RESUMEN
Platensilin, platensimycin, and platencin are potent inhibitors of ß-ketoacyl-acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels-Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom-transfer hydrogenation and subsequent Cu-catalyzed carbenoid C-H insertion afford platensilin. Furthermore, the intramolecular Diels-Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC80 = 0.0625 µg/mL) against S. aureus compared to platensimycin.
Asunto(s)
Adamantano , Aminobenzoatos , Aminofenoles , Anilidas , Compuestos Policíclicos , Aminofenoles/química , Aminofenoles/farmacología , Aminofenoles/síntesis química , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/síntesis química , Adamantano/química , Adamantano/farmacología , Adamantano/síntesis química , Adamantano/análogos & derivados , Anilidas/farmacología , Anilidas/química , Anilidas/síntesis química , Aminobenzoatos/farmacología , Aminobenzoatos/química , Aminobenzoatos/síntesis química , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Staphylococcus aureus/efectos de los fármacos , Estructura Molecular , Reacción de Cicloadición , Pruebas de Sensibilidad Microbiana , Estereoisomerismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/químicaRESUMEN
AIM: To evaluate the mediating roles of occupational resilience and the moderationg role of perceived organizational support in the relationship between career calling and nurse burnout. BACKGROUND: Burnout is a frequent and serious problem in the field of nursing, and it poses a serious threat to both nurses' health and patient safety. Although many studies have described the links between burnout, career calling, and occupational resilience, little is known about the actual mechanisms between career calling and nurse burnout. METHODS: A cross-sectional study of 615 nurses in China was conducted using a convenience sampling method. The data were analyzed using descriptive statistics and Pearson correlation analysis. Hypotheses were tested using structural equation models and bootstrapping methods. STROBE guidelines were followed. RESULTS: Career calling was found to be negatively associated with nurse burnout, and occupational resilience mediated the relationship between career calling and burnout. Additionally, perceived organizational support was found to play a moderating role in the relationship between occupational resilience and burnout. CONCLUSION: Career calling can reduce burnout by increasing nurses' levels of occupational resilience, and perceived organizational support moderates this mechanism. Hence, policies focused on encouraging and sustaining career calling should be provided by nurse managers in order to enhance stress resistance and reduce burnout.
RESUMEN
Soybean is a short-day plant that typically flowers earlier when exposed to short-day conditions. However, the identification of genes associated with earlier flowering time but without a yield penalty is rare. In this study, we conducted genome-wide association studies (GWAS) using two re-sequencing datasets that included 113 wild soybeans (G. soja) and 1192 cultivated soybeans (G. max), respectively, and simultaneously identified a candidate flowering gene, qFT13-3, which encodes a protein homologous to the pseudo-response regulator (PRR) transcription factor. We identified four major haplotypes of qFT13-3 in the natural population, with haplotype H4 (qFT13-3H4) being lost during domestication, while qFT13-3H1 underwent natural and artificial selection, increasing in proportion from 4.5% in G. soja to 43.8% in landrace and to 81.9% in improve cultivars. Notably, most cultivars harbouring qFT13-3H1 were located in high-latitude regions. Knockout of qFT13-3 accelerated flowering and maturity time under long-day conditions, indicating that qFT13-3 functions as a flowering inhibitor. Our results also showed that qFT13-3 directly downregulates the expression of GmELF3b-2 which is a component of the circadian clock evening complex. Field trials revealed that the qft13-3 mutants shorten the maturity period by 11 days without a concomitant penalty on yield. Collectively, qFT13-3 can be utilized for the breeding of high-yield cultivars with a short maturity time suitable for high latitudes.
Asunto(s)
Estudio de Asociación del Genoma Completo , Glycine max , Glycine max/genética , Fitomejoramiento , Haplotipos/genética , Fotoperiodo , Flores/genética , Regulación de la Expresión Génica de las Plantas/genética , Proteínas de Plantas/genéticaRESUMEN
Mylnudones A-G (1-7), unprecedented 1,10-seco-aromadendrane-benzoquinone-type heterodimers, and a highly rearranged aromadendrane-type sesquiterpenoid (8), along with four known analogs (9-12), were isolated from the liverwort Mylia nuda. Compounds 1-6 and 7, bearing tricyclo[6.2.1.02,7] undecane and tricyclo[5.3.1.02,6] undecane backbones, likely formed via a Diels-Alder reaction and radical cyclization, respectively. Their structures were determined by spectroscopic analysis, computational calculation, and single-crystal X-ray diffraction analysis. Dimeric compounds displayed cytoprotective effects against glutamic acid-induced neurological deficits.
