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1.
Proc Natl Acad Sci U S A ; 120(15): e2209435120, 2023 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-37011206

RESUMO

Aberrantly upregulated choline phospholipid metabolism is a novel emerging hallmark of cancer, and choline kinase α (CHKα), a key enzyme for phosphatidylcholine production, is overexpressed in many types of human cancer through undefined mechanisms. Here, we demonstrate that the expression levels of the glycolytic enzyme enolase-1 (ENO1) are positively correlated with CHKα expression levels in human glioblastoma specimens and that ENO1 tightly governs CHKα expression via posttranslational regulation. Mechanistically, we reveal that both ENO1 and the ubiquitin E3 ligase TRIM25 are associated with CHKα. Highly expressed ENO1 in tumor cells binds to I199/F200 of CHKα, thereby abrogating the interaction between CHKα and TRIM25. This abrogation leads to the inhibition of TRIM25-mediated polyubiquitylation of CHKα at K195, increased stability of CHKα, enhanced choline metabolism in glioblastoma cells, and accelerated brain tumor growth. In addition, the expression levels of both ENO1 and CHKα are associated with poor prognosis in glioblastoma patients. These findings highlight a critical moonlighting function of ENO1 in choline phospholipid metabolism and provide unprecedented insight into the integrated regulation of cancer metabolism by crosstalk between glycolytic and lipidic enzymes.


Assuntos
Colina , Glioblastoma , Fosfopiruvato Hidratase , Humanos , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Colina/metabolismo , Glioblastoma/genética , Fosfolipídeos/metabolismo , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo
2.
Plant J ; 118(3): 766-786, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38271098

RESUMO

Rhus chinensis Mill., an economically valuable Anacardiaceae species, is parasitized by the galling aphid Schlechtendalia chinensis, resulting in the formation of the Chinese gallnut (CG). Here, we report a chromosomal-level genome assembly of R. chinensis, with a total size of 389.40 Mb and scaffold N50 of 23.02 Mb. Comparative genomic and transcriptome analysis revealed that the enhanced structure of CG and nutritional metabolism contribute to improving the adaptability of R. chinensis to S. chinensis by supporting CG and galling aphid growth. CG was observed to be abundant in hydrolysable tannins (HT), particularly gallotannin and its isomers. Tandem repeat clusters of dehydroquinate dehydratase/shikimate dehydrogenase (DQD/SDH) and serine carboxypeptidase-like (SCPL) and their homologs involved in HT production were determined as specific to HT-rich species. The functional differentiation of DQD/SDH tandem duplicate genes and the significant contraction in the phenylalanine ammonia-lyase (PAL) gene family contributed to the accumulation of gallic acid and HT while minimizing the production of shikimic acid, flavonoids, and condensed tannins in CG. Furthermore, we identified one UDP glucosyltransferase (UGT84A), three carboxylesterase (CXE), and six SCPL genes from conserved tandem repeat clusters that are involved in gallotannin biosynthesis and hydrolysis in CG. We then constructed a regulatory network of these genes based on co-expression and transcription factor motif analysis. Our findings provide a genomic resource for the exploration of the underlying mechanisms of plant-galling insect interaction and highlight the importance of the functional divergence of tandem duplicate genes in the accumulation of secondary metabolites.


Assuntos
Genoma de Planta , Taninos Hidrolisáveis , Rhus , Taninos Hidrolisáveis/metabolismo , Animais , Rhus/genética , Genoma de Planta/genética , Afídeos/fisiologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Cromossomos de Plantas/genética , Regulação da Expressão Gênica de Plantas , Interações Hospedeiro-Parasita
3.
Appl Environ Microbiol ; : e0054524, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38899887

