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Primary metabolism provides energy for growth and development as well as secondary metabolites for diverse environmental responses. Here we describe an unexpected consequence of disruption of a glycolytic enzyme enolase named LOW EXPRESSION OF OSMOTICALLY RESPONSIVE GENE 2 (LOS2) in causing constitutive defense responses or autoimmunity in Arabidopsis thaliana. The autoimmunity in the los2 mutant is accompanied by a higher expression of about one-quarter of intracellular immune receptor nucleotide-binding leucine-rich repeat (NLR) genes in the genome and is partially dependent on one of these NLR genes. The LOS2 gene was hypothesized to produce an alternatively translated protein c-Myc Binding Protein (MBP-1) that functions as a transcriptional repressor. Complementation tests show that LOS2 executes its function in growth and immunity regulation through the canonical enolase activity but not the production of MBP-1. In addition, the autoimmunity in the los2 mutants leads to a higher accumulation of sugars and organic acids and a depletion of glycolytic metabolites. These findings indicate that LOS2 does not exert its function in immune responses through an alternatively translated protein MBP-1. Rather, they show that a perturbation of glycolysis from the reduction of the enolase activity results in activation of NLR-involved immune responses which further influences primary metabolism and plant growth, highlighting the complex interaction between primary metabolism and plant immunity.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Glucólisis/genética , Fosfopiruvato Hidratasa/genética , Fosfopiruvato Hidratasa/metabolismo , Inmunidad de la Planta/genéticaRESUMEN
Chemical defense systems involving tryptophan-derived secondary metabolites (TDSMs) and salicylic acid (SA) are induced by general nonself signals and pathogen signals, respectively, in Arabidopsis thaliana. Whether and how these chemical defense systems are connected and balanced is largely unknown. In this study, we identified the AVRRPT2-INDUCED GENE2A (AIG2A) and AIG2B genes as gatekeepers that prevent activation of SA defense systems by TDSMs. These genes also were identified as important contributors to natural variation in disease resistance among A. thaliana natural accessions. The loss of AIG2A and AIG2B function leads to upregulation of both SA and TDSM defense systems. Suppressor screens and genetic analysis revealed that a functional TDSM system is required for the upregulation of the SA pathway in the absence of AIG2A and AIG2B, but not vice versa. Furthermore, the AIG2A and AIG2B genes are co-induced with TDSM biosynthesis genes by general pathogen elicitors and nonself signals, thereby functioning as a feedback control of the TDSM defense system, as well as limiting activation of the SA defense system by TDSMs. Thus, this study uncovers an AIG2A- and AIG2B-mediated mechanism that fine-tunes and balances SA and TDSM chemical defense systems in response to nonpathogenic and pathogenic microbes.
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Proteínas de Arabidopsis , Arabidopsis , Resistencia a la Enfermedad , Enfermedades de las Plantas , Ácido Salicílico , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Resistencia a la Enfermedad/genética , Regulación de la Expresión Génica de las Plantas , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/inmunología , Ácido Salicílico/metabolismo , Metabolismo Secundario , Triptófano/metabolismoRESUMEN
Plants contain many nucleotide-binding leucine-rich repeat (NLR) proteins that are postulated to function as intracellular immune receptors but do not yet have an identified function during plant-pathogen interactions. SUPPRESSOR OF NPR1-1, CONSTITUTIVE 1 (SNC1) is one such NLR protein of the Toll-interleukin 1 receptor (TIR) type, despite its well-characterized gain-of-function activity and its involvement in autoimmunity in Arabidopsis (Arabidopsis thaliana). Here, we investigated the role of SNC1 in natural plant-pathogen interactions and genetically tested the importance of the enzymatic activities of its TIR domain for its function. The SNC1 loss-of-function mutants were more susceptible to avirulent bacterial pathogen strains of Pseudomonas syringae containing specific effectors, especially under constant light growth condition. The mutants also had reduced defense gene expression induction and hypersensitive responses upon infection by avirulent pathogens under constant light growth condition. In addition, genetic and biochemical studies supported that the TIR enzymatic activity of SNC1 is required for its gain-of-function activity. In sum, our study uncovers the role of SNC1 as an amplifier of plant defense responses during natural plant-pathogen interactions and indicates its use of enzymatic activity and intermolecular interactions for triggering autoimmune responses.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Dominios Proteicos , Inmunidad de la Planta/genética , Enfermedades de las Plantas/microbiología , Mutación/genéticaRESUMEN