Asunto(s)
Alcanos , Hepatophyta , Sesquiterpenos de Guayano , Sesquiterpenos , Hepatophyta/química , Estructura Molecular , Sesquiterpenos/farmacología , Sesquiterpenos/química , ChinaRESUMEN
Epothilone B (Epo B) is a potent antitumor natural product with sub-nanomolar anti-proliferation action against several human cancer cells. However, poor selectivity to tumor cells and unacceptable therapeutic windows of Epo B and its analogs are the major obstacles to their development into clinical drugs. Herein, we present self-assembled nanomicelles based on an amphiphilic carbohydrate-Epo B conjugate that is inactive until converted to active Epo B within the tumor. Four Epo B-Rhamnose conjugates linked via two linkers containing a disulfide bond that is sensitive to GSH were synthesized. Conjugate 34 can self-assemble into nanomicelles with a high concentration of Rha on the surface, allowing for better tumor targeting. After internalization by cancer cells, the disulfide bond can be cleaved in the presence of high levels of GSH to release active Epo B, thereby exhibiting significant anticancer efficiency and selectivity in vitro and in vivo.
Asunto(s)
Epotilonas , Nanopartículas , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Carbohidratos/uso terapéutico , Disulfuros , Línea Celular Tumoral , Nanopartículas/químicaRESUMEN
- Seven previously undescribed ent-eudesmane sesquiterpenoids (1-7), as well as seven known analogs (8-14), were isolated from the Chinese liverwort Chiloscyphus polyanthus var. rivularis. Their structures were established based on comprehensive spectroscopy analysis, electronic circular dichroism calculations, as well as biosynthetic considerations. The cytotoxicity against HepG2 (Human hepatocellular carcinomas) cancer cell line, and antifungal activity against Candida albicans SC5314 of all isolated ent-eudesmane sesquiterpenoids were preliminarily tested, results showed that the tested compounds did not display obvious cytotoxicity and antifungal activities under the tested concentration.
Asunto(s)
Antifúngicos , Antineoplásicos , Hepatophyta , Sesquiterpenos de Eudesmano , Sesquiterpenos , Antifúngicos/farmacología , Antifúngicos/química , China , Hepatophyta/química , Estructura Molecular , Sesquiterpenos/química , Sesquiterpenos de Eudesmano/farmacología , Sesquiterpenos de Eudesmano/química , Células Hep G2/efectos de los fármacos , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologíaRESUMEN
Three unprecedented ent-labdane and pallavicinin based dimers pallamins A-C formed via [4 + 2] Diels-Alder cycloaddition, together with eight biosynthetically related monomers were isolated from Pallavicinia ambigua. Their structures were determined by the extensive analysis of HRESIMS and NMR spectra. The absolute configurations of the labdane dimers were determined by single crystal X-ray diffraction of the homologous labdane units, and 13C NMR and ECD calculations. Moreover, a preliminary evaluation of the anti-inflammatory activities of the isolated compounds was performed using the zebrafish model. Three of the monomers demonstrated significant anti-inflammatory activity.
Asunto(s)
Diterpenos , Hepatophyta , Animales , Diterpenos/farmacología , Diterpenos/química , Hepatophyta/química , Estructura Molecular , Pez Cebra , ChinaRESUMEN
Cancer stem cells (CSCs) are a subset of cancer cells with stem cell characteristics. The discovery of CSCs has opened a new era for cancer research. CSCs not only play a critical role in tumorigenesis, but also are responsible for the failure of cancer treatments. Here, we performed weighted gene co-expression network analysis (WGCNA) to identify key stemness genes and prognostic signatures using the data of an Asian liver cancer patient cohort and a White liver cancer patient cohort in The Cancer Genome Atlas (TCGA) database. To compare the difference in tumorigenesis between the Asian patients and the White patients, the prognostic value of the key genes from the Asian patients was evaluated in the White patient cohort and vice versa. We found that some key genes could predict the survival of the patients regardless of race. In addition, the key genes, NUCB2 and KLF4A, were selected from Asian patients and White patients, respectively, for further experimental validation. Knocking down NUCB2 could inhibit the activity of the AKT/mTOR signaling pathway and reverse the epithelial-mesenchymal transition (EMT) in liver cancer cells. We also confirmed that the knockdown of KLF4A suppressed ABCG2 activity and reduced the side population (SP) in liver cancer cells for the first time. Our results suggest that the stemness index is a useful method to identify key genes in tumorigenesis. Compared to the analysis for all patients, applying this index to the analysis of the patients of different races will provide more potential therapeutic targets for cancer treatment.
