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With the development of intelligent vehicle technology, the probability of road traffic accidents occurring has been effectively reduced to a certain extent. However, there is still insufficient research on head injuries in human vehicle collisions, making it impossible to effectively predict pedestrian head injuries in accidents. To study the efficacy of a combined active and passive safety system on pedestrian head protection through the combined effect of the exterior airbag and the braking control systems of an intelligent vehicle, a "vehicle-pedestrian" interaction system is constructed in this study and is verified by real collision cases. On this basis, a combined active and passive system database is developed to analyze the cross-influence of the engine hood airbag and the vehicle braking curve parameters on pedestrian HIC (head injury criterion). Meanwhile, a hierarchy design strategy for a combined active and passive system is proposed, and a rapid prediction of HIC is achieved via the establishment of a fitting equation for each grading. The results show that the exterior airbag can effectively protect the pedestrian's head, prevent the collision between the pedestrian's head and the vehicle front structure, and reduce the HIC. The braking parameter H2 is significantly correlated with head injury, and when H2 is less than 1.8, the HIC value is less than 1000 in nearly 90% of cases. The hierarchy design strategy and HIC prediction method of the combined active and passive system proposed in this paper can provide a theoretical basis for rapid selection and parameter design.
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BACKGROUND: The protein arginine methyltransferase family includes nine members, with PRMT5 being the major type II arginine methyltransferase. PRMT5 is upregulated in a variety of tumors and promotes tumorigenesis and tumor cell proliferation and metastasis, making it a potential tumor therapy target. Recently, PRMT5 inhibitor research and development have become hotspots in the tumor therapy field. METHODS: We classified and summarized PRMT5 inhibitors according to different binding mechanisms. We mainly analyzed the structure, biological activity, and binding interactions of PRMT5 inhibitors with the PRMT5 enzyme. RESULTS: At present, many PRMT5 inhibitors with various mechanisms of action have been reported, including substrate-competitive inhibitors, SAM-competitive inhibitors, dual substrate-/SAMcompetitive inhibitors, allosteric inhibitors, PRMT5 degraders, MTA-cooperative PRMT5 inhibitors and PPI inhibitors. CONCLUSION: These inhibitors are beneficial to the treatment of tumors. Some drugs are being used in clinical trials. PRMT5 inhibitors have broad application prospects in tumor therapy.
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Neoplasias , Proteína-Arginina N-Metiltransferasas , Humanos , Proteína-Arginina N-Metiltransferasas/química , Proteína-Arginina N-Metiltransferasas/metabolismo , Neoplasias/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Línea Celular Tumoral , Arginina/metabolismoRESUMEN
Background: Given the benzimidazole derivatives have anti-ovarian cancer effects, the authors aimed to determine whether benzimidazole-2-substituted pyridine and phenyl propenone derivatives exert anti-ovarian cancer activity. Materials & methods: 21 derivatives were synthesized and assayed for their antiproliferative activities. Western blotting in A2780 cells was used to detect the effects of compound A-6 on apoptosis-related proteins. Invasion, migration and apoptosis were assayed in SKOV3 cells treated with A-6. The in vivo activity was also examined. Results: A-6 could inhibit proliferation, invasion and migration and induce apoptosis in SKOV3 cells. Additionally, A-6 had potent inhibitory activity in a xenograft mouse model. Conclusion: A-6 shows potent efficacy in the treatment of ovarian cancer and may be a potential antitumor agent.
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Antineoplásicos , Neoplasias Ováricas , Humanos , Animales , Ratones , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Bencimidazoles/farmacología , Piridinas/farmacología , Piridinas/uso terapéutico , Proliferación CelularRESUMEN
In higher plants, the structure of a flower is precisely controlled by a series of genes. An aberrance flower results in abnormal fruit morphology. Previously, we reported multi-silique rapeseed (Brassica napus) line zws-ms. We identified two associated regions and investigated differentially expressed genes (DEGs); thus, some candidate genes underlying the multi-silique phenotype in warm area Xindu were selected. However, this phenotype was switched off by lower temperature, and the responsive genes, known as thermomorphogenesis-related genes, remained elusive. So, based on that, in this study, we further investigated the transcriptome data from buds of zws-ms and its near-isogenic line zws-217 grown in colder area Ma'erkang, where both lines showed normal siliques only, and the DEGs between them analyzed. We compared the 129 DEGs from Xindu to the 117 ones from Ma'erkang and found that 33 of them represented the same or similar expression trends, whereas the other 96 DEGs showed different expression trends, which were defined as environment-specific. Furthermore, we combined this with the gene annotations and ortholog information and then selected BnaA09g45320D (chaperonin gene CPN10-homologous) and BnaC08g41780D [Seryl-tRNA synthetase gene OVULE ABORTION 7 (OVA7)-homologous] the possible thermomorphogenesis-related genes, which probably switched off the multi-silique under lower temperature. This study paves a way to a new perspective into flower/fruit development in Brassica plants.
