RESUMO
Species of the tribe Delphinieae (Ranunculaceae) have long been the focus of morphological, ecological, and evolutionary studies due to their highly specialized, nearly zygomorphic (bilaterally symmetrical) spiral flowers with nested petal and sepal spurs and reduced petals. The mechanisms underlying the development and evolution of Delphinieae flowers, however, remain unclear. Here, by conducting extensive phylogenetic, comparative transcriptomic, expression, and functional studies, we clarified the evolutionary histories, expression patterns, and functions of floral organ identity and symmetry genes in Delphinieae. We found that duplication and/or diversification of APETALA3-3 (AP3-3), AGAMOUS-LIKE6 (AGL6), CYCLOIDEA (CYC), and DIVARICATA (DIV) lineage genes was tightly associated with the origination of Delphinieae flowers. Specifically, an AGL6-lineage member (such as the Delphinium ajacis AGL6-1a) represses sepal spur formation and petal development in the lateral and ventral parts of the flower while determining petal identity redundantly with AGL6-1b. By contrast, two CYC2-like genes, CYC2b and CYC2a, define the dorsal and lateral-ventral identities of the flower, respectively, and form complex regulatory links with AP3-3, AGL6-1a, and DIV1. Therefore, duplication and diversification of floral symmetry genes, as well as co-option of the duplicated copies into the preexisting floral regulatory network, have been key for the origin of Delphinieae flowers.
Assuntos
Flores , Duplicação Gênica , Ranunculaceae , Flores/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/genética , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ranunculaceae/genéticaRESUMO
BACKGROUND: GPCRs (G-protein-coupled receptors) play a central role in the regulation of smooth muscle cell (SMC) contractility, but the function of SMC-expressed orphan GPCR class C group 5 member C (GPRC5C) is unclear. The aim of this project is to define the role of GPRC5C in SMC in vitro and in vivo. METHODS: We studied the role of GPRC5C in the regulation of SMC contractility and differentiation in human and murine SMC in vitro, as well as in tamoxifen-inducible, SMC-specific GPRC5C knockout mice under basal conditions and in vascular disease in vivo. RESULTS: Mesenteric arteries from tamoxifen-inducible, SMC-specific GPRC5C knockout mice showed ex vivo significantly reduced angiotensin II (Ang II)-dependent calcium mobilization and contraction, whereas responses to other relaxant or contractile factors were normal. In vitro, the knockdown of GPRC5C in human aortic SMC resulted in diminished Ang II-dependent inositol phosphate production and lower myosin light chain phosphorylation. In line with this, tamoxifen-inducible, SMC-specific GPRC5C knockout mice showed reduced Ang II-induced arterial hypertension, and acute inactivation of GPRC5C was able to ameliorate established arterial hypertension. Mechanistically, we show that GPRC5C and the Ang II receptor AT1 dimerize, and knockdown of GPRC5C resulted in reduced binding of Ang II to AT1 receptors in HEK293 cells, human and murine SMC, and arteries from tamoxifen-inducible, SMC-specific GPRC5C knockout mice. CONCLUSIONS: Our data show that GPRC5C regulates Ang II-dependent vascular contraction by facilitating AT1 receptor-ligand binding and signaling.
Assuntos
Angiotensina II , Músculo Liso Vascular , Receptores Acoplados a Proteínas G , Animais , Humanos , Masculino , Camundongos , Angiotensina II/farmacologia , Células Cultivadas , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertensão/induzido quimicamente , Hipertensão/genética , Artérias Mesentéricas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Muscular , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , VasoconstriçãoRESUMO
Polyploidy is recurrent across the tree of life and known as an evolutionary driving force in plant diversification and crop domestication. How polyploid plants adapt to various habitats has been a fundamental question that remained largely unanswered. Brassica napus is a major crop cultivated worldwide, resulting from allopolyploidy between unknown accessions of diploid B. rapa and B. oleracea. Here, we used whole-genome resequencing data of accessions representing the majority of morphotypes and ecotypes from the species B. rapa, B. oleracea, and B. napus to investigate the role of polyploidy during domestication. To do so, we first reconstructed the phylogenetic history of B. napus, which supported the hypothesis that the emergence of B. napus derived from the hybridization of European turnip of B. rapa and wild B. oleracea. These analyses also showed that morphotypes of swede and Siberian kale (used as vegetable and fodder) were domesticated before rapeseed (oil crop). We next observed that frequent interploidy introgressions from sympatric diploids were prominent throughout the domestication history of B. napus. Introgressed genomic regions were shown to increase the overall genetic diversity and tend to be localized in regions of high recombination. We detected numerous candidate adaptive introgressed regions and found evidence that some of the genes in these regions contributed to phenotypic diversification and adaptation of different morphotypes. Overall, our results shed light on the origin and domestication of B. napus and demonstrate interploidy introgression as an important mechanism that fuels rapid diversification in polyploid species.