RESUMO

White-rot fungi differentially express laccases when they encounter aromatic compounds. However, the underlying mechanisms are still being explored. Here, proteomics analysis revealed that in addition to increased laccase activity, proteins involved in sphingolipid metabolism and toluene degradation as well as some cytochrome P450s (CYP450s) were differentially expressed and significantly enriched during 48 h of o-toluidine exposure, in Trametes hirsuta AH28-2. Two Zn2Cys6-type transcription factors (TFs), TH8421 and TH4300, were upregulated. Bioinformatics docking and isothermal titration calorimetry assays showed that each of them could bind directly to o-toluidine and another aromatic monomer, guaiacol. Binding to aromatic compounds promoted the formation of TH8421/TH4300 heterodimers. TH8421 and TH4300 silencing in T. hirsuta AH28-2 led to decreased transcriptional levels and activities of LacA and LacB upon o-toluidine and guaiacol exposure. EMSA and ChIP-qPCR analysis further showed that TH8421 and TH4300 bound directly with the promoter regions of lacA and lacB containing CGG or CCG motifs. Furthermore, the two TFs were involved in direct and positive regulation of the transcription of some CYP450s. Together, TH8421 and TH4300, two key regulators found in T. hirsuta AH28-2, function as heterodimers to simultaneously trigger the expression of downstream laccases and intracellular enzymes. Monomeric aromatic compounds act as ligands to promote heterodimer formation and enhance the transcriptional activities of the two TFs.IMPORTANCEWhite-rot fungi differentially express laccase isoenzymes when exposed to aromatic compounds. Clarification of the molecular mechanisms underlying differential laccase expression is essential to elucidate how white-rot fungi respond to the environment. Our study shows that two Zn2Cys6-type transcription factors form heterodimers, interact with the promoters of laccase genes, and positively regulate laccase transcription in Trametes hirsuta AH28-2. Aromatic monomer addition induces faster heterodimer formation and rate of activity. These findings not only identify two new transcription factors involved in fungal laccase transcription but also deepen our understanding of the mechanisms underlying the response to aromatics exposure in white-rot fungi.

4.
Hepatology ; 2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-38016019

RESUMO

BACKGROUND AND AIMS: Base editing has shown great potential for treating human diseases with mutated genes. However, its potential for treating HCC has not yet been explored. APPROACH AND RESULTS: We employed adenine base editors (ABEs) to correct a telomerase reverse transcriptase ( TERT ) promoter mutation, which frequently occurs in various human cancers, including HCC. The mutated TERT promoter -124 C>T is corrected to -124 C by a single guide (sg) RNA-guided and deactivated Campylobacter jejuni Cas9 (CjCas9)-fused adenine base editor (CjABE). This edit impairs the binding of the E-twenty six/ternary complex factor transcription factor family, including E-twenty six-1 and GABPA, to the TERT promoter, leading to suppressed TERT promoter and telomerase activity, decreased TERT expression and cell proliferation, and increased cell senescence. Importantly, injection of adeno-associated viruses expressing sgRNA-guided CjABE or employment of lipid nanoparticle-mediated delivery of CjABE mRNA and sgRNA inhibits the growth of liver tumors harboring TERT promoter mutations. CONCLUSIONS: These findings demonstrate that a sgRNA-guided CjABE efficiently converts the mutated TERT promoter -124 C>T to -124 C in HCC cells and underscore the potential to treat HCC by the base editing-mediated correction of TERT promoter mutations.

5.
BMC Cancer ; 24(1): 330, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468232

RESUMO

TMEFF1 is a new protein involved in the physiological functions of the central nervous system, and we previously reported TMEFF1 can promote ovarian cancer. ST14 was determined to be involved in the processes of epidermal differentiation, epithelial cell integrity, and vascular endothelial cell migration, etc. The relationship between ST14 and TMEFF1 in the ovary remains unknown. In this study, we detected the expression of ST14 and TMEFF1 in 130 different ovarian cancer tissues through immunohistochemistry. We determined ST14 and TMEFF1 were highly expressed in ovarian cancer, indicating a higher degree of tumor malignancy and a worse prognosis. Tissues significantly expressing ST14 also highly expressed TMEFF1, and the expression of the two proteins was positively correlated. Consistently, immunofluorescence double staining demonstrated the co-localization of ST14 and TMEFF1 in the same region, and immunoprecipitation confirmed the interaction between ST14 and TMEFF1. TMEFF1 expression was also reduced after knocking down ST14 through Western blot. MTT, wound healing and Transwell assays results determined that knockdown of ST14 inhibited proliferation, migration and invasion of ovarian cancer cells in vitro, but the inhibitory effect was restored after adding TMEFF1 exogenous protein. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways analysis showed that ST14 and its related genes were enriched in the processes of epithelial formation, intercellular adhesion, protein localization, and mitosis regulation. We also clarified the kinase, microRNA, and transcription factor target networks and the impact of genetic mutations on prognosis. Overall, high expression of ST14 and TMEFF1 in ovarian cancer predicts higher tumor malignancy and a worse prognosis. ST14 and TMEFF1 co-localize and interact with each other in ovarian cancer. ST14 can regulate TMEFF1 expression to promote proliferation, migration and invasion of ovarian cancer cells. We speculate that the relationship between ST14 and TMEFF1 in ovarian cancer could become a potential target for anti-cancer therapy.


