RESUMO
The extracellular pH is a vital regulator of various biological processes in plants. However, how plants perceive extracellular pH remains obscure. Here, we report that plant cell-surface peptide-receptor complexes can function as extracellular pH sensors. We found that pattern-triggered immunity (PTI) dramatically alkalinizes the acidic extracellular pH in root apical meristem (RAM) region, which is essential for root meristem growth factor 1 (RGF1)-mediated RAM growth. The extracellular alkalinization progressively inhibits the acidic-dependent interaction between RGF1 and its receptors (RGFRs) through the pH sensor sulfotyrosine. Conversely, extracellular alkalinization promotes the alkaline-dependent binding of plant elicitor peptides (Peps) to its receptors (PEPRs) through the pH sensor Glu/Asp, thereby promoting immunity. A domain swap between RGFR and PEPR switches the pH dependency of RAM growth. Thus, our results reveal a mechanism of extracellular pH sensing by plant peptide-receptor complexes and provide insights into the extracellular pH-mediated regulation of growth and immunity in the RAM.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Concentração de Íons de Hidrogênio , Meristema/metabolismo , Peptídeos/metabolismo , Células Vegetais , Raízes de Plantas/metabolismo , Plantas/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de SinaisRESUMO
Ethylene is a gaseous phytohormone that plays vital roles in plant growth and development. Previous studies uncovered EIN2 as an essential signal transducer linking ethylene perception on ER to transcriptional regulation in the nucleus through a "cleave and shuttle" model. In this study, we report another mechanism of EIN2-mediated ethylene signaling, whereby EIN2 imposes the translational repression of EBF1 and EBF2 mRNA. We find that the EBF1/2 3' UTRs mediate EIN2-directed translational repression and identify multiple poly-uridylates (PolyU) motifs as functional cis elements of 3' UTRs. Furthermore, we demonstrate that ethylene induces EIN2 to associate with 3' UTRs and target EBF1/2 mRNA to cytoplasmic processing-body (P-body) through interacting with multiple P-body factors, including EIN5 and PABs. Our study illustrates translational regulation as a key step in ethylene signaling and presents mRNA 3' UTR functioning as a "signal transducer" to sense and relay cellular signaling in plants. VIDEO ABSTRACT.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Etilenos/metabolismo , Regulação da Expressão Gênica de Plantas , Receptores de Superfície Celular/metabolismo , Proteínas de Arabidopsis/genética , Exorribonucleases/metabolismo , Proteínas F-Box/genética , Conformação de Ácido Nucleico , Proteínas de Plantas/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/química , RNA Mensageiro/metabolismoRESUMO
Pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) in plants enable them to respond to pathogens by activating the production of defence metabolites that orchestrate immune responses1-4. How the production of defence metabolites is promoted by immune receptors and coordinated with broad-spectrum resistance remains elusive. Here we identify the deubiquitinase PICI1 as an immunity hub for PTI and ETI in rice (Oryza sativa). PICI1 deubiquitinates and stabilizes methionine synthetases to activate methionine-mediated immunity principally through biosynthesis of the phytohormone ethylene. PICI1 is targeted for degradation by blast fungal effectors, including AvrPi9, to dampen PTI. Nucleotide-binding domain, leucine-rich-repeat-containing receptors (NLRs) in the plant immune system, such as PigmR, protect PICI1 from effector-mediated degradation to reboot the methionine-ethylene cascade. Natural variation in the PICI1 gene contributes to divergence in basal blast resistance between the rice subspecies indica and japonica. Thus, NLRs govern an arms race with effectors, using a competitive mode that hinges on a critical defence metabolic pathway to synchronize PTI with ETI and ensure broad-spectrum resistance.