Amino acid homeostasis is interconnected with the immune network of plants. During plant-pathogen interaction, amino acid transporters (AATs) have been shown to be involved in plant immune responses. However, the molecular mechanism by which how AATs function in this process remains elusive. In this study, we identify OsMP1 that acts as a quantitative trait locus against blast fungus from a joint analysis of GWAS and QTL mapping in rice. Heterogeneous expression of OsMP1 in yeast supports its function in transporting a wide range of amino acids, including Thr, Ser, Phe, His and Glu. OsMP1 could also mediate 15N-Glu efflux and influx in Xenopus oocyte cells. The expression of OsMP1 is dramatically induced by Magnaporthe oryzae in the resistant landrace Heikezijing, while remaining unresponsive in the susceptible landrace Suyunuo. Overexpressing OsMP1 in Suyunuo enhances disease resistance to blast fungus and leaf-blight bacterium without yield penalty. Furthermore, the overexpression of OsMP1 leads to increased accumulation of Thr, Ser, Phe and His in the leaves. And the heightened levels of these amino acids contribute to reduced disease susceptibility, which is associated with upregulated jasmonic acid pathway. Thus, our results elucidate the pivotal role of OsMP1 in disease resistance and provide a potential target for breeding more resistant rice cultivars without compromising yield.
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BACKGROUND: Nephrotic syndrome (NS) can occur as a paraneoplastic disorder in association with various types of carcinoma. However, paraneoplastic nephrotic syndrome (PNS) is often misdiagnosed as idiopathic nephrotic syndrome or as an adverse effect of oncology treatment, leading to delayed diagnosis and suboptimal treatment. The characteristics of NS associated with solid malignancies are not yet elucidated. We systematically summarized the clinical data for 128 cases of NS combined with solid malignancies with the aim of informing the clinical management of PNS. METHODS: We searched the PubMed database for articles published from the date of inception through to October 2023 using the following keywords: "cancer" or "malignant neoplasms" or "neoplasia" or "tumors" and "nephrotic syndrome", "nephrotic" or "syndrome, nephrotic". All data were extracted from case reports and case series, and the extraction included a method for identifying individual-level patient data. RESULTS: A literature search yielded 105 cases of PNS and 23 of NS induced by cancer therapy. The median age at diagnosis was 60 years, with a male to female ratio of 1.8:1. In patients with PNS, manifestations of NS occurred before, concomitantly with, or after diagnosis of the tumor (in 36%, 30%, and 34% of cases, respectively). Membranous nephropathy (49%) was the most prevalent renal pathology and found particularly in patients with lung, colorectal, or breast carcinoma. Regardless of whether treatment was for cancer alone or in combination with NS, the likelihood of remission was high. CONCLUSION: The pathological type of NS may be associated with specific malignancies in patients with PNS. Prompt identification of PNS coupled with suitable therapeutic intervention has a significant impact on the outcome for patients.
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Neoplasias , Síndrome Nefrótico , Síndromes Paraneoplásicos , Humanos , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/etiología , Neoplasias/complicaciones , Glomerulonefritis Membranosa/complicacionesRESUMEN
Objective: To evaluate the effectiveness and safety of pericapsular nerve group (PENG) block for hip fracture surgery under spinal anesthesia. Methods: This meta-analysis was registered on INPLASY (INPLASY202270005). PubMed, Embase, Cochrane, CNKI, and Wanfang databases were searched to collect the randomized controlled trials of the PENG block applied to hip fracture surgery in the setting of spinal anesthesia, with the search period from inception to 1 May 2023. Two independent researchers gradually screened the literature, evaluated the quality, extracted the data, and eventually pooled data using RevMan 5.4. Results: Fifteen articles with 890 patients were enrolled. The combined results showed that the PENG block reduced pain scores during position placement (SMD = -0.35; 95% CI [-0.67, 0.02]; P=0.04; I2 = 0%). Subgroup analyses showed that compared to the unblocked group, the PENG block reduced pain scores at 12 h, 24 h, and 48 h postoperatively. The incidence of postoperative hypokinesia was reduced (RR = 0.11; 95% CI [0.01, 0.86]; P=0.04; I2 = 0.00%). The time to first walking was advanced (SMD = -0.90; 95% CI [-1.17, 0.63]; P < 0.00001; I2 = 0%). Conclusion: The PENG block can reduce postoperative pain and pain during spinal anesthesia positioning, which is helpful to improve the operability and comfort of spinal anesthesia and facilitate postoperative muscle strength recovery and early activity.