Assuntos
MicroRNAs , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , MicroRNAs/genética , Fatores de Transcrição/genética , Mutação , Prognóstico , Proliferação de Células/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica
6.
Anticancer Drugs ; 35(6): 569-575, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38527281

RESUMO

For critically ill patients with non-small cell lung cancer (NSCLC) in need of life-saving treatment, there is currently no reported evidence regarding the use of medication specifically targeting epidermal growth factor receptor ( EGFR ) p.C797S mutation, which is known to cause resistance to third-generation tyrosine kinase inhibitors (TKIs). Our report aims to investigate and explore treatment strategies to overcome resistance associated with EGFR p.C797S mutation in order to provide potential therapeutic options for these patients. Here, we reported two cases with NSCLC who initially harbored an EGFR -sensitive mutation and were both treated with osimertinib, a third-generation TKI. Next-generation sequencing tests conducted prior to the initiation of fifth-line therapy in critically ill patients revealed the presence of EGFR p.C797S mutations in both patients, suggesting acquired resistance. In the course of fifth-line therapy, the administration of a combination of brigatinib and cetuximab proved vital in saving critically ill patients, moderately extending their overall survival period. Our findings suggested that a combined regimen of brigatinib and cetuximab could serve as a potentially life-saving therapeutic strategy for critically ill patients with NSCLC, particularly those demonstrating EGFR p.C797S-mediated resistance. Further studies, however, are required to validate and expand upon these promising findings.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Cetuximab , Receptores ErbB , Neoplasias Pulmonares , Mutação , Compostos Organofosforados , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores ErbB/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Masculino , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/administração & dosagem , Pessoa de Meia-Idade , Feminino , Estado Terminal , Idoso , Resistencia a Medicamentos Antineoplásicos , Acrilamidas/uso terapêutico , Compostos de Anilina , Indóis
7.
Anal Bioanal Chem ; 416(1): 203-214, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37914955

RESUMO

In this study, an integrated QuEChERS method was developed for the rapid determination of 22 per- and polyfluoroalkyl substances (PFASs) in milk by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The extraction and purification processes were combined into one step with this method. Meanwhile, the solid-liquid separation was carried out by magnetic suction (Fe3O4-SiO2) instead of the centrifugal process. The primary experimental parameters were optimized, including the type of extraction solvent, the amounts of magnetic nanomaterials (Fe3O4-SiO2), and the purification materials (ZrO2 and C18). The developed method exhibits high precision (RSDs < 9.9%), low limits of detection (0.004-0.079 µg/kg) and limits of quantitation (0.01-0.26 µg/kg), and acceptable recovery (71.7-116%) under optimized conditions. The developed integrated QuEChERS method had clear superiority in terms of sample pretreatment time, operating procedures, reagent amount, and recovery. This makes it an excellent alternative analytical technique for PFAS residue measurement at low micrograms-per-kilogram ranges with desirable sensitivity.


Assuntos
Fluorocarbonos , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Extração em Fase Sólida/métodos , Leite/química , Dióxido de Silício , Espectrometria de Massa com Cromatografia Líquida , Fluorocarbonos/análise
8.
Appl Microbiol Biotechnol ; 108(1): 135, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38229306