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Focal adhesion kinase (FAK) is responsible for the development and progression of various malignancies. With the aim to explore novel FAK inhibitors as anticancer agents, a series of 2,4-dianilinopyrimidine derivatives 8a-8i and 9a-9g containing 4-(morpholinomethyl)phenyl and N-substituted benzamides have been designed and synthesized. Among them, compound 8a displayed potent anti-FAK activity (IC50 = 0.047 ± 0.006 µM) and selective antiproliferative effects against H1975 (IC50 = 0.044 ± 0.011 µM) and A431 cells (IC50 = 0.119 ± 0.036 µM). Furthermore, compound 8a also induced apoptosis in a dose-dependent manner, arresting the cells in S/G2 phase and inhibiting the migration of H1975 cells, all of which were superior to those of TAE226. The docking analysis of compound 8a was performed to elucidate its possible binding modes with FAK. These results established 8a as our lead compound to be further investigated as a potential FAK inhibitor and anticancer agent.
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Benzamidas/farmacología , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Fenoles/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzamidas/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Proteína-Tirosina Quinasas de Adhesión Focal/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Morfolinas/farmacología , Neoplasias/tratamiento farmacológico , Fenoles/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Novel peptidic glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have increased efficacy over GLP-1R monoagonists for the treatment of diabetes and obesity. We identified a novel Xenopus GLP-1-based dual GLP-1R/GCGR agonist (xGLP/GCG-13) designed with a proper activity ratio favoring the GLP-1R versus the GCGR. However, the clinical utility of xGLP/GCG-13 is limited by its short in vivo half-life. Starting from xGLP/GCG-13, dual Cys mutation was performed, followed by covalent side-chain stapling and serum albumin binder incorporation, resulting in a stabilized secondary structure, enhanced agonist potency at GLP-1R and GCGR, and improved stability. The lead peptide 2c (stapled xGLP/GCG-13 analogue with a palmitic acid albumin binder) exhibits balanced GLP-1R and GCGR activations and potent, long-lasting effects on in vivo glucose control. 2c was further explored pharmacologically in diet-induced obesity and db/db rodent models. Chronic administration of 2c potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, increased energy expenditure, and normalized lipid metabolism and adiposity in relevant animal models. These results indicated that 2c has potential for development as a novel antidiabetic and/or antiobesity drug. Furthermore, we propose that the incorporation of a proper serum protein-binding motif into a di-Cys staple is an effective method for improving the stabilities and bioactivities of peptides. This approach is likely applicable to other therapeutic peptides, such as glucose-dependent insulin-tropic peptide receptor (GIPR) and GLP-1R dual agonists or GLP-1R/GCGR/GIPR triagonists.
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Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/administración & dosificación , Receptor del Péptido 1 Similar al Glucagón/agonistas , Obesidad/tratamiento farmacológico , Péptidos/administración & dosificación , Receptores de Glucagón/agonistas , Animales , Células CHO , Cricetulus , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Obesidad/etiología , Obesidad/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Glucagón/metabolismo , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacos , XenopusRESUMEN
In recent years, metal coordination macrocycles have obtained great interests due to the fact that they combined the rich host-guest properties of macro-cyclic hosts and the unique optical properties of the organic ligands. In this work, we constructed two porphyrin-based organoplatinum(II) metallacycles (MC1 and MC2) through coordination-driven self-assembly. 1H NMR, 31P NMR, and HRMS technologies were used to characterize the structures of MC1 and MC2. Interestingly, MC1 and MC2 can be used as catalysts for photooxidization under light irradiation with higher efficiency compared with the porphyrin ligand only. We hope that the coordination-driven self-assembly strategy can provide an efficient method to construct photo-active materials.