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Anestesia Raquidea , Fracturas de Cadera , Humanos , Anestesia Raquidea/efectos adversos , Nervio Femoral , Fracturas de Cadera/cirugía , Dolor Postoperatorio/prevención & control , Bases de Datos FactualesRESUMEN
Objective: To evaluate the effect of scalp nerve block (SNB) on postoperative analgesia and stress response in patients undergoing craniotomy by meta-analysis. Methods: PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases were searched for randomized controlled trials involving SNB for elective craniotomy under general anesthesia from inception to August 1, 2022. Meta-analysis was performed using RevMan 5.4 and Stata MP17.0. Based on scalp block operation time (preoperative block, postoperative block), different control groups (no block, normal saline), local anesthetic types (bupivacaine, levobupivacaine, ropivacaine), the postoperative pain score at different time points was analyzed by subgroup analysis. Results: 23 studies involving 1515 patients were included. The combined results showed that SNB could significantly reduce the pain scores at all time points compared with the control group (P < .05). Subgroup analysis showed that the analgesic effect of preoperative scalp nerve block was better than that of postoperative block, and the effect of ropivacaine and levobupivacaine was better than bupivacaine. SNB could reduce morphine consumption within 48 hours after surgery (SMD = -1.51, 95% CI -2.80 -0.21, P = .02, I2 = 89%). The first rescue analgesia time was significantly longer in the SNB group than the control group (SMD = 0.57, 95% CI 0.16-0.99, P = .01, I2 = 68.76%). Compared with the control group, the levels of postoperative angiotensin, intraoperative blood glucose, and both intraoperative and postoperative cortisol levels were significantly decreased (P < .05). SNB can inhibit hemodynamic changes caused by surgical stimulation and effectively reduce the incidence of postoperative nausea and vomiting (RR = 0.71, 95% CI 0.51~0.97, P = .03). Conclusion: Scalp nerve block is an effective analgesic that reduces pain within 48 hours after craniotomy. It effectively inhibit the stress response caused by surgical stimulation, stabilize hemodynamics, and reduce the incidence of postoperative nausea and vomiting.
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Rice blast is one of the most devastating diseases, causing a significant reduction in global rice production. Developing and utilizing resistant varieties has proven to be the most efficient and cost-effective approach to control blasts. However, due to environmental pressure and intense pathogenic selection, resistance has rapidly broken down, and more durable resistance genes are being discovered. In this paper, a novel wall-associated kinase (WAK) gene, Pb4, which confers resistance to rice blast, was identified through a genome-wide association study (GWAS) utilizing 249 rice accessions. Pb4 comprises an N-terminal signal peptide, extracellular GUB domain, EGF domain, EGF-Ca2+ domain, and intracellular Ser/Thr protein kinase domain. The extracellular domain (GUB domain, EGF domain, and EGF-Ca2+ domain) of Pb4 can interact with the extracellular domain of CEBiP. Additionally, its expression is induced by chitin and polygalacturonic acid. Furthermore, transgenic plants overexpressing Pb4 enhance resistance to rice blast. In summary, this study identified a novel rice blast-resistant gene, Pb4, and provides a theoretical basis for understanding the role of WAKs in mediating rice resistance against rice blast disease.
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Factor de Crecimiento Epidérmico , Estudio de Asociación del Genoma Completo , Quitina , Leucocitos , Plantas Modificadas Genéticamente/genéticaRESUMEN
The expression of an intracellular immune receptor gene SNC1 (SUPPRESSOR OF npr1, CONSTITUTIVE 1) is regulated by multiple chromatin-associated proteins for tuning immunity and growth in Arabidopsis. Whether and how these regulators coordinate to regulate SNC1 expression under varying environmental conditions is not clear. Here, we identified two activation and one repression regulatory modules based on genetic and molecular characterizations of five chromatin-associated regulators of SNC1. Modifier of snc1 (MOS1) constitutes the first module and is required for the interdependent functions of ARABIDOPSIS TRITHORAX-RELATED 7 (ATXR7) and HISTONE MONOUBIQUITINATION 1 (HUB1) to deposit H3K4me3 and H2Bub1 at the SNC1 locus. CHROMATIN REMODELING 5 (CHR5) constitutes a second module and works independently of ATXR7 and HUB1 in the MOS1 module. HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 15 (HOS15) constitutes a third module responsible for removing H3K9ac to repress SNC1 expression under nonpathogenic conditions. The upregulation of SNC1 resulting from removing the HOS15 repression module is partially dependent on the function of the CHR5 module and the MOS1 module. Together, this study reveals both the distinct and interdependent regulatory mechanisms at the chromatin level for SNC1 expression regulation and highlights the intricacy of regulatory mechanisms of NLR expression under different environment.