Assuntos
Oryza , Doenças das Plantas , Metionina , Oryza/genética , Oryza/microbiologia , Doenças das Plantas/microbiologia , Imunidade Vegetal/genética , Plantas , Transdução de Sinais/genéticaRESUMO
Protein O-glycosylation is a nutrient signaling mechanism that plays an essential role in maintaining cellular homeostasis across different species. In plants, SPINDLY (SPY) and SECRET AGENT (SEC) posttranslationally modify hundreds of intracellular proteins with O-fucose and O-linked N-acetylglucosamine, respectively. SPY and SEC play overlapping roles in cellular regulation, and loss of both SPY and SEC causes embryo lethality in Arabidopsis (Arabidopsis thaliana). Using structure-based virtual screening of chemical libraries followed by in vitro and in planta assays, we identified a SPY O-fucosyltransferase inhibitor (SOFTI). Computational analyses predicted that SOFTI binds to the GDP-fucose-binding pocket of SPY and competitively inhibits GDP-fucose binding. In vitro assays confirmed that SOFTI interacts with SPY and inhibits its O-fucosyltransferase activity. Docking analysis identified additional SOFTI analogs that showed stronger inhibitory activities. SOFTI treatment of Arabidopsis seedlings decreased protein O-fucosylation and elicited phenotypes similar to the spy mutants, including early seed germination, increased root hair density, and defective sugar-dependent growth. In contrast, SOFTI did not visibly affect the spy mutant. Similarly, SOFTI inhibited the sugar-dependent growth of tomato (Solanum lycopersicum) seedlings. These results demonstrate that SOFTI is a specific SPY O-fucosyltransferase inhibitor that can be used as a chemical tool for functional studies of O-fucosylation and potentially for agricultural management.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas Repressoras/metabolismo , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Fucose/metabolismo , Plântula/metabolismo , Açúcares/metabolismoRESUMO
Identifying the essential factors and underlying mechanisms regulating plant heat stress (HS) responses is crucial for mitigating the threat posed by HS on plant growth, development, distribution, and productivity. Here, we found that the Arabidopsis (Arabidopsis thaliana) super-killer2 (ski2) dicer-like4 (dcl4) mutant, characterized by RNA processing defects and accumulation of abundant 22-nt small interfering RNAs (siRNAs) derived from protein-coding transcripts, displayed significantly increased expression levels of HS-responsive genes and enhanced thermotolerance. These traits primarily resulted from the suppression of SMAX1-LIKE4 (SMXL4) and SMXL5, which encode two putative transcriptional regulators that belong to the SMXL protein family. While smxl4 and smxl5 single mutants were similar to wild type, the smxl4 smxl5 double mutant displayed substantially heightened seedling thermotolerance. Further investigation demonstrated that SMXL4 and SMXL5 repressed the transcription of HEAT SHOCK TRANSCRIPTION FACTOR A2 (HSFA2), encoding a master regulator of thermotolerance, independently of EAR motifs. Moreover, SMXL4 and SMXL5 interacted with HSFA1d and HSFA1e, central regulators sensing and transducing HS stimuli, and antagonistically affected their transactivation activity. In addition, HSFA2 directly bound to the SMXL4 and SMXL5 promoters, inducing their expression during recovery from HS. Collectively, our findings elucidate the role of the SMXL4/SMXL5-HSFA2 regulatory module in orchestrating plant thermotolerance under HS.
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Acetylation is an important posttranslational modification (PTM) that regulates almost all core processes of autophagy in yeast and mammals. However, the role of protein acetylation in plant autophagy and the underlying regulatory mechanisms remain unclear. Here, we show the essential role of the putative acetyltransferase HOOKLESS1 (HLS1) in acetylation of the autophagy-related protein ATG18a, a key autophagy component that regulates autophagosome formation in Arabidopsis (Arabidopsis thaliana). Loss of HLS1 function suppressed starvation-induced autophagy and increased plant susceptibility to nutrient deprivation. We discovered that HLS1 physically interacts with and directly acetylates ATG18a both in vitro and in vivo. In contrast, mutating putative active sites in HLS1 inhibited ATG18a acetylation and suppressed autophagy upon nutrient deprivation. Accordingly, overexpression of ATG18a mutant variants with lower acetylation levels inhibited the binding activity of ATG18a to PtdIns(3)P and autophagosome formation under starvation conditions. Moreover, HLS1-modulated autophagy was uncoupled from its function in hook development. Taken together, these findings shed light on a key regulator of autophagy and further elucidate the importance of PTMs in modulating autophagy in plants.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Processamento de Proteína Pós-Traducional , Nutrientes , Autofagia/genéticaRESUMO
Small interfering RNAs (siRNAs) are essential for proper development and immunity in eukaryotes1. Plants produce siRNAs with lengths of 21, 22 or 24 nucleotides. The 21- and 24-nucleotide species mediate cleavage of messenger RNAs and DNA methylation2,3, respectively, but the biological functions of the 22-nucleotide siRNAs remain unknown. Here we report the identification and characterization of a group of endogenous 22-nucleotide siRNAs that are generated by the DICER-LIKE 2 (DCL2) protein in plants. When cytoplasmic RNA decay and DCL4 are deficient, the resulting massive accumulation of 22-nucleotide siRNAs causes pleiotropic growth disorders, including severe dwarfism, meristem defects and pigmentation. Notably, two genes that encode nitrate reductases-NIA1 and NIA2-produce nearly half of the 22-nucleotide siRNAs. Production of 22-nucleotide siRNAs triggers the amplification of gene silencing and induces translational repression both gene specifically and globally. Moreover, these 22-nucleotide siRNAs preferentially accumulate upon environmental stress, especially those siRNAs derived from NIA1/2, which act to restrain translation, inhibit plant growth and enhance stress responses. Thus, our research uncovers the unique properties of 22-nucleotide siRNAs, and reveals their importance in plant adaptation to environmental stresses.