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A series of benzimidazole-derived chalcones containing aromatic amide substituent were designed and synthesized. All of the chalcone compounds were tested for their in vitro antitumor activity against human cancer cell lines (HCT116, HepG2, A549, and CRL-5908). The antiproliferative activity of compounds 3, 6, 9, 14, 15, 16 against HCT116 cells was significantly better than that that of 5-Fluorouracil (IC50: 94.63 µM). The antitumor activity of these compounds showed obvious differences between the wild type HCT116 and mutant HCT116 (TP53-/-) cells. A preliminary mechanistic study suggested that these compounds act by upregulating the expression of TP53 protein in tumor cells without inhibiting the MDM2-TP53 interaction.
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Amidas/química , Bencimidazoles/química , Chalconas/química , Chalconas/farmacología , Técnicas de Química Sintética , Diseño de Fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Chalconas/síntesis química , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica , Humanos , Estructura Molecular , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: The third-generation irreversible Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) inhibit the T790M mutation while sparing EGFRWT. However, the C797S point mutation confers resistance to existing irreversible EGFRT790M inhibitors. OBJECTIVE: Novel EGFRT790M inhibitors were designed through hybridization of quinoline and anilinopyrimidine, and biologically evaluated their antiproliferative activity against Non-Small Cell Lung Cancer (NSCLC) cell lines. METHODS: The target compounds 11a-h were synthesized and structurally characterized with 1H, 13C Nuclear Magnetic Resonance (NMR) spectroscopy and High-Resolution Mass Spectrometry (HRMS). Their inhibitory effects on tumor cell proliferation and EGFR kinase were biologically evaluated. Additionally, molecular docking studies were also performed on the representative typical EGFRT790M inhibitor. RESULTS: Most of the evaluated compounds displayed moderate antiproliferative activity on H1975 cells with EGFRL858R/T790M. However, compound 11a (IC50 = 2.235 ± 0.565µM) showed stronger inhibition than gefitinib (IC50 = 8.830 ± 0.495µM) in concentration- and time-dependent manner. Moreover, compound 11a exhibited weaker inhibitory activities on cells with EGFRWT. Specifically, compound 11a strongly suppressed EGFRL858R/T790M (IC50 = 0.515 ± 0.011µM) relative to EGFRWT (IC50 = 0.913 ± 0.068µM). Furthermore, molecular docking studies demonstrated its strong binding contacts with the EGFRT790M enzyme through hydrogen bonds and other non-bonded interactions. CONCLUSION: Taken together, these results indicate that the hybrid of quinoline and anilinopyrimidine 11a, could be a potential inhibitor of EGFRT790M in NSCLC, which warrants further in-depth studies.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Pirimidinas/farmacología , Quinazolinas/farmacología , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Simulación del Acoplamiento Molecular , Mutación Puntual/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Quinazolinas/químicaRESUMEN
Leaf is an important organ for higher plants, and the shape of it is one of the crucial traits of crops. In this study, we investigated a unique aberrant leaf morphology trait in a mutational rapeseed material, which displayed ectopic blade-like outgrowths on the adaxial side of leaf. The abnormal line 132000B-3 was crossed with the normal line 827-3. Based on the F2 : 3 family, we constructed two DNA pools (normal pool and abnormal pool) by the bulked segregant analysis (BSA) method and performed whole genome re-sequencing (WGR), obtaining the single-nucleotide polymorphism (SNP) and insertion/deletion (InDel) data. The SNP-index method was used to calculate the Δ(SNP/InDel-index), and then an association region was identified on chromosome A10 with a length of 5.5 Mbp, harboring 1048 genes totally. Subsequently, the fine mapping was conducted by using the penta-primer amplification refractory mutation system (PARMS), and the associated region was narrowed down to a 35.1-kbp segment, containing only seven genes. These seven genes were then analyzed according to their annotations and finally, BnA10g0422620 and BnA10g0422610, orthologs of LATE MERISTEM IDENTITY1 (LMI1) gene from Arabidopsis and REDUCED COMPLEXITY (RCO) gene from its relative Cardamine hirsuta, respectively, were identified as the candidate genes responding to this blade-like outgrowth trait in rapeseed. This study provides a novel perspective into the leaf formation in Brassica plants.
