Filogenia , Triticum , Enzimas Ubiquitina-Conjugadoras , Triticum/genética , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Regulación de la Expresión Génica de las Plantas , Genoma de Planta , Estrés Fisiológico/genética , Genes de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estudio de Asociación del Genoma Completo , Perfilación de la Expresión Génica
16.
BMC Plant Biol ; 24(1): 718, 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39069623

RESUMEN

BACKGROUND: Powdery mildew (caused by Blumeria graminis f. sp. tritici (Bgt)) and leaf rust (caused by Puccinia triticina (Pt)) are prevalent diseases in wheat (Triticum aestivum L.) production. Thinopyrum ponticum (2n = 10x = 70, EeEeEbEbExExStStStSt) contains genes that confer high levels of resistance to these diseases. RESULTS: An elite wheat-Th. ponticum disomic substitution line, DS5Ag(5D), was developed in the Bainong Aikang 58 (AK58) background. The line was assessed using genomic in situ hybridization (GISH), oligo-nucleotide probe multiplex (ONPM) fluorescence in situ hybridization (FISH), and molecular markers. Twenty eight chromosome-specific molecular markers were identified for the alien chromosome, and 22 of them were co-dominant. Additionally, SNP markers from the wheat 660 K SNP chip were utilized to confirm chromosome identification and they provide molecular tools for tagging the chromosome in concern. The substitution line demonstrated high levels of resistance to powdery mildew throughout its growth period and to leaf rust at the adult stage. Based on the resistance evaluation of five F5 populations between the substitution lines and wheat genotypes with different levels of sensitivity to the two diseases. Results showed that the resistance genes located on 5Ag confered stable resistance against both diseases across different backgrounds. Resistance spectrum analysis combined with diagnostic marker detection of known resistance genes of Th. ponticum revealed that 5Ag contained two novel genes, Pm5Ag and Lr5Ag, which conferred resistance to powdery mildew and leaf rust, respectively. CONCLUSIONS: In this study, a novel wheat-Th. ponticum disomic substitution line DS5Ag(5D) was successfully developed. The Th. ponticum chromosome 5Ag contain new resistance genes for powdery mildew and leaf rust. Chromosomic-specific molecular markers were generated and they can be used to track the 5Ag chromosome fragments. Consequently, this study provides new elite germplasm resources and molecular markers to facilitate the breeding of wheat varieties that is resistant to powdery mildew and leaf rust.


Asunto(s)
Ascomicetos , Basidiomycota , Resistencia a la Enfermedad , Enfermedades de las Plantas , Puccinia , Triticum , Triticum/genética , Triticum/microbiología , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Resistencia a la Enfermedad/genética , Ascomicetos/fisiología , Basidiomycota/fisiología , Puccinia/fisiología , Genes de Plantas , Cromosomas de las Plantas/genética , Poaceae/genética , Poaceae/microbiología , Polimorfismo de Nucleótido Simple , Marcadores Genéticos , Fitomejoramiento
17.
New Phytol ; 243(2): 580-590, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38488228

RESUMEN

Non-structural carbohydrates (NSCs), as the labile fraction and dominant carbon currency, are essential mediators of plant adaptation to environments. However, whether and how NSC coordinates with plant economic strategy frameworks, particularly the well-recognized leaf economics spectrums (LES) and root economics space (RES), remains unclear. We examined the relationships between NSC and key plant economics traits in leaves and fine roots across 90 alpine coniferous populations on the Tibetan Plateau, China. We observed contrasting coordination of NSC with economics traits in leaves and roots. Leaf total NSC and soluble sugar aligned with the leaf economic spectrum, conveying a trade-off between growth and storage in leaves. However, NSC in roots was independent of the root economic spectrum, but highly coordinated with root foraging, with more starch and less sugar in forage-efficient, thinner roots. Further, NSC-trait coordination in leaves and roots was, respectively, driven by local temperature and precipitation. These findings highlight distinct roles of NSC in shaping the above- and belowground multidimensional economics trait space, and NSC-based carbon economics provides a mechanistic understanding of how plants adapt to heterogeneous habitats and respond to environmental changes.