Assuntos
Aclimatação/genética , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Biossíntese de Proteínas/genética , RNA de Plantas/genética , RNA Interferente Pequeno/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas Argonautas/metabolismo , Proteínas de Ciclo Celular , Inativação Gênica , Mutação , Nitrato Redutase/genética , Doenças das Plantas/genética , Estabilidade de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/biossíntese , Ribonuclease III/metabolismoRESUMO
Although the role of ethylene in tomato (Solanum lycopersicum) fruit ripening has been intensively studied, its role in tomato fruit growth remains poorly understood. In addition, the relationship between ethylene and the developmental factors NON-RIPENING (NOR) and RIPENING INHIBITOR (RIN) during ripening is under debate. Here, we carried out comprehensive genetic analyses of genome-edited mutants of tomato ETHYLENE INSENSITIVE 2 (SlEIN2), four EIN3-like genes (SlEIL1-4), and three EIN3 BINDING F-box protein genes (SlEBF1-3). Both slein2-1 and the high-order sleil mutant (sleil1 sleil2 sleil3/SlEIL3 sleil4) showed reduced fruit size, mainly due to decreased auxin biosynthesis. During fruit maturation, slein2 mutants displayed the complete cessation of ripening, which was partially rescued by slebf1 but not slebf2 or slebf3. We also discovered that ethylene directly activates the expression of the developmental genes NOR, RIN, and FRUITFULL1 (FUL1) via SlEIL proteins. Indeed, overexpressing these genes partially rescued the ripening defects of slein2-1. Finally, the signal intensity of the ethylene burst during fruit maturation was intimately connected with the progression of full ripeness. Collectively, our work uncovers a critical role of ethylene in fruit growth and supports a molecular framework of ripening control in which the developmental factors NOR, RIN, and FUL1 act downstream of ethylene signaling.
Assuntos
Solanum lycopersicum , Etilenos , Frutas , Regulação da Expressão Gênica de Plantas , Proteínas de PlantasRESUMO
Auxin inactivation is critical for plant growth and development. To develop plant growth regulators functioning in auxin inactivation pathway, we performed a phenotype-based chemical screen in Arabidopsis and identified a chemical, nalacin, that partially mimicked the effects of auxin. Genetic, pharmacological, and biochemical approaches demonstrated that nalacin exerts its auxin-like activities by inhibiting indole-3-acetic acid (IAA) conjugation that is mediated by Gretchen Hagen 3 (GH3) acyl acid amido synthetases. The crystal structure of Arabidopsis GH3.6 in complex with D4 (a derivative of nalacin) together with docking simulation analysis revealed the molecular basis of the inhibition of group II GH3 by nalacin. Sequence alignment analysis indicated broad bioactivities of nalacin and D4 as inhibitors of GH3s in vascular plants, which were confirmed, at least, in tomato and rice. In summary, our work identifies nalacin as a potent inhibitor of IAA conjugation mediated by group II GH3 that plays versatile roles in hormone-regulated plant development and has potential applications in both basic research and agriculture.