Assuntos
Brassica napus , Gastrópodes , Animais , Brassica napus/genética , Domesticação , Filogenia , Ração Animal , PoliploidiaRESUMO
The Brassicaceae Database (BRAD version 3.0, BRAD V3.0; http://brassicadb.cn) has evolved from the former Brassica Database (BRAD V2.0), and represents an important community portal hosting genome information for multiple Brassica and related Brassicaceae plant species. Since the last update in 2015, the complex genomes of numerous Brassicaceae species have been decoded, accompanied by many omics datasets. To provide an up-to-date service, we report here a major upgrade of the portal. The Model-View-ViewModel (MVVM) framework of BRAD has been re-engineered to enable easy and sustainable maintenance of the database. The collection of genomes has been increased to 26 species, along with optimization of the user interface. Features of the previous version have been retained, with additional new tools for exploring syntenic genes, gene expression and variation data. In the 'Syntenic Gene @ Subgenome' module, we added features to view the sequence alignment and phylogenetic relationships of syntenic genes. New modules include 'MicroSynteny' for viewing synteny of selected fragment pairs, and 'Polymorph' for retrieval of variation data. The updated BRAD provides a substantial expansion of genomic data and a comprehensive improvement of the service available to the Brassicaceae research community.
Assuntos
Brassicaceae/classificação , Bases de Dados Genéticas , Genômica , Brassicaceae/genética , Genoma de Planta/genética , Filogenia , Sintenia/genéticaRESUMO
BACKGROUND: The behaviors and ontogeny of Aedes aegypti are closely related to the spread of diseases caused by dengue (DENV), chikungunya (CHIKV), Zika (ZIKV), and yellow fever (YFV) viruses. During the life cycle, Ae. aegypti undergoes drastic morphological, metabolic, and functional changes triggered by gene regulation and other molecular mechanisms. Some essential regulatory factors that regulate insect ontogeny have been revealed in other species, but their roles are still poorly investigated in the mosquito. RESULTS: Our study identified 6 gene modules and their intramodular hub genes that were highly associated with the ontogeny of Ae. aegypti in the constructed network. Those modules were found to be enriched in functional roles related to cuticle development, ATP generation, digestion, immunity, pupation control, lectins, and spermatogenesis. Additionally, digestion-related pathways were activated in the larvae and adult females but suppressed in the pupae. The integrated proteinâprotein network also identified cilium-related genes. In addition, we verified that the 6 intramodular hub genes encoding proteins such as EcKinase regulating larval molt were only expressed in the larval stage. Quantitative RTâPCR of the intramodular hub genes gave similar results as the RNA-Seq expression profile, and most hub genes were ontogeny-specifically expressed. CONCLUSIONS: The constructed gene coexpression network provides a useful resource for network-based data mining to identify candidate genes for functional studies. Ultimately, these findings will be key in identifying potential molecular targets for disease control.