Asunto(s)
Bosques , Hojas de la Planta , Raíces de Plantas , Tracheophyta , Hojas de la Planta/fisiología , Hojas de la Planta/metabolismo , Raíces de Plantas/metabolismo , Tracheophyta/fisiología , Metabolismo de los Hidratos de Carbono , Carbohidratos , Carácter Cuantitativo Heredable , Temperatura
18.
J Exp Bot ; 75(16): 4712-4728, 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-38655916

RESUMEN

Endocytic recycling is an intracellular trafficking pathway that returns endocytosed molecules to the plasma membrane via the recycling endosome. This pathway plays a crucial role in remodelling plasma membrane composition and is thus essential for cellular homeostasis. In plants, endocytic recycling regulates the localization and abundance of receptors, transporters, and channels at the plasma membrane that are involved in many aspects of plant growth and development. Despite its importance, the recycling endosome and the underlying sorting mechanisms for cargo recycling in plants remain understudied in comparison to the endocytic recycling pathways in animals. In this review, we focus on the cumulative evidence suggesting the existence of endosomes decorated by regulators that contribute to recycling in plant cells. We summarize the chemical inhibitors used for analysing cargo recycling and discuss recent advances in our understanding of how endocytic recycling participates in various plant cellular and physiological events.


Asunto(s)
Endocitosis , Endosomas , Endocitosis/fisiología , Endosomas/metabolismo , Plantas/metabolismo , Membrana Celular/metabolismo
19.
Chemistry ; 30(40): e202401435, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-38739532

RESUMEN

Artificial organelles serve as functional counterparts to natural organelles, which are primarily employed to artificially replicate, restore, or enhance cellular functions. While most artificial organelles exhibit basic functions, we diverge from this norm by utilizing poly(ferrocenylmethylethylthiocarboxypropylsilane) microcapsules (PFC MCs) to construct multifunctional artificial organelles through water/oil interfacial self-assembly. Within these PFC MCs, enzymatic cascades are induced through active molecular exchange across the membrane to mimic the functions of enzymes in mitochondria. We harness the inherent redox properties of the PFC polymer, which forms the membrane, to facilitate in-situ redox reactions similar to those supported by the inner membrane of natural mitochondria. Subsequent studies have demonstrated the interaction between PFC MCs and living cell including extended lifespans within various cell types. We anticipate that functional PFC MCs have the potential to serve as innovative platforms for organelle mimics capable of executing specific cellular functions.


Asunto(s)
Compuestos Ferrosos , Oxidación-Reducción , Silanos , Compuestos Ferrosos/química , Silanos/química , Orgánulos/química , Orgánulos/metabolismo , Mitocondrias/metabolismo , Mitocondrias/química , Humanos , Biomimética/métodos , Materiales Biomiméticos/química , Cápsulas/química , Polímeros/química
20.
Chemistry ; 30(43): e202401700, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38797874

RESUMEN

In oxygen (O2)-dependent photodynamic therapy (PDT), photosensitizers absorb light energy, which is then transferred to ambient O2 and subsequently generates cytotoxic singlet oxygen (1O2). Therefore, the availability of O2 and the utilization efficiency of generated 1O2 are two significant factors that influence the effectiveness of PDT. However, tumor microenvironments (TMEs) characterized by hypoxia and limited utilization efficiency of 1O2 resulting from its short half-life and short diffusion distance significantly restrict the applicability of PDT for hypoxic tumors. To address these challenges, numerous macromolecular nano-assemblies (MNAs) have been designed to relieve hypoxia, utilize hypoxia or enhance the utilization efficiency of 1O2. Herein, we provide a comprehensive review on recent advancements achieved with MNAs in enhancing the effectiveness of O2-dependent PDT against hypoxic tumors.


Asunto(s)
Neoplasias , Oxígeno , Fotoquimioterapia , Fármacos Fotosensibilizantes , Oxígeno Singlete , Microambiente Tumoral , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Humanos , Oxígeno/química , Oxígeno Singlete/metabolismo , Oxígeno Singlete/química , Neoplasias/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Animales , Hipoxia Tumoral/efectos de los fármacos , Nanoestructuras/química , Nanopartículas/química , Sustancias Macromoleculares/química , Sustancias Macromoleculares/farmacología
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