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Proteínas de Arabidopsis , Arabidopsis , Cromatina , Regulación de la Expresión Génica de las Plantas , Receptores Inmunológicos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Inmunidad de la Planta/genética , Receptores Inmunológicos/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/genética , UbiquitinaciónRESUMEN
BACKGROUND AND AIM: Endotoxin-induced acute lung injury (ALI) is a complicated and fatal condition with no specific or efficient clinical treatments. 5-Methoxytryptophan (5-MTP), an endogenous metabolite of tryptophan, was revealed to block systemic inflammation. However, the specific mechanism by which 5-MTP affects ALI still needs to be clarified. The purpose of this study was to determine whether 5-MTP protected the lung by inhibiting NLRP3 inflammasome-mediated pyroptosis through the Nrf2/HO-1 signaling pathway. METHODS AND RESULTS: We used lipopolysaccharide (LPS)-stimulated C57BL/6 J mice and MH-S alveolar macrophages to create models of ALI, and 5-MTP (100 mg/kg) administration attenuated pathological lung damage in LPS-exposed mice, which was associated with decreased inflammatory cytokines and oxidative stress levels, upregulated protein expression of Nrf2 and HO-1, and suppressed Caspase-1 activation and NLRP3-mediated pyroptosis protein levels. Moreover, Nrf2-deficient mice or MH-S cells were treated with 5-MTP to further confirm the protective effect of the Nrf2/HO-1 pathway on lung damage. We found that Nrf2 deficiency partially eliminated the beneficial effect of 5-MTP on reducing oxidative stress levels and inflammatory responses and abrogating the inhibition of NLRP3-mediated pyroptosis induced by LPS. CONCLUSION: These findings suggested that 5-MTP could effectively ameliorate ALI by inhibiting NLRP3-mediated pyroptosis via the Nrf2/HO-1 signaling pathway.
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Lesión Pulmonar Aguda , Inflamasomas , Ratones , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Triptófano/efectos adversos , Endotoxinas/farmacología , Lipopolisacáridos/farmacología , Piroptosis , Ratones Endogámicos C57BL , Transducción de Señal , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismoRESUMEN
How likely genetic variations associated with environment identified in silico from genome wide association study are functionally relevant to environmental adaptation has been largely unexplored experimentally. Here we analyzed top 29 genes containing polymorphisms associated with local temperature variation (minimum, mean, maximum) among 1129 natural accessions of Arabidopsis thaliana. Their loss-of-function mutants were assessed for growth and stress tolerance at five temperatures. Twenty genes were found to affect growth or tolerance at one or more of these temperatures. Significantly, genes associated with maximum temperature more likely have a detect a function at higher temperature, while genes associated with minimum temperature more likely have a function at lower temperature. In addition, gene variants are distributed more frequently at geographic locations where they apparently offer an enhanced growth or tolerance for five genes tested. Furthermore, variations in a large proportion of the in silico identified genes associated with minimum or mean-temperatures exhibited a significant association with growth phenotypes experimentally assessed at low temperature for a small set of natural accessions. This study shows a functional relevance of gene variants associated with environmental variables and supports the feasibility of the use of local temperature factors in investigating the genetic basis of temperature adaptation.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas , Estudio de Asociación del Genoma Completo , TemperaturaRESUMEN
BACKGROUND: Ki-67 proliferation index (PI) is important for providing information on tumor behavior, treatment response, and prognosis. Integrated positron emission tomography/magnetic resonance (PET/MR) may have the potential to assess Ki-67 PI in patients with lung adenocarcinoma. PURPOSE: To explore the value of simultaneous 18 F-fluorodeoxyglucose (18 F-FDG) PET/MR-derived parameters in assessing the proliferation status of lung adenocarcinoma and to determine the best combination of parameters. STUDY TYPE: Prospective. POPULATION: Seventy-eight patients with lung adenocarcinoma and with Ki-67 PI. FIELD STRENGTH/SEQUENCE: 3.0 T, simultaneous PET/MRI including diffusion-weighted imaging (DWI) and 18 F-FDG PET. ASSESSMENT: DWI-derived parameters, namely, apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudo diffusion coefficient (D*), perfusion fraction (f), diffusion heterogeneity index (α), and distributed diffusion coefficient (DDC); and PET-derived parameters, namely, maximum standardized uptake value (SUVmax ), metabolic tumor volume (MTV), and total lesion glycolytic volume (TLG), were calculated and compared between the high (>25%) and low (≤25%) Ki-67 PI groups. The correlations between PET-derived parameters and DWI-derived parameters were analyzed. STATISTICAL TESTS: Student's t-test, Mann-Whitney U test, chi-square test, and receiver operating characteristic (ROC) curves. A P-value <0.05 was considered statistically significant. RESULTS: The SUVmax , MTV, TLG, ADC, D, and DDC values were significantly different between the high (N = 35) and low Ki-67 PI groups (N = 43). D, SUVmax , and MTV independently predicted the Ki-67 PI status. The combination of D, SUVmax , and MTV had the largest area under the ROC curve (AUC = 0.900), which was significantly larger than the AUC alone of DDC (AUC = 0.725), SUVmax (AUC = 0.815), MTV (AUC = 0.774), or TLG (AUC = 0.783). The perfusion fraction did not correlate with SUVmax , MTV, or TLG (r = -0.03, -0.11, and -0.04, respectively; P = 0.786, 0.348, and 0.733). DATA CONCLUSION: The combination of D, SUVmax , and MTV may predict Ki-67 PI status. No correlation was observed between perfusion parameters and metabolic parameters. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.
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Adenocarcinoma del Pulmón , Fluorodesoxiglucosa F18 , Proliferación Celular , Imagen de Difusión por Resonancia Magnética/métodos , Humanos , Antígeno Ki-67 , Imagen por Resonancia Magnética , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Rice blast is a worldwide fungal disease that seriously affects the yield and quality of rice. Identification of resistance genes against rice blast disease is one of the effective ways to control this disease. However, panicle blast resistance genes, which are useful in the fields, have rarely been studied due to the difficulty in phenotypic identification and the environmental influences. Here, panicle blast resistance-3 (Pb3) was identified by a genome-wide association study (GWAS) based on the panicle blast resistance phenotypes of 230 Rice Diversity Panel I (RDP-I) accessions with 700,000 single-nucleotide polymorphism (SNP) markers. A total of 16 panicle blast resistance loci (PBRLs) within three years including one repeated locus PBRL3 located in chromosome 11 were identified. In addition, 7 genes in PBRL3 were identified as candidate genes by haplotype analysis, which showed significant differences between resistant and susceptible varieties. Among them, one nucleotide-binding domain and Leucine-rich Repeat (NLR) gene Pb3 was highly conserved in multiple resistant rice cultivars, and its expression was significantly induced after rice blast inoculation. Evolutionary analysis showed that Pb3 was a typical disease resistance gene containing coiled-coil, NB-ARC, and LRR domains. T-DNA insertion mutants and CRISPR lines of Pb3 showed significantly reduced panicle blast resistance. These results indicate that Pb3 is a panicle blast resistance gene and GWAS is a rapid method for identifying panicle blast resistance in rice.
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Magnaporthe , Oryza , Estudio de Asociación del Genoma Completo , Proteínas NLR/genética , Proteínas NLR/metabolismo , Magnaporthe/genética , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/microbiología , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
The SAUR26 subfamily genes play an important role in conferring variations of thermo-responsiveness of growth architecture among natural accessions of Arabidopsis thaliana. The expression variations are critical for their activity variations, but how expression variations are generated is unknown. We identified genetic loci for gene expression variations through expression genome-wide association study (eGWAS) and investigated their mechanisms through molecular analyses. We found that cis elements are the major determinants for expression variations of SAUR26, SAUR27, and SAUR28. Polymorphisms in the promoter region likely impact PIF4 regulation while those at the 3'UTR affect mRNA stability to generate variations in SAUR26 expression levels. These polymorphisms also differentially affect the mRNA stability of SAUR26 at two temperatures. This study reveals two mechanisms involving cis elements in generating gene expression diversity, which is likely important for local adaptations in Arabidopsis natural accessions.