Assuntos
Aedes , Dengue , Febre Amarela , Infecção por Zika virus , Zika virus , Masculino , Animais , Feminino , Febre Amarela/genética , Zika virus/genética , Redes Reguladoras de Genes , Mosquitos Vetores , Proteínas/genética , LarvaRESUMO
Genetic recombination plays a critical role in the emergence of pathogens with phenotypes such as drug resistance, virulence, and host adaptation. Here, we tested the hypothesis that recombination between sympatric ancestral populations leads to the emergence of divergent variants of the zoonotic parasite Cryptosporidium parvum with modified host ranges. Comparative genomic analyses of 101 isolates have identified seven subpopulations isolated by distance. They appear to be descendants of two ancestral populations, IIa in northwestern Europe and IId from southwestern Asia. Sympatric recombination in areas with both ancestral subtypes and subsequent selective sweeps have led to the emergence of new subpopulations with mosaic genomes and modified host preference. Subtelomeric genes could be involved in the adaptive selection of subpopulations, while copy number variations of genes encoding invasion-associated proteins are potentially associated with modified host ranges. These observations reveal ancestral origins of zoonotic C. parvum and suggest that pathogen import through modern animal farming might promote the emergence of divergent subpopulations of C. parvum with modified host preference.
Assuntos
Criptosporidiose , Cryptosporidium parvum , Cryptosporidium , Animais , Criptosporidiose/parasitologia , Cryptosporidium/genética , Cryptosporidium parvum/genética , Variações do Número de Cópias de DNA , Recombinação GenéticaRESUMO
BACKGROUND: Alternative splicing (AS) is a co-transcriptional regulatory mechanism of plants in response to environmental stress. However, the role of AS in biotic and abiotic stress responses remains largely unknown. To speed up our understanding of plant AS patterns under different stress responses, development of informative and comprehensive plant AS databases is highly demanded. DESCRIPTION: In this study, we first collected 3,255 RNA-seq data under biotic and abiotic stresses from two important model plants (Arabidopsis and rice). Then, we conducted AS event detection and gene expression analysis, and established a user-friendly plant AS database termed PlaASDB. By using representative samples from this highly integrated database resource, we compared AS patterns between Arabidopsis and rice under abiotic and biotic stresses, and further investigated the corresponding difference between AS and gene expression. Specifically, we found that differentially spliced genes (DSGs) and differentially expressed genes (DEG) share very limited overlapping under all kinds of stresses, suggesting that gene expression regulation and AS seemed to play independent roles in response to stresses. Compared with gene expression, Arabidopsis and rice were more inclined to have conserved AS patterns under stress conditions. CONCLUSION: PlaASDB is a comprehensive plant-specific AS database that mainly integrates the AS and gene expression data of Arabidopsis and rice in stress response. Through large-scale comparative analyses, the global landscape of AS events in Arabidopsis and rice was observed. We believe that PlaASDB could help researchers understand the regulatory mechanisms of AS in plants under stresses more conveniently. PlaASDB is freely accessible at http://zzdlab.com/PlaASDB/ASDB/index.html .
Assuntos
Arabidopsis , Oryza , Processamento Alternativo , Arabidopsis/metabolismo , Plantas/genética , Perfilação da Expressão Gênica , Estresse Fisiológico/genética , Regulação da Expressão Gênica de Plantas , Oryza/metabolismo , Proteínas de Plantas/genéticaRESUMO
Two new 1,10-seco-eudesmanolides (1 and 2) were isolated from the flowers of Inula japonica together with two eudesmanolide analogs (3 and 4) and two monoterpene derivatives (5 and 6). Their structures were established on the basis of detailed spectroscopic analyses and electronic circular dichroism data. All isolates were evaluated for their antiproliferative activities against human hepatocarcinoma HepG2 and SMMC-7721 cells. Japonipene B (3) exhibited the most potent effect with the IC50 values of 14.60±1.62 and 22.06±1.34â µM against HepG2 and SMMC-7721 cells, respectively. Furthermore, japonipene B (3) showed significant efficacies of arresting the cell cycle at the S/G2-M stages, inducing mitochondria-mediated apoptosis, and inhibiting cell migration in HepG2 cells.