RESUMEN
An unprecedented 4,9-seco-oplopanane (1), two undescribed drimane epimers (2 and 3), and five known drimane sesquiterpenoids (4-8) were isolated from the Chinese liverwort Lejeunea flava (Sw.) Nees. The structures of the new sesquiterpenoids were determined using nuclear magnetic resonance spectroscopy, electronic circular dichroism calculations, and single-crystal X-ray diffraction measurements. The inhibitory capacity of the new compounds against nitric oxide production in lipopolysaccharide-induced RAW 264.7 murine macrophages, along with the cytotoxicity of the new compounds against A549 and HepG-2 human cancer cell lines, were discussed.
Asunto(s)
Anemone , Hepatophyta , Sesquiterpenos , Animales , China , Hepatophyta/química , Humanos , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Óxido Nítrico , Sesquiterpenos Policíclicos , Sesquiterpenos/química , Sesquiterpenos/farmacologíaRESUMEN
Cancer stem cell (CSC) refers to cancer cells with stem cell properties, that is, they have the ability of "self-renewal" and "differentiation." Cancer stem cells exist in cancer cells and are the "culprit" of cancer recurrence and metastasis. It is difficult to be found because of its small amount, and it is difficult for anticancer drugs to produce effects on it. At present, the isolation and identification of cancer stem cells from many solid tumors are still quite difficult, mainly due to the lack of specific molecular markers of cancer stem cells. In this review, cancer stem cell surface markers and functional markers in urinary system were summarized. These markers can provide molecular targets for cancer therapy.
RESUMEN
Innovations in genomics have enabled the development of low-cost, high-resolution, single nucleotide polymorphism (SNP) genotyping arrays that accelerate breeding progress and support basic research in crop science. Here, we developed and validated the SoySNP618K array (618,888 SNPs) for the important crop soybean. The SNPs were selected from whole-genome resequencing data containing 2,214 diverse soybean accessions; 29.34% of the SNPs mapped to genic regions representing 86.85% of the 56,044 annotated high-confidence genes. Identity-by-state analyses of 318 soybeans revealed 17 redundant accessions, highlighting the potential of the SoySNP618K array in supporting gene bank management. The patterns of population stratification and genomic regions enriched through domestication were highly consistent with previous findings based on resequencing data, suggesting that the ascertainment bias in the SoySNP618K array was largely compensated for. Genome-wide association mapping in combination with reported quantitative trait loci enabled fine-mapping of genes known to influence flowering time, E2 and GmPRR3b, and of a new candidate gene, GmVIP5. Moreover, genomic prediction of flowering and maturity time in 502 recombinant inbred lines was highly accurate (>0.65). Thus, the SoySNP618K array is a valuable genomic tool that can be used to address many questions in applied breeding, germplasm management, and basic crop research.
Asunto(s)
Glycine max , Polimorfismo de Nucleótido Simple , Genoma de Planta/genética , Estudio de Asociación del Genoma Completo , Genómica , Genotipo , Fitomejoramiento , Polimorfismo de Nucleótido Simple/genética , Glycine max/genéticaRESUMEN
A practical route to 2-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)cyclohexan-1-one was developed, featuring the use of inexpensive starting materials/reagents and readily attainable reaction conditions. The overall transformation was achieved in 53% yield with one chromatographic purification via NaOH-mediated aldol condensation, ethylene glycol protection of the ketone group in the presence of HC(OEt)3/concd HCl, saturation of the C=C bond and the benzene ring with Al-Ni alloy in aqueous KOH, and oxidation of the intermediate cyclohexanol with aqueous NaClO/TEMPO/KBr.