RESUMO

Apoptotic-like programmed cell death (PCD) is one of the main strategies for fungi to resist environmental stresses and maintain homeostasis. The apoptosis-inducing factor (AIF) has been shown in different fungi to trigger PCD through upregulating reactive oxygen species (ROS). This study identified a mitochondrial localized AIF homolog, CcAIF1, from Coprinopsis cinerea monokaryon Okayama 7. Heterologous overexpression of CcAIF1 in Saccharomyces cerevisiae caused apoptotic-like PCD of the yeast cells. Ccaif1 was increased in transcription when C. cinerea interacted with Gongronella sp. w5, accompanied by typical apoptotic-like PCD in C. cinerea, including phosphatidylserine externalization and DNA fragmentation. Decreased mycelial ROS levels were observed in Ccaif1 silenced C. cinerea transformants during cocultivation, as well as reduction of the apoptotic levels, mycelial growth, and asexual sporulation. By comparison, Ccaif1 overexpression led to the opposite phenotypes. Moreover, the transcription and expression levels of laccase Lcc9 decreased by Ccaif1 silencing but increased firmly in Ccaif1 overexpression C. cinerea transformants in coculture. Thus, in conjunction with our previous report that intracellular ROS act as signal molecules to stimulate defense responses, we conclude that CcAIF1 is a regulator of ROS to promote apoptotic-like PCD and laccase expression in fungal-fungal interactions. In an axenic culture of C. cinerea, CcAIF1 overexpression and H2O2 stimulation together increased laccase secretion with multiplied production yield. The expression of two other normally silent isozymes, Lcc8 and Lcc13, was unexpectedly triggered along with Lcc9. KEY POINTS: • Mitochondrial CcAIF1 induces PCD during fungal-fungal interactions • CcAIF1 is a regulator of ROS to trigger the expression of Lcc9 for defense • CcAIF1 overexpression and H2O2 stimulation dramatically increase laccase production.


Assuntos
Fator de Indução de Apoptose , Lacase , Lacase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Peróxido de Hidrogênio/metabolismo , Apoptose , Saccharomyces cerevisiae/metabolismo
9.
Appl Microbiol Biotechnol ; 108(1): 324, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38713211

RESUMO

Laccase, a copper-containing polyphenol oxidase, is an important green biocatalyst. In this study, Laccase Lcc5 was homologous recombinantly expressed in Coprinopsis cinerea and a novel strategy of silencing chitinase gene expression was used to enhance recombinant Lcc5 extracellular yield. Two critical chitinase genes, ChiEn1 and ChiE2, were selected by analyzing the transcriptome data of C. cinerea FA2222, and their silent expression was performed by RNA interference (RNAi). It was found that silencing either ChiEn1 or ChiE2 reduced sporulation and growth rate, and increased cell wall sensitivity, but had no significant effect on mycelial branching. Among them, the extracellular laccase activity of the ChiE2-silenced engineered strain Cclcc5-antiChiE2-5 and the control Cclcc5-13 reached the highest values (38.2 and 25.5 U/mL, respectively) at 250 and 150 rpm agitation speeds, corresponding to productivity of 0.35 and 0.19 U/mL·h, respectively, in a 3-L fermenter culture. Moreover, since Cclcc5-antiChiE2-5 could withstand greater shear forces, its extracellular laccase activity was 2.6-fold higher than that of Cclcc5-13 when the agitation speed was all at 250 rpm. To our knowledge, this is the first report of enhanced recombinant laccase production in C. cinerea by silencing the chitinase gene. This study will pave the way for laccase industrial production and accelerate the development of a C. cinerea high-expression system. KEY POINTS: • ChiEn1 and ChiE2 are critical chitinase genes in C. cinerea FA2222 genome. • Chitinase gene silencing enhanced the tolerance of C. cinerea to shear forces. • High homologous production of Lcc5 is achieved by fermentation in a 3-L fermenter.


Assuntos
Quitinases , Inativação Gênica , Lacase , Quitinases/genética , Quitinases/metabolismo , Quitinases/biossíntese , Lacase/genética , Lacase/metabolismo , Lacase/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Agaricales/genética , Agaricales/enzimologia , Fermentação , Interferência de RNA , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Micélio/genética , Micélio/crescimento & desenvolvimento , Micélio/enzimologia , Parede Celular/metabolismo , Parede Celular/genética
10.
BMC Pediatr ; 24(1): 11, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38178076