Assuntos
Antineoplásicos , Inula , Humanos , Inula/química , Terpenos/farmacologia , Terpenos/análise , Estrutura Molecular , Flores/químicaRESUMO
Alternative splicing (AS) is an essential co-transcriptional regulatory mechanism in eukaryotes. The accumulation of plant RNA-Seq data provides an unprecedented opportunity to investigate the global landscape of plant AS events. However, most existing AS identification tools were originally designed for animals, and their performance in plants was not rigorously benchmarked. In this work, we developed a simple and easy-to-use bioinformatics tool named ASTool for detecting AS events from plant RNA-Seq data. As an exon-based method, ASTool can detect 4 major AS types, including intron retention (IR), exon skipping (ES), alternative 5' splice sites (A5SS), and alternative 3' splice sites (A3SS). Compared with existing tools, ASTool revealed a favorable performance when tested in simulated RNA-Seq data, with both recall and precision values exceeding 95% in most cases. Moreover, ASTool also showed a competitive computational speed and consistent detection results with existing tools when tested in simulated or real plant RNA-Seq data. Considering that IR is the most predominant AS type in plants, ASTool allowed the detection and visualization of novel IR events based on known splice sites. To fully present the functionality of ASTool, we also provided an application example of ASTool in processing real RNA-Seq data of Arabidopsis in response to heat stress.
Assuntos
Processamento Alternativo , Arabidopsis , Animais , Arabidopsis/genética , Biologia Computacional/métodos , Sítios de Splice de RNA , RNA de Plantas/genética , RNA-Seq , Análise de Sequência de RNA/métodosRESUMO
BACKGROUND: Protein-protein interactions (PPIs) play very important roles in diverse biological processes. Experimentally validated or predicted PPI data have become increasingly available in diverse plant species. To further explore the biological functions of PPIs, understanding the interaction details of plant PPIs (e.g., the 3D structural contexts of interaction sites) is necessary. By integrating bioinformatics algorithms, interaction details can be annotated at different levels and then compiled into user-friendly databases. In our previous study, we developed AraPPISite, which aimed to provide interaction site information for PPIs in the model plant Arabidopsis thaliana. Considering that the application of AraPPISite is limited to one species, it is very natural that AraPPISite should be evolved into a new database that can provide interaction details of PPIs in multiple plants. DESCRIPTION: PlaPPISite (http://zzdlab.com/plappisite/index.php) is a comprehensive, high-coverage and interaction details-oriented database for 13 plant interactomes. In addition to collecting 121 experimentally verified structures of protein complexes, the complex structures of experimental/predicted PPIs in the 13 plants were also constructed, and the corresponding interaction sites were annotated. For the PPIs whose 3D structures could not be modelled, the associated domain-domain interactions (DDIs) and domain-motif interactions (DMIs) were inferred. To facilitate the reliability assessment of predicted PPIs, the source species of interolog templates, GO annotations, subcellular localizations and gene expression similarities are also provided. JavaScript packages were employed to visualize structures of protein complexes, protein interaction sites and protein interaction networks. We also developed an online tool for homology modelling and protein interaction site annotation of protein complexes. All data contained in PlaPPISite are also freely available on the Download page. CONCLUSION: PlaPPISite provides the plant research community with an easy-to-use and comprehensive data resource for the search and analysis of protein interaction details from the 13 important plant species.
Assuntos
Arabidopsis/metabolismo , Bases de Dados de Proteínas/estatística & dados numéricos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Biologia ComputacionalRESUMO
Sirtuin-1 (Sirt-1), an NAD-dependent deacetylase, promotes tumorigenesis in glioma; however, whether the Sirt-1 specific inhibitor, EX527 exerts antitumor effects and the underlying mechanism in glioma requires further investigation. In the present study, the proliferative and colony formation abilities of two glioma cell lines (U87MG and LN-299) were inhibited by EX527. Treatment with EX527 increased the number of apoptotic cells (Annexin V-fluorescein isothiocyanate/propidium iodide); pretreatment with the caspase inhibitor Z-VAD-FMK suppressed EX527-induced apoptosis, suggesting that EX527 induced caspase-dependent apoptosis. In addition, western blotting revealed that EX527 treatment increased the expression of cleaved-caspase-3, poly (ADP-ribose) polymerase-1, B-cell lymphoma 2 (Bcl-2)-associated-X-protein and Bcl-2-like 11 but decreased that of Bcl-2. p53 is deacetylated by Sirt-1, attenuating its function. Furthermore, EX527 upregulated the expression of p53, acetylated p53 and the p53 target gene p21. This result suggests that EX527 induced cell apoptosis by activating p53 in glioma. Of note, EX527 exhibited antitumor effects on patient-derived glioma cells under three-dimensional culture conditions. Collectively, the results of the present study indicated that EX527 may be used as an effective compound in the treatment of glioma.