Assuntos
Arabidopsis , Ligases , Arabidopsis/genética , Ácidos Indolacéticos/farmacologia , Fenômenos Químicos , Reguladores de Crescimento de Plantas/farmacologia , Testes GenéticosRESUMO
Lung cancer is a major cause of morbidity and mortality. The specific pulmonary structure to directly connect with ambient air makes it more susceptible to damage from airborne toxins. External oxidative stimuli and endogenous reactive oxygen species (ROS) play a crucial role in promoting lung carcinogenesis and development. The biological properties of higher ROS levels in tumor cells than in normal cells make them more sensitive and vulnerable to ROS injury. Therefore, the strategy of targeting ROS has been proposed for cancer therapy for decades. However, it is embarrassing that countless attempts at ROS-based therapies have had very limited success, and no FDA approval in the anticancer list was mechanistically based on ROS manipulation. Even compared with the untargetable proteins, such as transcription factors, ROS are more difficult to be targeted due to their chemical properties. Thus, the pleiotropic roles of ROS provide therapeutic potential for anticancer drug discovery, while a better dissection of the mechanistic action and signaling pathways is a prerequisite for future breakthroughs. This review discusses the critical roles of ROS in cancer carcinogenesis, ROS-inspired signaling pathways, and ROS-based treatment, exemplified by lung cancer. In particular, an eight considerations rule is proposed for ROS-targeting strategies and drug design and development.
Assuntos
Carcinogênese , Neoplasias Pulmonares , Espécies Reativas de Oxigênio , Humanos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Carcinogênese/metabolismo , Animais , Transdução de Sinais , Antineoplásicos/farmacologiaRESUMO
The signaling pathways for the phytohormones ethylene and abscisic acid (ABA) have antagonistic effects on seed germination and early seedling establishment. However, the underlying molecular mechanisms remain unclear. In Arabidopsis thaliana, ETHYLENE INSENSITIVE 2 (EIN2) localizes to the endoplasmic reticulum (ER); although its biochemical function is unknown, it connects the ethylene signal with the key transcription factors EIN3 and EIN3-LIKE 1 (EIL1), leading to the transcriptional activation of ethylene-responsive genes. In this study, we uncovered an EIN3/EIL1-independent role for EIN2 in regulating the ABA response. Epistasis analysis demonstrated that this distinct role of EIN2 in the ABA response depends on HOOKLESS 1 (HLS1), the putative histone acetyltransferase acting as a positive regulator of ABA responses. Protein interaction assays supported a direct physical interaction between EIN2 and HLS1 in vitro and in vivo. Loss of EIN2 function resulted in an alteration of HLS1-mediated histone acetylation at the ABA-INSENSITIVE 3 (ABI3) and ABI5 loci, which promotes gene expression and the ABA response during seed germination and early seedling growth, indicating that the EIN2-HLS1 module contributes to ABA responses. Our study thus revealed that EIN2 modulates ABA responses by repressing HLS1 function, independently of the canonical ethylene pathway. These findings shed light on the intricate regulatory mechanisms underling the antagonistic interactions between ethylene and ABA signaling, with significant implications for our understanding of plant growth and development.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Ácido Abscísico/metabolismo , Plântula/metabolismo , Germinação , Proteínas de Arabidopsis/metabolismo , Etilenos/metabolismo , Regulação da Expressão Gênica de Plantas , Sementes/genética , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismoRESUMO
Scoring functions are important components in molecular docking for structure-based drug discovery. Traditional scoring functions, generally empirical- or force field-based, are robust and have proven to be useful for identifying hits and lead optimizations. Although multiple highly accurate deep learning- or machine learning-based scoring functions have been developed, their direct applications for docking and screening are limited. We describe a novel strategy to develop a reliable protein-ligand scoring function by augmenting the traditional scoring function Vina score using a correction term (OnionNet-SFCT). The correction term is developed based on an AdaBoost random forest model, utilizing multiple layers of contacts formed between protein residues and ligand atoms. In addition to the Vina score, the model considerably enhances the AutoDock Vina prediction abilities for docking and screening tasks based on different benchmarks (such as cross-docking dataset, CASF-2016, DUD-E and DUD-AD). Furthermore, our model could be combined with multiple docking applications to increase pose selection accuracies and screening abilities, indicating its wide usage for structure-based drug discoveries. Furthermore, in a reverse practice, the combined scoring strategy successfully identified multiple known receptors of a plant hormone. To summarize, the results show that the combination of data-driven model (OnionNet-SFCT) and empirical scoring function (Vina score) is a good scoring strategy that could be useful for structure-based drug discoveries and potentially target fishing in future.