RESUMO

Community-acquired bacterial meningitis (CABM) is the main cause of morbidity and mortality in children. The epidemiology of CABM is regional and highly dynamic. To clarify the diagnostic status and epidemiological characteristics of children with CABM in this region, and pay attention to the disease burden, so as to provide evidence for the prevention and treatment of CABM. By retrospective case analysis, the clinical data of 918 CABM cases in children aged 0-14 years in Zhejiang Province from January, 2019 to December, 2020 were collected. The etiological diagnosis rate of CABM in children was 23.1%, the annual incidence rate 4.42-6.15/100,000, the annual mortality rate 0.06-0.09/100,000,the cure and improvement rate 94.4%, and the case fatality rate 1.4%. The total incidence of neuroimaging abnormalities was 20.6%. The median length of stay for CABM children was 20(16) days, with an average cost of 21,531(24,835) yuan. In addition, the incidence rate was decreased with age. Escherichia coli(E.coli) and group B Streptococcus agalactiae(GBS) were the principal pathogens in CABM infant<3 months(43.3%, 34.1%), and Streptococcus pneumoniae(S. pneumoniae) was the most common pathogen in children ≥ 3 months(33.9%). In conclusion, the annual incidence and mortality of CABM in children aged 0-14 years in Zhejiang Province are at intermediate and low level. The distribution of CABM incidence and pathogen spectrum are different in age; the incidence of abnormal neuroimaging is high; and the economic burden is heavy.


Assuntos
Meningites Bacterianas , Criança , Lactente , Humanos , Estudos Retrospectivos , Meningites Bacterianas/diagnóstico , Meningites Bacterianas/epidemiologia , Meningites Bacterianas/tratamento farmacológico , Streptococcus pneumoniae , Streptococcus agalactiae , Escherichia coli , Incidência
11.
J Sci Food Agric ; 104(10): 5999-6007, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38436580

RESUMO

BACKGROUND: Isomaltulose is a 'generally recognized as safe' ingredient and is widely used in the food, pharmaceutical and chemical industries. The exploration and development of efficient technologies is essential for enhancing isomaltulose yield. RESULTS: In the present study, a simple and efficient surface display platform mediated by a non-yeast signal peptide was developed in Yarrowia lipolytica and utilized to efficiently produce isomaltulose from sucrose. We discovered that the signal peptide SP1 of sucrose isomerase from Pantoea dispersa UQ68J (PdSI) could guide SIs anchoring to the cell surface of Y. lipolytica, demonstrating a novel and simple cell surface display strategy. Furthermore, the PdSI expression level was significantly increased through optimizing the promoters and multi-site integrating genes into chromosome. The final strain gained 451.7 g L-1 isomaltulose with a conversion rate of 90.3% and a space-time yield of 50.2 g L-1 h-1. CONCLUSION: The present study provides an efficient way for manufacturing isomaltulose with a high space-time yield. This heterogenous signal peptide-mediated cell surface display strategy featured with small fusion tag (approximately 2.2 kDa of SP1), absence of enzyme leakage in fermentation broth and ample room for optimization, providing a convenient way to construct whole-cell biocatalysts to synthesize other products and broadening the array of molecular toolboxes accessible for engineering Y. lipolytica. © 2024 Society of Chemical Industry.


Assuntos
Isomaltose , Sinais Direcionadores de Proteínas , Yarrowia , Yarrowia/genética , Yarrowia/metabolismo , Isomaltose/metabolismo , Isomaltose/análogos & derivados , Engenharia Metabólica , Pantoea/genética , Pantoea/metabolismo , Pantoea/enzimologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Técnicas de Visualização da Superfície Celular , Glucosiltransferases/genética , Glucosiltransferases/metabolismo
12.
EMBO Rep ; 22(1): e51352, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33295692

RESUMO

Fibroblast growth factor 21 (FGF21) is a regulator of glucose and lipid metabolism. It has been widely considered as a promising candidate for the treatment of type 2 diabetes mellitus (T2DM) and other related metabolic disorders. However, lack of structural and dynamic information has limited FGF21-based drug development. Here, using nuclear magnetic resonance (NMR) spectroscopy, we determine the structure of FGF21 and find that its non-canonical flexible ß-trefoil conformation affects the folding of ß2-ß3 hairpin and further overall protein stability. To modulate folding dynamics, we designed an FGF21-FGF19 chimera, FGF21SS . As expected, FGF21SS shows better thermostability without inducing hepatocyte proliferation. Functional characterization of FGF21SS shows its better insulin sensitivity, reduced inflammation in 3T3-L1 adipocytes, and lower blood glucose and insulin levels in ob/ob mice compared with wild type. Our dynamics-based rational design provides a promising approach for FGF21-based therapeutic development against T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Fatores de Crescimento de Fibroblastos , Resistência à Insulina , Animais , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Fatores de Crescimento de Fibroblastos/genética , Resistência à Insulina/genética , Camundongos
13.
Mol Divers ; 2023 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-37737959