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Abscisic acid (ABA) is a vital phytohormone that accumulates in response to various biotic and abiotic stresses, as well as plant growth. In Arabidopsis thaliana, there are 14 members of the ABA receptor family, which are key positive regulators involved in ABA signaling. Besides reduced drought stress tolerance, the quadruple and sextuple mutants (pyr1pyl1pyl2pyl4 (1124) and pyr1pyl1pyl2pyl4pyl5pyl8 (112458) show abnormal growth phenotypes, such as decreases in yield and height, under non-stress conditions. However, it remains unknown whether ABA receptors mediate ABA signaling to regulate plant growth and development. Here, we showed the primary metabolite profiles of 1124, 112458 and wild-type (WT) plants grown under normal conditions. The metabolic changes were significantly different between ABA receptor mutants and WT. Guanosine, for the biosynthesis of cyclic guanosine 3',5'-monophosphate (cGMP), is an important second messenger that acts to regulate the level of ABA. In addition, other amino acids were increased in the 112458 mutant, including proline. These results, together with phenotype analysis, indicated that ABA receptors are involved in ABA signaling to modulate metabolism and plant growth under normal conditions.
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MAIN CONCLUSION: The 5-leaf-stage rape seedlings were more insensitive to Pi starvation than that of the 3-leaf-stage plants, which may be attributed to the higher expression levels of ethylene signaling and sugar-metabolism genes in more mature seedlings. Traditional suppression subtractive hybridization (SSH) and RNA-Seq usually screen out thousands of differentially expressed genes. However, identification of the most important regulators has not been performed to date. Here, we employed two methods, namely, a two-round SSH and two-factor transcriptome analysis derived from the two-factor ANOVA that is commonly used in the statistics, to identify development-associated inorganic phosphate (Pi) starvation-induced genes in Brassica napus. Several of these genes are related to ethylene signaling (such as EIN3, ACO3, ACS8, ERF1A, and ERF2) or sugar metabolism (such as ACC2, GH3, LHCB1.4, XTH4, and SUS2). Although sucrose and ethylene may counteract each other at the biosynthetic level, they may also work synergistically on Pi-starvation-induced gene expression (such as PT1, PT2, RNS1, ACP5, AT4, and IPS1) and root acid phosphatase activation. Furthermore, three new transcription factors that are responsive to Pi starvation were identified: the zinc-finger MYND domain-containing protein 15 (MYND), a Magonashi family protein (MAGO), and a B-box zinc-finger family salt-tolerance protein. This study indicates that the two methods are highly efficient for functional gene screening in non-model organisms.
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Brassica napus/genética , Regulación de la Expresión Génica de las Plantas , Fosfatos/deficiencia , Transducción de Señal , Factores de Transcripción/genética , Transcriptoma , Análisis de Varianza , Brassica napus/crecimiento & desarrollo , Brassica napus/fisiología , Etilenos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Fosfatos/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Hojas de la Planta/genética , Hojas de la Planta/crecimiento & desarrollo , Hojas de la Planta/fisiología , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Análisis de Secuencia de ARN , Técnicas de Hibridación Sustractiva , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Although rapeseed (Brassica napus L.) mutant forming multiple siliques was morphologically described and considered to increase the silique number per plant, an important agronomic trait in this crop, the molecular mechanism underlying this beneficial trait remains unclear. Here, we combined bulked-segregant analysis (BSA) and whole genome re-sequencing (WGR) to map the genomic regions responsible for the multi-silique trait using two pools of DNA from the near-isogenic lines (NILs) zws-ms (multi-silique) and zws-217 (single-silique). We used the Euclidean Distance (ED) to identify genomic regions associated with this trait based on both SNPs and InDels. We also conducted transcriptome sequencing to identify differentially expressed genes (DEGs) between zws-ms and zws-217. RESULTS: Genetic analysis using the ED algorithm identified three SNP- and two InDel-associated regions for the multi-silique trait. Two highly overlapped parts of the SNP- and InDel-associated regions were identified as important intersecting regions, which are located on chromosomes A09 and C08, respectively, including 2044 genes in 10.20-MB length totally. Transcriptome sequencing revealed 129 DEGs between zws-ms and zws-217 in buds, including 39 DEGs located in the two abovementioned associated regions. We identified candidate genes involved in multi-silique formation in rapeseed based on the results of functional annotation. CONCLUSIONS: This study identified the genomic regions and candidate genes related to the multi-silique trait in rapeseed.