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Descoberta de Drogas , Proteínas , Descoberta de Drogas/métodos , Ligantes , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Ligação Proteica , Proteínas/químicaRESUMO
High salinity stress promotes plant ethylene biosynthesis and triggers the ethylene signalling response. However, the precise mechanism underlying how plants transduce ethylene signalling in response to salt stress remains largely unknown. In this study, we discovered that SALT OVERLY SENSITIVE 2 (SOS2) inhibits the kinase activity of CONSTITUTIVE TRIPLE RESPONSE1 (CTR1) by phosphorylating the 87th serine (S87). This phosphorylation event activates the ethylene signalling response, leading to enhanced plant salt resistance. Furthermore, through genetic analysis, we determined that the loss of CTR1 or the gain of SOS2-mediated CTR1 phosphorylation both contribute to improved plant salt tolerance. Additionally, in the sos2 mutant, we observed compromised proteolytic processing of ETHYLENE INSENSITIVE 2 (EIN2) and reduced nuclear localization of EIN2 C-terminal fragments (EIN2-C), which correlate with decreased accumulation of ETHYLENE INSENSITIVE 3 (EIN3). Collectively, our findings unveil the role of the SOS2-CTR1 regulatory module in promoting the activation of the ethylene signalling pathway and enhancing plant salt tolerance.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Etilenos/metabolismo , Plantas/metabolismo , Tolerância ao Sal/fisiologiaRESUMO
During leaf senescence, the final stage of leaf development, nutrients are recycled from leaves to other organs, and therefore proper control of senescence is thus critical for plant fitness. Although substantial progress has been achieved in understanding leaf senescence in annual plants, the molecular factors that control leaf senescence in perennial woody plants are largely unknown. Using RNA sequencing, we obtained a high-resolution temporal profile of gene expression during autumn leaf senescence in poplar (Populus tomentosa). Identification of hub transcription factors (TFs) by co-expression network analysis of genes revealed that senescence-associated NAC family TFs (Sen-NAC TFs) regulate autumn leaf senescence. Age-dependent alternative splicing (AS) caused an intron retention (IR) event in the pre-mRNA encoding PtRD26, a NAC-TF. This produced a truncated protein PtRD26IR, which functions as a dominant-negative regulator of senescence by interacting with multiple hub Sen-NAC TFs, thereby repressing their DNA-binding activities. Functional analysis of senescence-associated splicing factors identified two U2 auxiliary factors that are involved in AS of PtRD26IR. Correspondingly, silencing of these factors decreased PtRD26IR transcript abundance and induced early senescence. We propose that an age-dependent increase of IR splice variants derived from Sen-NAC TFs is a regulatory program to fine tune the molecular mechanisms that regulate leaf senescence in trees.
Assuntos
Processamento Alternativo/genética , Folhas de Planta/genética , Proteínas de Plantas/genética , Populus/genética , Fatores de Transcrição/genética , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Modelos Biológicos , Proteínas de Plantas/metabolismo , Populus/crescimento & desenvolvimento , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estações do Ano , Fatores de Tempo , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Traditional biopsies pose risks and may not accurately reflect soft tissue sarcoma (STS) heterogeneity. MRI provides a noninvasive, comprehensive alternative. PURPOSE: To assess the diagnostic accuracy of histological grading and prognosis in STS patients when integrating clinical-imaging parameters with deep learning (DL) features from preoperative MR images. STUDY TYPE: Retrospective/prospective. POPULATION: 354 pathologically confirmed STS patients (226 low-grade, 128 high-grade) from three hospitals and the Cancer Imaging Archive (TCIA), divided into training (n = 185), external test (n = 125), and TCIA cohorts (n = 44). 12 patients (6 low-grade, 6 high-grade) were enrolled into prospective validation cohort. FIELD STRENGTH/SEQUENCE: 1.5 T and 3.0 T/Unenhanced T1-weighted and fat-suppressed-T2-weighted. ASSESSMENT: DL features were extracted from MR images using a parallel ResNet-18 model to construct DL signature. Clinical-imaging characteristics included age, gender, tumor-node-metastasis stage and MRI semantic features (depth, number, heterogeneity at T1WI/FS-T2WI, necrosis, and peritumoral edema). Logistic regression analysis identified significant risk factors for the clinical model. A DL clinical-imaging signature (DLCS) was constructed by incorporating DL signature with risk factors, evaluated for risk stratification, and assessed for progression-free survival (PFS) in retrospective cohorts, with an average follow-up of 23 ± 22 months. STATISTICAL TESTS: Logistic regression, Cox regression, Kaplan-Meier curves, log-rank test, area under the receiver operating characteristic curve (AUC)ï¼and decision curve analysis. A P-value <0.05 was considered significant. RESULTS: The AUC values for DLCS in the external test, TCIA, and prospective test cohorts (0.834, 0.838, 0.819) were superior to clinical model (0.662, 0.685, 0.694). Decision curve analysis showed that the DLCS model provided greater clinical net benefit over the DL and clinical models. Also, the DLCS model was able to risk-stratify patients and assess PFS. DATA CONCLUSION: The DLCS exhibited strong capabilities in histological grading and prognosis assessment for STS patients, and may have potential to aid in the formulation of personalized treatment plans. TECHNICAL EFFICACY: Stage 2.