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease with complex pathogenesis. Despite the pathogenesis is unknown, the misfolding and accumulation of ß-amyloid (Aß) peptide play the important role in the occurrence and development of AD. Hence, multi-aspect intervention of the misfolded Aß peptides aggregation is a promising therapy for AD. In previous work, we obtained the emodin derivatives (a-d) with multifunctional anti-AD activities, including metal ions chelation, cholinesterase inhibition, and hydroxyl/superoxide anion radical elimination. In this work, we predicted the interaction of emodin derivatives (a-d) with Aß by combining molecular docking simulation and molecular dynamics simulation, and evaluated the ability to intervene with the self-, Cu2+- and AChE-induced Aß aggregation via in vitro methods. The results indicated that a-d could act as the potent multi-aspect intervention agents for Aß aggregation. In addition, a-d could effectively eliminate peroxyl radical, had virtually no neurotoxicity, and protect cells from oxidative and Aß-induced damage. The prediction results of ADMET properties showed that a-d had suitable pharmacokinetic characteristics. It suggested that a-d could act as the promising multi-targeted directed ligands (MTDLs) for AD. These results may provide meaningful information for the development of the potential MTDLs for AD which are modified from natural-origin scaffolds.

14.
Cell Mol Life Sci ; 80(1): 19, 2022 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-36574072

RESUMO

Congenital heart disease (CHD) is the most common birth defect worldwide and a main cause of perinatal and infant mortality. Our previous genome-wide association study identified 53 SNPs that associated with CHD in the Han Chinese population. Here, we performed functional screening of 27 orthologous genes in zebrafish using injection of antisense morpholino oligos. From this screen, 5 genes were identified as essential for heart development, including iqgap2, ptprt, ptpn22, tbck and maml3. Presumptive roles of the novel CHD-related genes include heart chamber formation (iqgap2 and ptprt) and atrioventricular canal formation (ptpn22 and tbck). While deficiency of maml3 led to defective cardiac trabeculation and consequent heart failure in zebrafish embryos. Furthermore, we found that maml3 mutants showed decreased cardiomyocyte proliferation which caused a reduction in cardiac trabeculae due to inhibition of Notch signaling. Together, our study identifies 5 novel CHD-related genes that are essential for heart development in zebrafish and first demonstrates that maml3 is required for Notch signaling in vivo.


Assuntos
Cardiopatias Congênitas , Defeitos dos Septos Cardíacos , Animais , Peixe-Zebra/genética , Estudo de Associação Genômica Ampla , Coração , Cardiopatias Congênitas/genética , Proteínas de Peixe-Zebra/genética
15.
BMC Womens Health ; 23(1): 329, 2023 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-37344881

RESUMO

BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease with high penetrance caused by a germline variant of TP53 gene. We report the first case of endometrial cancer after yolk sac tumor with LFS. CASE PRESENTATION: The presented female patient underwent right adnexectomy at age 23 because of a yolk sac tumor of the ovary. At the age of 27, the patient was diagnosed with endometrial adenocarcinoma, received cytoreductive surgery and chemotherapy. Given that her personal cancer history along with a strong family history of cancer, her father passing away from lung cancer at age 48 and her grandmother dying of ovarian cancer at age 50, the patient was referred for genetic counseling and testing. Genetic screening revealed a heterozygous pathogenic TP53 c.844C > T, p.( R282 W) with NM_000546.5 variant, a class 5 (C5) variant. This is the first reported case of a yolk sac tumor accompanied by subsequent endometrial cancer that is associated with LFS. CONCLUSIONS: We reported a first case of an endometrial cancer after yolk sac tumor patient with a tumor family history of harboring the germline TP53 pathogenic variation which expanded types of tumor that can be presented in patients with LFS. This case highlights the importance of genetic testing for patients with malignant tumors, as well as patients with a family history of malignant tumors. And our case highlights the necessity of screening for gynecologic tumor in LFS patients.