Assuntos
Carbazóis/farmacologia , Glioma/tratamento farmacológico , Sirtuína 1/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Clorometilcetonas de Aminoácidos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Inibidores de Caspase/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glioma/metabolismo , Glioma/patologia , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Three new sesquiterpene lactone dimers (1-3) were isolated from the flowers of Inula japonica together with twenty-two known sesquiterpene derivatives (4-25). Their structures were established on the basis of detailed spectroscopic analyses. All isolates were evaluated for their antiproliferative activities against paclitaxel-resistant human non-small-cell lung cancer cell line A549/PTX. The preliminary structure-activity relationship was discussed. Compound 24 exhibited the most potent effect with the IC50 value of 0.34 ± 0.10 µM, even more active than the clinically used drug paclitaxel (PTX, IC50 = 1.40 ± 0.52 µM). Compound 24 showed significant efficacy of arresting the cell cycle at the G2-M stage, inducing apoptosis through mitochondria-mediated pathway, and inhibiting cell migration and invasion. Furthermore, compound 24 could reverse multidrug resistance through suppressing the expression of ABC family proteins.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Flores/química , Inula/química , Neoplasias Pulmonares/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Humanos , Estrutura Molecular , Sesquiterpenos/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEH) is rare; it is reported in < 1 person in 1,000,000 individuals. For accurate diagnosis, information regarding multiple graphic modalities in HEH is required. However, there is very little information concerning Sonazoid® contrast enhanced ultrasonography (CEUS) in HEH. CASE PRESENTATION: The present report describes the histologically proven three HEH cases evaluated using Sonazoid® CEUS. Case 1 was a 33-year-old female patient with no relevant past medical history, who experienced right upper quadrant pain. Conventional abdominal US revealed multiple low echoic liver nodules with vague borderlines. In CEUS, the vascularity of the nodules was similar to that seen in the neighboring normal liver. Later in the portal venous and late phases (PVLP) and post vascular phase, washout of Sonazoid® was detected in the nodules. Case 2 was a 93-year-old female patient with a previous medical history including operations for breast cancer and ovary cancer in her 50's. Conventional abdominal US revealed multiple low echoic nodules, some of which contained cystic lesions. In the early vascular phase of CEUS, nodules excluding the central anechoic regions were enhanced from peripheral sites. Although the enhancement inside the nodules persisted in both the PVLP and post vascular phase, anechoic areas in the center of some nodules were not enhanced at all. Case 3 was a 39-year-old male patient presented with right upper-quadrant pain, without any relevant past medical history. Conventional abdominal US revealed multiple low echoic liver nodules. In the early vascular phase of CEUS, nodules were gradually enhanced from the peripheral sites as ringed enhancement. Sonazoid®was washed out from the nodules in the PVLP and post vascular phase. CONCLUSIONS: The most important feature was peripheral enhancement in the early vascular phase. In case 2, the enhancement of the parenchyma of liver nodules persisted even in the PVLP; indicating the lower degree of malignant potential than others. Actually, the tumors did not extend without any treatment in case 2. Since case 2 is the first case report of HEH with cystic lesions, in patients with liver nodules including cystic lesions, HEH is a potential diagnosis.