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RATIONALE: Myocardial infarction (MI) is one of the most dangerous adverse cardiovascular events. Our previous study found that lysophosphatidic acid (LPA) is increased in human peripheral blood after MI, and LPA has a protective effect on the survival and proliferation of various cell types. However, the role of LPA and its receptors in MI is less understood. OBJECTIVES: To study the unknown role of LPA and its receptors in heart during MI. METHODS AND RESULTS: In this study, we found that mice also had elevated LPA level in peripheral blood, as well as increased cardiac expression of its receptor LPA2 in the early stages after MI. With adult and neonate MI models in global Lpar2 knockout (Lpar2-KO) mice, we found Lpar2 deficiency increased vascular leak leading to disruption of its homeostasis, so as to impaired heart function and increased early mortality. Histological examination revealed larger scar size, increased fibrosis, and reduced vascular density in the heart of Lpar2-KO mice. Furthermore, Lpar2-KO also attenuated blood flow recovery after femoral artery ligation with decreased vascular density in gastrocnemius. Our study revealed that Lpar2 was mainly expressed and altered in cardiac endothelial cells during MI, and use of endothelial-specific Lpar2 knockout mice phenocopied the global knockout mice. Additionally, adenovirus-Lpar2 and pharmacologically activated LPA2 significantly improved heart function, reduced scar size, increased vascular formation, and alleviated early mortality by maintaining vascular homeostasis owing to protecting vessels from leakage. Mechanistic studies demonstrated that LPA-LPA2 signaling could promote endothelial cell proliferation through PI3K-Akt/PLC-Raf1-Erk pathway and enhanced endothelial cell tube formation via PKD1-CD36 signaling. CONCLUSIONS: Our results indicate that endothelial LPA-LPA2 signaling promotes angiogenesis and maintains vascular homeostasis, which is vital for restoring blood flow and repairing tissue function in ischemic injuries. Targeting LPA-LPA2 signal might have clinical therapeutic potential to protect the heart from ischemic injury.
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Infarto do Miocárdio , Receptores de Ácidos Lisofosfatídicos , Animais , Cicatriz , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Homeostase , Humanos , Lisofosfolipídeos , Camundongos , Camundongos Knockout , Infarto do Miocárdio/genética , Fosfatidilinositol 3-Quinases , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Remodelação VentricularRESUMO
Targeting specific molecular drivers of tumor growth is a key approach in cancer therapy. Among these targets, the low-density lipoprotein receptor-related protein 6 (LRP6), a vital component of the Wnt signaling pathway, has emerged as an intriguing candidate. As a cell-surface receptor and vital co-receptor, LRP6 is frequently overexpressed in various cancer types, implicating its pivotal role in driving tumor progression. The pursuit of LRP6 as a target for cancer treatment has gained substantial traction, offering a promising avenue for therapeutic intervention. Here, this comprehensive review explores recent breakthroughs in our understanding of LRP6's functions and underlying molecular mechanisms, providing a profound discussion of its involvement in cancer pathogenesis and drug resistance. Importantly, we go beyond discussing LRP6's role in cancer by discussing diverse potential therapeutic approaches targeting this enigmatic protein. These approaches encompass a wide spectrum, including pharmacological agents, natural compounds, non-coding RNAs, epigenetic factors, proteins, and peptides that modulate LRP6 expression or disrupt its interactions. In addition, also discussed the challenges associated with developing LRP6 inhibitors and their advantages over Wnt inhibitors, as well as the drugs that have entered phase II clinical trials. By shedding light on these innovative strategies, we aim to underscore LRP6's significance as a valuable and multifaceted target for cancer treatment, igniting enthusiasm for further research and facilitating translation into clinical applications.