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Proteínas de Arabidopsis/genética , Arabidopsis , Péptidos y Proteínas de Señalización Intracelular/genética , Adaptación Fisiológica , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Expresión Génica , Regulación de la Expresión Génica de las Plantas , Estudio de Asociación del Genoma Completo , TemperaturaRESUMEN
Chilling is a major stress to plants of subtropical and tropical origins including maize (Zea mays L.). To reveal molecular mechanisms underlying chilling tolerance and survival, we investigated transcriptomic responses to chilling stress in differentiated leaves and roots as well as in crowns with meristem activity in maize. Chilling stress on shoots and roots is found to each contributes to seedling lethality in maize. Comparison of maize lines with different chilling tolerance capacities reveals that chilling survival is highly associated with upregulation of abscisic acid biosynthesis and response as well as transcriptional regulators in leaves and crowns. It is also associated with the downregulation of translation in leaves and heat response in crowns. Chilling treatment on whole or part of the plants reveals that response to distal-chilling is very distinct from, and sometimes opposite to, response to local- or whole-plant chilling in both leaves and roots, suggesting a communication between shoots and roots in environmental response. This study thus provides transcriptomic responses in leaves, roots and crowns under differential chilling stresses in maize and reveals potential chilling tolerance and survival mechanisms which lays ground for improving chilling tolerance in crop plants.
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Mitochondrial fission and fusion are important for mitochondrial function, and dynamin 1-like protein (DNM1L) is a key regulator of mitochondrial fission. We investigated the effect of mitochondrial fission on mitochondrial function and inflammation in fibroblast-like synoviocytes (FLSs) during rheumatoid arthritis (RA). DNM1L expression was determined in synovial tissues (STs) from RA and non-RA patients. FLSs were isolated from STs and treated with a DNM1L inhibitor (mdivi-1, mitochondrial division inhibitor 1) or transfected with DNM1L-specific siRNA. Mitochondrial morphology, DNM1L expression, cell viability, mitochondrial membrane potential, reactive oxygen species (ROS), apoptosis, inflammatory cytokine expression and autophagy were examined. The impact of mdivi-1 treatment on development and severity of collagen-induced arthritis (CIA) was determined in mice. Up-regulated DNM1L expression was associated with reduced mitochondrial length in STs from patients with RA and increased RA severity. Inhibition of DNM1L in FLSs triggered mitochondrial depolarization, mitochondrial elongation, decreased cell viability, production of ROS, IL-8 and COX-2, and increased apoptosis. DNM1L deficiency inhibited IL-1ß-mediated AKT/IKK activation, NF-κBp65 nuclear translocation and LC3B-related autophagy, but enhanced NFKBIA expression. Treatment of CIA mice with mdivi-1 decreased disease severity by modulating inflammatory cytokine and ROS production. Our major results are that up-regulated DNM1L and mitochondrial fission promoted survival, LC3B-related autophagy and ROS production in FLSs, factors that lead to inflammation by regulating AKT/IKK/NFKBIA/NF-κB signalling. Thus, inhibition of DNM1L may be a new strategy for treatment of RA.
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Artritis Reumatoide/patología , Dinaminas/antagonistas & inhibidores , Fibroblastos/patología , Inflamación/patología , Dinámicas Mitocondriales , Sinoviocitos/patología , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Dinaminas/deficiencia , Dinaminas/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/ultraestructura , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos DBA , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Dinámicas Mitocondriales/efectos de los fármacos , FN-kappa B/metabolismo , Quinazolinonas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Índice de Severidad de la Enfermedad , Sinoviocitos/efectos de los fármacos , Sinoviocitos/ultraestructuraRESUMEN
Overexpression of ATP-binding cassette (ABC) transporter is one of the most important factors taking responsibility for the progress of multidrug resistance (MDR) in multiple cancers. In this study, we investigated that veliparib, a PARP inhibitor which is in clinical development, could overcome ABCB1-mediated MDR in liver cancer cells. Veliparib could significantly enhance the cytotoxic effects of a series of conventional chemotherapeutic drugs in ABCB1-overexpression liver cancer cells. Mechanism study showed that veliparib could significantly enhance the accumulation of doxorubicin in ABCB1-overexpression liver cancer cells, without down-regulating the expression level of ABCB1. Finally, veliparib could significantly inhibit the ATPase activity of ABCB1 transporter. This study could provide information that combine veliparib with other chemotherapeutic drugs may benefit liver cancer patients.