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Brassica napus/genética , Genómica , Sitios de Carácter Cuantitativo/genética , Perfilación de la Expresión Génica , Mutación INDEL , Anotación de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Homología de Secuencia de Ácido NucleicoRESUMEN
Decreasing saturated fatty acids and increasing monounsaturated fatty acids are desirable to improve oil for food. Seed oil content and fatty acid composition are affected by genotype and environment. Therefore, we systematically analyzed the agronomic traits and fatty acid metabolic profiling of Brassica napus (B. napus) seeds at different developmental stages in high level of oleic acid (HOA), medium level of oleic acid (MOA), and low level of oleic acid (LOA) B. napus cultivars, both sown in winter and summer. The results showed that all winter-sown cultivars produced 20% more seed yield than the summer-sown crop. The longer growing period of winter-sown B. napus resulted in higher biomass production. However, the fatty acid metabolism of individual cultivars was different between winter-sown rape (WAT) and summer-sown rape (SAT). The absolute fatty acid content of LOA and MOA cultivars in WAT were significantly higher than that in SAT, but that of HOA was opposite. Importantly, the levels of monounsaturated fatty acids (18:1; 20:1) in SAT were far more than those in WAT. These data indicate the quality of oil from the HOA in SAT is more suitable for human consumption than that in WAT.
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BACKGROUND: Autotaxin-LPA signaling has been implicated in cancer progression, and targeted for the discovery of cancer therapeutic agents. OBJECTIVE: Potential ATX inhibitors were synthesized to develop novel leading compounds and effective anticancer agents. METHODS: The present work designs and synthesizes a series of 2,7-subsitituted carbazole derivatives with different terminal groups R [R = -Cl (I), -COOH (II), -B(OH)2 (III), or -PO(OH)2 (I-IV)]. The inhibition of these compounds on the enzymatic activity of ATX was measured using FS-3 and Bis-pNpp as substrates, and the cytotoxicity of these compounds was evaluated using SW620, SW480, PANC-1, and SKOV-3 human carcinoma cells. Furthermore, the binding of leading compound with ATX was analyzed by molecular docking. RESULTS: Compound III was shown to be a promising antitumor candidate by demonstrating both good inhibition of ATX enzymatic activity and high cytotoxicity against human cancer cell lines. Molecular docking study shows that compound III is located in a pocket, which mainly comprises amino acids 209 to 316 in domain 2 of ATX, and binds with these residues of ATX through van der Waals, conventional hydrogen bonds, and hydrophobic interactions. CONCLUSION: Compound III with the terminal group R = -B(OH)2 has the most potent inhibitory effect with the greatest cytotoxicity to cancer cells. Moreover, the docking model provides a structural basis for the future optimization of promising antitumor compounds.
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Antineoplásicos/farmacología , Carbazoles/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Carbazoles/síntesis química , Carbazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Femenino , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Plants constantly suffer from simultaneous infection by multiple pathogens, which can be divided into biotrophic, hemibiotrophic, and necrotrophic pathogens, according to their lifestyles. Many studies have contributed to improving our knowledge of how plants can defend against pathogens, involving different layers of defense mechanisms. In this sense, the review discusses: (1) the functions of PAMP (pathogen-associated molecular pattern)-triggered immunity (PTI) and effector-triggered immunity (ETI), (2) evidence highlighting the functions of salicylic acid (SA) and jasmonic acid (JA)/ethylene (ET)-mediated signaling pathways downstream of PTI and ETI, and (3) other defense aspects, including many novel small molecules that are involved in defense and phenomena, including systemic acquired resistance (SAR) and priming. In particular, we mainly focus on SA and (JA)/ET-mediated signaling pathways. Interactions among them, including synergistic effects and antagonistic effects, are intensively explored. This might be critical to understanding dynamic disease regulation.