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Antineoplásicos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Terapia de Alvo Molecular , Neoplasias , Animais , Humanos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
In this research, we utilize porous tantalum, known for its outstanding elastic modulus and biological properties, as a base material in biomedical applications. The human skeletal system is rich in elements like Ca and Zn. The role of Zn is crucial for achieving a spectrum of sterilizing effects, while Ca is known to effectively enhance cell differentiation and boost cellular activity. The focus of this study is the modification of porous tantalum using a hydrothermal method to synthesize Ca2+/Zn2+-doped Ta2O5nanorods. These nanorods are subjected to extensive characterization techniques to confirm their structure and composition. Additionally, their biological performance is evaluated through a range of tests, including antibacterial assessments, MTT assays, and bacteria/cell scanning electron microscopy (SEM) analyses. The objective is to determine the most effective method of surface modification for porous tantalum, thereby laying a foundational theoretical framework for its surface enhancement.
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Antibacterianos , Cálcio , Tantálio , Zinco , Tantálio/química , Antibacterianos/farmacologia , Antibacterianos/química , Zinco/química , Zinco/farmacologia , Cálcio/química , Humanos , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície , Porosidade , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade MicrobianaRESUMO
The gaseous phytohormone ethylene mediates numerous aspects of plant growth and development as well as stress responses. The F-box proteins EIN3-binding F-box protein 1 (EBF1) and EBF2 are key components that ubiquitinate and degrade the master transcription factors ethylene insensitive 3 (EIN3) and EIN3-like 1 (EIL1) in the ethylene response pathway. Notably, EBF1 and EBF2 themselves undergo the 26S proteasome-mediated proteolysis induced by ethylene and other stress signals. However, despite their importance, little is known about the mechanisms regulating the degradation of these proteins. Here, we show that a really interesting new gene (RING)-type E3 ligase, salt- and drought-induced ring finger 1 (SDIR1), positively regulates the ethylene response and promotes the accumulation of EIN3. Further analyses indicate that SDIR1 directly interacts with EBF1/EBF2 and targets them for ubiquitination and proteasome-dependent degradation. We show that SDIR1 is required for the fine tuning of the ethylene response to ambient temperature changes by mediating temperature-induced EBF1/EBF2 degradation and EIN3 accumulation. Thus, our work demonstrates that SDIR1 functions as an important modulator of ethylene signaling in response to ambient temperature changes, thereby enabling plant adaptation under fluctuating environmental conditions.
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Proteínas de Arabidopsis/genética , Arabidopsis/genética , Proteínas de Ligação a DNA/genética , Proteínas F-Box/genética , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Arabidopsis/crescimento & desenvolvimento , Secas , Etilenos/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Reguladores de Crescimento de Plantas/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Complexo de Endopeptidases do Proteassoma/genética , Proteólise , Transdução de Sinais/genética , Temperatura , Ubiquitinação/genéticaRESUMO
The exogenous light signal and endogenous auxin are two critical factors that antagonistically regulate hypocotyl growth. However, the regulatory mechanisms integrating light and auxin signaling pathways need further investigation. In this study, we identified a direct link between the light and auxin signaling pathways mediated by the auxin transcriptional repressor IAA3 and light-controlled PIF transcription factors in Arabidopsis. The gain-of-function mutation in IAA3 caused hyposensitivity to light, whereas disruption of IAA3 led to an elongated hypocotyl under different light intensity conditions, indicating that IAA3 is required in light regulated hypocotyl growth. Genetic studies showed that the function of IAA3 in hypocotyl elongation is dependent on PIFs. Our data further demonstrated that IAA3 interacts with PIFs in vitro and in vivo, and it attenuates the DNA binding activities of PIFs to the target genes. Moreover, IAA3 negatively regulates the expression of PIFs-dependent genes. Collectively, our study reveals an interplay mechanism of light and auxin on the regulation of hypocotyl growth, coordinated by the IAA3 and PIFs transcriptional regulatory module.