Assuntos
Compostos Férricos/farmacologia , Hemangioendotelioma Epitelioide , Ferro/farmacologia , Neoplasias Hepáticas , Óxidos/farmacologia , Ultrassonografia/métodos , Adulto , Idoso de 80 Anos ou mais , Meios de Contraste/farmacologia , Diagnóstico Diferencial , Feminino , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/patologia , Humanos , Aumento da Imagem/métodos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Masculino , Imagem de PerfusãoRESUMO
One new eudesmane sesquiterpenoid, 11ß-hydroxy-13-chloro-eudesm-5-en-12, 8-olide (1), was isolated from the roots of Inula helenium together with nine eudesmanolides (2-10) and one germacranolide (11). Their structures were elucidated on the basis of detailed spectroscopic analyses. All isolates were evaluated for their antiproliferative activities against human leukemia stem-like cell line KG1a. Compound 10 exhibited the most potent effect with the IC50 value of 3.36⯱â¯0.18⯵M. A further investigation revealed that compound 10 could significantly induce apoptosis of KG1a cells. Additionally, compound 10 had an obvious effect on the levels of apoptosis-related proteins (Bcl-2, Bax, cytochrome c, caspase 9 and caspase 3), indicating that the antiproliferative effect of compound 10 on KG1a cells might be mediated through a mitochondria-dependent apoptotic pathway.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Inula/química , Leucemia Mieloide Aguda/tratamento farmacológico , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Sesquiterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of parthenolide-SAHA hybrids were synthesized and evaluated for their anti-AML activities against HL-60 and HL-60/ADR cell lines. The most active compound 26 exhibited high activity against HL-60/ADR cell line with IC50 value of 0.15⯵M, which demonstrated 16.8-fold improvement compared to that of the parent compound PTL (IC50â¯=â¯2.52⯵M). Moreover, it was six times more potent than the reference drug SAHA (IC50â¯=â¯0.90⯵M) and fifty-one times more potent than ADR (IC50â¯=â¯7.72⯵M). The preliminary molecular mechanism of 26 indicated that compound 26 could significantly induce apoptosis of HL-60/ADR cells. The effect of compound 26 was mainly through mitochondria pathway. Further investigation revealed that the protein level of HDAC1 and HDAC6 were reduced after the treatment of compound 26 with a dose-dependent manner. Compound 26 could significantly decrease ABCC1 expression, which increased the accumulation of intracellular drug for overcoming the drug resistance. On the base of these results, compound 26 might be considered as a promising candidate for further evaluation as a potential anti-AML drug.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Sesquiterpenos/farmacologia , Vorinostat/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Leucemia Mieloide Aguda/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Sesquiterpenos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Vorinostat/químicaRESUMO
A 52-year-old woman with epigastralgia and abdominal discomfort was admitted to our hospital. The abdominal CT scan showed that she had intestinal obstruction and peritoneal dissemination. Colonoscopy also revealed a submucosal tumor around the orifice of the appendix. Moreover, histological examination results indicated signet ring cell carcinoma. She was then treated with modified FOLFOX chemotherapy;however, the disease condition progressed after an 8-course treatment, and she died 12 months after the chemotherapy was initiated.
Assuntos
Neoplasias do Apêndice , Carcinoma de Células em Anel de Sinete , Neoplasias Colorretais , Feminino , Fluoruracila , Humanos , Leucovorina , Pessoa de Meia-IdadeRESUMO
Cucurbitacin B shows potent activity against tumor cells, but its high toxicity limits its application in the clinic. A series of cucurbitacin B derivatives was synthesized and evaluated for their anti-hepatocellular carcinoma (HCC) activities against the HepG-2 cell line. These compounds were also tested for their toxicity against the L-O2 normal cell line. The compound with the most potential, 10b, exhibited potent activity against the HepG-2 cell line with an IC50 value of 0.63 µM. Moreover, compound 10b showed the highest TI value (4.71), which is a 14.7-fold improvement compared to its parent compound cucurbitacin B. A preliminary molecular mechanism study of 10b indicated that 10b could inhibit P-STAT3 to induce the activation of mitochondrial apoptotic pathways. An in vivo acute toxicity study indicated that the compound 10b has preferable safety and tolerability compared with cucurbitacin B. These findings indicate that compound 10b might be considered as a lead compound for exploring effective anti-HCC drugs.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos , Fator de Transcrição STAT3/metabolismo , Triterpenos/químicaRESUMO
Microfluidic systems can accelerate clinical translation of nanoparticles due to their ability to generate nanoparticles in a well-controlled and reproducible manner. In this study, a single-step process based on microfluidic focusing (MF) was employed to synthesize transferrin-conjugated lipid nanoparticles (Tf-LNPs) and the method was compared with a multi-steps bulk mixing (BM) method. The results indicate that this single-step MF process enables rapid and efficient synthesis of Tf-LNPs, which were named Tf-LNPs-MF. Tf-LNPs-MF was shown to have a smaller size and more uniform structures compared to LNPs produced by multi-steps BM method (Tf-LNPs-BM). Furthermore, efficient cellular uptake of Tf-LNPs-MF in vitro as well as greater tumor inhibition in vivo proved that Tf-LNPs-MF had higher siRNA delivery efficiency in vitro and in vivo. Taken together, this single-step microfluidic synthesis significantly simplified the Tf-LNPs production and improved their drug delivery properties and may serve as a valuable tool for developing new cancer therapies.