Assuntos
Tumor do Seio Endodérmico , Neoplasias do Endométrio , Síndrome de Li-Fraumeni , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Síndrome de Li-Fraumeni/complicações , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/diagnóstico , Genes p53 , Tumor do Seio Endodérmico/complicações , Tumor do Seio Endodérmico/genética , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/genética , Mutação em Linhagem Germinativa , Predisposição Genética para Doença
16.
BMC Med Educ ; 23(1): 182, 2023 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-36964607

RESUMO

BACKGROUND: Position transition training for general practitioners in Zhejiang Province started in 2017 and has since been held once a year. By the beginning of 2022, four training sessions were completed. The purpose of this survey was to establish the current situation of trainees after their graduation and provide reference for the evaluation of the training effect. METHODS: Of the 738 trainees who completed the training, 253 were contacted and followed up. A self-designed questionnaire was used to conduct the survey through online filling in. The content included questions to elucidate the following information: whereabouts after the training, registration as a general practitioner, undertaken general practice teaching and scientific research work, current occupational environment, improvement of post competence after receiving position transition training, willingness to complete survey, willingness to participate in future training programs, etc. RESULTS: A number of 253 valid questionnaires were collected with a recovery rate of 100%. Notably, 93.68% of the participants successfully completed their training and obtained the Training Certificate of General Practitioners. Further, 83.4% were registered as general practitioners, 82.94% of which added on the basis of the original registered scope of practice. Currently, most of them work in primary health care institutions, primarily occupied with medical treatment, chronic disease management, COVID-19 prevention and control, health education, and prevention and health care. Of them, 27.01% were currently undertaking teaching work, and only 3.32% of them were conducting scientific research work related to general practice. The overall satisfaction of the trainees in the three theoretical training bases was above 90%, with no statistically significant difference among them (P > 0.05). Importantly, 84.11% of the followed-up personnel hoped to continue to participate in similar training in the future to improve their general practitioner core competences. CONCLUSION: The position transition training in Zhejiang Province has achieved good results, but the details of training and the implementation of policies in individual regions need to be improved. Most of the graduates were willing to continue their education, especially in general practitioners with special interests.


Assuntos
COVID-19 , Medicina Geral , Clínicos Gerais , Humanos , Clínicos Gerais/educação , Seguimentos , Medicina Geral/educação , Inquéritos e Questionários
17.
Molecules ; 28(19)2023 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-37836792

RESUMO

Fabricating heterostructures with abundant interfaces and delicate nanoarchitectures is an attractive approach for optimizing photocatalysts. Herein, we report the facile synthesis of BiOCl nanoflake/FeOCl nanospindle heterostructures through a solution chemistry method at room temperature. Characterizations, including XRD, SEM, TEM, EDS, and XPS, were employed to investigate the synthesized materials. The results demonstrate that the in situ reaction between the Bi precursors and the surface Cl- of FeOCl enabled the bounded nucleation and growth of BiOCl on the surface of FeOCl nanospindles. Stable interfacial structures were established between BiOCl nanoflakes and FeOCl nanospindles using Cl- as the bridge. Regulating the Bi-to-Fe ratios allowed for the optimization of the BiOCl/FeOCl interface, thereby facilitating the separation of photogenerated carriers and accelerating the photocatalytic degradation of RhB. The BiOCl/FeOCl heterostructures with an optimal composition of 15% BiOCl exhibited ~90 times higher visible-light photocatalytic activity than FeOCl. Based on an analysis of the band structures and reactive oxygen species, we propose an S-scheme mechanism to elucidate the significantly enhanced photocatalytic performance observed in the BiOCl/FeOCl heterostructures.