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Antineoplásicos/farmacología , Bencimidazoles/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismoRESUMEN
Plant immune responses need to be tightly controlled for growth-defense balance. The mechanism underlying this tight control is not fully understood. Here we identify epigenetic regulation of nucleotide-binding leucine rich repeat or Nod-Like Receptor (NLR) genes as an important mechanism for immune responses. Through a sensitized genetic screen and molecular studies, we identified and characterized HOS15 and its associated protein HDA9 as negative regulators of immunity and NLR gene expression. The loss-of-function of HOS15 or HDA9 confers enhanced resistance to pathogen infection accompanied with increased expression of one-third of the 207 NLR genes in Arabidopsis thaliana. HOS15 and HDA9 are physically associated with some of these NLR genes and repress their expression likely through reducing the acetylation of H3K9 at these loci. In addition, these NLR genes are repressed by HOS15 under both pathogenic and nonpathogenic conditions but by HDA9 only under infection condition. Together, this study uncovers a previously uncharacterized histone deacetylase complex in plant immunity and highlights the importance of epigenetic regulation of NLR genes in modulating growth-defense balance.
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Proteínas de Arabidopsis/genética , Arabidopsis , Proteínas Cromosómicas no Histona/genética , Histona Desacetilasas , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Epigénesis Genética , Regulación de la Expresión Génica de las Plantas , Histona Desacetilasas/genética , Histonas/metabolismo , Proteínas NLR/genética , Inmunidad de la Planta/genéticaRESUMEN
Sugars, which are important signaling molecules, regulate diverse biological processes in plants. However, the convergent regulatory mechanisms governing these physiological activities have not been fully elucidated. MODIFIER OF snc1-1 (MOS1), a modulator of plant immunity, also regulates floral transition, cell cycle control, and other biological processes. However, there was no evidence of whether this protein was involved in sugar responses. In this study, we found that the loss-of-function mutant mos1-6 (mos1) was hypersensitive to sugar and was characterized by defective germination and shortened roots when grown on high-sugar medium. The expression of MOS1 was enhanced by sucrose. Hexokinase 1, an important gene involved in sugar signaling, was upregulated in the mos1 mutant compared to wild-type Col-0 in response to sugar. Furthermore, the mos1 mutant accumulated more anthocyanin than did wild-type Col-0 when grown on high-sugar concentration medium or under high light. MOS1 was found to regulate the expression of flavonoid and anthocyanin biosynthetic genes in response to exogenous sucrose and high-light stress but with different underlying mechanisms, showing multiple functions in addition to immunity regulation in plant development. Our results suggest that the immune regulator MOS1 serves as a coordinator in the regulatory network, governing immunity and other physiological processes.
Asunto(s)
Antocianinas/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Azúcares/metabolismo , Factores de Transcripción/metabolismo , Antocianinas/genética , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Proteínas de Arabidopsis/genética , Vías Biosintéticas , Regulación de la Expresión Génica de las Plantas , Mutación con Pérdida de Función , Sacarosa/metabolismo , Factores de Transcripción/genéticaRESUMEN
Emerging evidence indicates a close connection between cell-cycle progression and the plant immune responses. In Arabidopsis, MODIFIER OF snc1-1 (MOS1) modulates a number of processes including endoreduplication and plant disease resistance, but the molecular mechanism underlying this modulation was not fully understood. Here, we provide biochemical and genetic evidence that TEOSINTE BRANCHED 1, CYCLOIDEA, PCF1 (TCP) transcription factors TCP15 and its homologues are mediators of MOS1 function in the immune response and are likely to be also involved in cell-cycle control. MOS1 and TCP proteins have a direct physical interaction. They both bind to the promoter of the immune receptor gene SUPRESSOR OF npr1-1, CONSTITUTIVE 1 (SNC1) and modulate its expression and consequently immune responses. MOS1 and TCP15 both affect the expression of cell-cycle genes D-type CYCLIN 3;1 (CYCD3;1), which may mediate the MOS1 function in cell-cycle modulation. In addition, CYCD3;1 overexpression upregulates immune responses, and SNC1 expression. This study investigated and revealed a role for MOS1 in transcriptional regulation through TCP15 and its homologues. This finding suggests the coordination of cell-cycle progression and plant immune responses at multiple levels.