Assuntos
Microfluídica , Nanopartículas , RNA Interferente Pequeno , Humanos , Lipídeos , TransferrinaRESUMO
BACKGROUND: Polyploidy is widely recognized as a significant evolutionary force in the plant kingdom, contributing to the diversification of plants. One of the notable features of allopolyploidy is the occurrence of homoeologous exchange (HE) events between the subgenomes, causing changes in genomic composition, gene expression, and phenotypic variations. However, the role of HE in plant adaptation and domestication remains unclear. RESULTS: Here we analyze the whole-genome resequencing data from Brassica napus accessions representing the different morphotypes and ecotypes, to investigate the role of HE in domestication. Our findings demonstrate frequent occurrence of HEs in Brassica napus, with substantial HE patterns shared across populations, indicating their potential role in promoting crop domestication. HE events are asymmetric, with the A genome more frequently replacing C genome segments. These events show a preference for specific genomic regions and vary among populations. We also identify candidate genes in HE regions specific to certain populations, which likely contribute to flowering-time diversification across diverse morphotypes and ecotypes. In addition, we assemble a new genome of a swede accession, confirming the HE signals on the genome and their potential involvement in root tuber development. By analyzing HE in another allopolyploid species, Brassica juncea, we characterize a potential broader role of HE in allopolyploid crop domestication. CONCLUSIONS: Our results provide novel insights into the domestication of polyploid Brassica species and highlight homoeologous exchange as a crucial mechanism for generating variations that are selected for crop improvement in polyploid species.
Assuntos
Brassica napus , Domesticação , Genoma de Planta , Poliploidia , Brassica napus/genética , Brassica/genéticaRESUMO
As one of the most studied Apicomplexan parasite Cryptosporidium, Cryptosporidium parvum (C. parvum) causes worldwide serious diarrhea disease cryptosporidiosis, which can be deadly to immunodeficiency individuals, newly born children, and animals. Proteome-wide identification of protein-protein interactions (PPIs) has proven valuable in the systematic understanding of the genome-phenome relationship. However, the PPIs of C. parvum are largely unknown because of the limited experimental studies carried out. Therefore, we took full advantage of three bioinformatics methods, i.e., interolog mapping (IM), domain-domain interaction (DDI)-based inference, and machine learning (ML) method, to jointly predict PPIs of C. parvum. Due to the lack of experimental PPIs of C. parvum, we used the PPI data of Plasmodium falciparum (P. falciparum), which owned the largest number of PPIs in Apicomplexa, to train an ML model to infer C. parvum PPIs. We utilized consistent results of these three methods as the predicted high-confidence PPI network, which contains 4,578 PPIs covering 554 proteins. To further explore the biological significance of the constructed PPI network, we also conducted essential network and protein functional analysis, mainly focusing on hub proteins and functional modules. We anticipate the constructed PPI network can become an important data resource to accelerate the functional genomics studies of C. parvum as well as offer new hints to the target discovery in developing drugs/vaccines.