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Nitric oxide (NO) has a general inhibitory effects on chlorophyll biosynthesis, especially to the step of 5-aminolevulinic acid (ALA) biosynthesis and protochlorophyllide (Pchlide) to chlorophyllide (Chlide) conversion (responsible by the NADPH:Pchlide oxidoreductase POR). Previous study suggested that barley large POR aggregates may be generated by dithiol oxidation of cysteines of two POR monomers, which can be disconnected by some reducing agents. POR aggregate assembly may be correlated with seedling greening in barley, but not in Arabidopsis. Thus, NO may affect POR activity and seedling greening differently between Arabidopsis and barley. We proved this assumption by non-denaturing gel-analysis and reactive oxygen species (ROS) monitoring during the greening. NO treatments cause S-nitrosylation to POR cysteine residues and disassembly of POR aggregates. This modification reduces POR activity and induces Pchlide accumulation and singlet oxygen generation upon dark-to-high-light shift (and therefore inducing photobleaching lesions) in barley leaf apex, but not in Arabidopsis seedlings. ROS staining and ROS-related-gene expression detection confirmed that superoxide anion and singlet oxygen accumulated in barley etiolated seedlings after the NO treatments, when exposed to a fluctuating light. The data suggest that POR aggregate assembly may be correlated with barley chlorophyll biosynthesis and redox homeostasis during greening. Cysteine S-nitrosylation may be one of the key reasons for the NO-induced inhibition to chlorophyll biosynthetic enzymes.
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Arabidopsis/metabolismo , Clorofilidas/biosíntesis , Hordeum/metabolismo , Óxido Nítrico/metabolismo , Oxígeno Singlete/metabolismoRESUMEN
Ubiquitin-mediated protein degradation plays a crucial role in enabling plants to effectively and efficiently cope with environmental stresses. The E3 ligases have emerged as a central component of the ubiquitination pathway and modulate plant response to abiotic stresses. However, few such studies have been reported in maize. In this study, a C3HC4-type RING finger E3 ligase in maize, ZmAIRP4 (Zea mays Abscisic acid [ABA]-Insensitive RING Protein 4), which is an ortholog of AtAIRP4, was isolated by reverse transcription polymerase chain reaction with specific primers, and its functions in tolerance to drought stress were described. ZmAIRP4 was upregulated by ABA, polyethylene glycol and sodium chloride. In vitro ubiquitination assays and subcellular localization indicated that ZmAIRP4 was an active E3 ligase predominantly localized in the cytoplasm and nucleus. Compared to wild type, ZmAIRP4-overexpressing Arabidopsis plants were hypersensitive to ABA during early seedling development, and showed enhanced drought tolerance. Moreover, the transcript levels of several drought-related downstream genes in transgenic plants were dramatically increased compared with wild type plants. Our results suggested that E3 ligase ZmAIRP4 is a positive regulator in the drought tolerance response pathway.
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Arabidopsis , Proteínas de Plantas , Plantas Modificadas Genéticamente , Ubiquitina-Proteína Ligasas , Zea mays/genética , Arabidopsis/enzimología , Arabidopsis/genética , Deshidratación/enzimología , Deshidratación/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/enzimología , Plantas Modificadas Genéticamente/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Zea mays/enzimologíaRESUMEN
A series of novel benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives were designed and synthesized. The biological activities of these derivatives were then evaluated as potential antitumour agents. These compounds were assayed for growth-inhibitory activity against HCT116, MCF-7 and HepG2 cell lines in vitro. The IC50 values of compounds A1 and A7 against the cancer cells were 0.06-3.64 µM and 0.04-9.80 µM, respectively. Their antiproliferative activities were significantly better than that of 5-Fluorouracil (IC50: 56.96-174.50 µM) and were close to that of Paclitaxel (IC50: 0.026-1.53 µM). The activity of these derivatives was over 100 times more effective than other reported structures of chalcone analogues (licochalcone A). A preliminary mechanistic study suggested that these compounds inhibit p53-MDM2 binding. Compounds A1, A7 and A9 effectively inhibited tumour growth in BALB/c mice with colon carcinoma HCT116 cells. The group administered 200 mg/kg of compound A7 showed a 74.6% tumour growth inhibition with no signs of toxicity at high doses that was similar to the inhibition achieved with the 12.5 mg/kg irinotecan positive control (70.2%). Therefore, this class of benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives represents a promising lead structure for the development of possible p53-MDM2 inhibitors as new antitumour agents.
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Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Diseño de Fármacos , Etilenos/farmacología , Cetonas/farmacología , Animales , Antineoplásicos/síntesis química , Bencimidazoles/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Etilenos/síntesis química , Etilenos/química , Células HCT116 , Células Hep G2 , Humanos , Cetonas/síntesis química , Cetonas/química , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Relación Estructura-ActividadRESUMEN
Supramolecular polymer networks, assembled via the combination of orthogonal terpyridine-Zn(2+), carbene-Ag(+), and pillar[10]arene/alkyl chain recognition motifs, exhibit dynamic properties responsive to various external stimuli.