18.
Molecules ; 28(5)2023 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-36903580

RESUMO

The rational regulation of catalyst active sites at atomic scale is a key approach to unveil the relationship between structure and catalytic performance. Herein, we reported a strategy for the controllable deposition of Bi on Pd nanocubes (Pd NCs) in the priority order from corners to edges and then to facets (Pd NCs@Bi). The spherical aberration-corrected scanning transmission electron microscopy (ac-STEM) results indicated that Bi2O3 with an amorphous structure covers the specific sites of Pd NCs. When only the corners and edges of the Pd NCs were covered, the supported Pd NCs@Bi catalyst exhibited an optimal trade-off between high conversion and selectivity in the hydrogenation of acetylene to ethylene under ethylene-rich conditions (99.7% C2H2 conversion and 94.3% C2H4 selectivity at 170 °C) with remarkable long-term stability. According to the H2-TPR and C2H4-TPD measurements, the moderate hydrogen dissociation and the weak ethylene adsorption are responsible for this excellent catalytic performance. Following these results, the selectively Bi-deposited Pd nanoparticle catalysts showed incredible acetylene hydrogenation performance, which provides a feasible perspective to design and develop highly selective hydrogenation catalysts for industrial applications.

19.
J Integr Plant Biol ; 65(4): 985-1002, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36398758

RESUMO

Flowering time (FTi) is a major factor determining how quickly cotton plants reach maturity. Early maturity greatly affects lint yield and fiber quality and is crucial for mechanical harvesting of cotton in northwestern China. Yet, few quantitative trait loci (QTLs) or genes regulating early maturity have been reported in cotton, and the underlying regulatory mechanisms are largely unknown. In this study, we characterized 152, 68, and 101 loci that were significantly associated with the three key early maturity traits-FTi, flower and boll period (FBP) and whole growth period (WGP), respectively, via four genome-wide association study methods in upland cotton (Gossypium hirsutum). We focused on one major early maturity-related genomic region containing three single nucleotide polymorphisms on chromosome D03, and determined that GhAP1-D3, a gene homologous to Arabidopsis thaliana APETALA1 (AP1), is the causal locus in this region. Transgenic plants overexpressing GhAP1-D3 showed significantly early flowering and early maturity without penalties for yield and fiber quality compared to wild-type (WT) plants. By contrast, the mutant lines of GhAP1-D3 generated by genome editing displayed markedly later flowering than the WT. GhAP1-D3 interacted with GhSOC1 (SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1), a pivotal regulator of FTi, both in vitro and in vivo. Changes in GhAP1-D3 transcript levels clearly affected the expression of multiple key flowering regulatory genes. Additionally, DNA hypomethylation and high levels of H3K9ac affected strong expression of GhAP1-D3 in early-maturing cotton cultivars. We propose that epigenetic modifications modulate GhAP1-D3 expression to positively regulate FTi in cotton through interaction of the encoded GhAP1 with GhSOC1 and affecting the transcription of multiple flowering-related genes. These findings may also lay a foundation for breeding early-maturing cotton varieties in the future.


Assuntos
Estudo de Associação Genômica Ampla , Gossypium , Gossypium/genética , Melhoramento Vegetal , Locos de Características Quantitativas , Fenótipo , Fibra de Algodão
20.
Fungal Genet Biol ; 161: 103716, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35691497

RESUMO

White rot fungi, especially Trametes spp., respond to a wide range of aromatic compounds and dramatically enhance laccase activity, while the activation mechanisms remain to be elucidated. Here, we show that an Hsp70 homolog named ThhspA1 regulates the transcription of laccase LacA in Trametes hirsuta AH28-2 when confronted with o-toluidine. ThhspA1 is pulled down by lacA promoter sequence from the nuclear mixture extracted from T. hirsuta AH28-2 induced by 2 mM o-toluidine. Silencing of ThhspA1 results in a sharp decrease in lacA transcripts and laccase activity in vivo. By comparison, ThhspA1 overexpression does not affect lacA transcription, and laccase activity shows slight enhancement or remains unchanged upon induction with o-toluidine. Electrophoretic mobility shift assays suggest a direct interaction between ThhspA1 and the lacA promoter region. Further investigation shows that the integrity of ThhspA1 is critical since its substrate binding domain (SBD) and nucleotide-binding domain (NBD) are both necessary for DNA binding, with a higher affinity of SBD than NBD based on fluorescence polarization assay. Our results demonstrate that ThhspA1 functions as an aromatic-stress-related DNA binding transcriptional factor required for LacA expression.


Assuntos
Lacase , Trametes , DNA/metabolismo , Lacase/metabolismo , Polyporaceae , Toluidinas , Trametes/genética , Trametes/metabolismo
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