RESUMEN
Herein, we have developed two types of photoredox-catalyzed cascade reactions using diaryliodonium salts for the concise synthesis of norascyronone A and ß-eudesmol. A rationally designed photoredox-catalyzed arylation/cyclization/Friedel-Crafts cascade reaction of enone was exploited to generate the norascyronone polycyclic skeleton. A visible-light-induced radical cyclization/acyloxy-migration reaction was explored to forge the decalin skeleton of eudesmol, and mechanistic studies indicated the reaction was initiated by one-electron oxidation of the enol ester.
RESUMEN
An EtOH extract of the Chinese liverwort Radula apiculata showed cytotoxic activity against the A549 lung cancer cell line. Bioassay-guided fractionation led to the isolation of 19 prenylated bibenzyls, including eight previously unknown dimeric prenylated bibenzyls [radulapins A-H (1-8)], four new prenylated bibenzyls (9-12), and seven known compounds (13-19). Compounds 1-11 were analyzed as racemates by chiral-phase separation. Their structures were determined by detailed analysis of their spectroscopic data and by single-crystal X-ray diffraction, chiral resolutions, and electronic circular dichroism measurements. Using an MTT assay, these dimers (1-8) showed significant cytotoxic activity against a panel of human cancer cell lines. Further investigation revealed that compound 4 induces PC-3 cell death via mitochondrial-derived apoptosis.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Bibencilos/farmacología , Hepatophyta/química , Células A549 , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Bibencilos/aislamiento & purificación , China , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Estructura Molecular , Células PC-3 , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Prenilación , EstereoisomerismoRESUMEN
An enantioselective synthetic approach for preparing manginoids and guignardones, two types of biogenetically related meroterpenoids, is reported. This bioinspired and divergent synthesis employs an oxidative 1,3-dicarbonyl radical-initiated cyclization and cyclodehydration of the common precursor to forge the central ring of the manginoids and guignardones, respectively, at a late stage. Key synthetic steps include silica-gel-promoted semipinacol rearrangement to form the 6-oxabicyclo[3.2.1]octane skeleton and the Suzuki-Miyaura reaction of vinyl bromide to achieve fragment coupling. This synthesis protocol enables the asymmetric syntheses of four fungal meroterpenoids from commercially available materials.
RESUMEN
Oxidative stress-induced granulosa cell (GC) death is a major cause of follicular atresia. As the major types of programmed cell death, autophagy and apoptosis have been observed in response to H2O2-mediated oxidative stress and have been demonstrated to be responsible for porcine GC death. To date, however, the cellular reactions linking autophagy to the apoptosis of porcine GC under oxidative stress are still poorly understood. Porcine GC were treated with H2O2, and autophagic flux was examined by western blotting. Cell viability and cell death assays were performed after cotreatment of porcine GC with autophagy activator (rapamycin) or inhibitor (3-methyladenine, 3-MA) together with H2O2. We revealed that short exposure (1-3 h) of porcine GC to H2O2 dramatically increased autophagic flux (1.8- to 2.5-fold over that in the control), whereas 6-12 h prolonged treatment decreased autophagy but elevated the caspase-3 activity and GC apoptotic rate. Furthermore, we showed that pretreatment with rapamycin exacerbated H2O2-mediated cytotoxicity and caspase-3 activation but that 3-MA or siRNAs specific for Beclin 1 and Atg7 genes ameliorated H2O2-mediated GC apoptosis. Together, our results indicate that autophagy plays a pivotal role in H2O2-mediated porcine GC apoptosis. Importantly, we show that the early induction of autophagic flux contributes to oxidative stress-induced apoptosis in porcine GC. The results also suggest that regulating the autophagy response in porcine GC under oxidative stress might be a new strategy for abnormal follicular atresia.
Asunto(s)
Apoptosis/fisiología , Autofagia/fisiología , Atresia Folicular/metabolismo , Células de la Granulosa/metabolismo , Estrés Oxidativo/fisiología , Animales , Caspasa 3/metabolismo , Supervivencia Celular/fisiología , Femenino , Malondialdehído/metabolismo , PorcinosRESUMEN
A divergent synthetic approach to biogenetically related diterpenoids such as ent-kauranes, ent-trachylobanes, ent-beyerane, and ent-atisane has been developed. The unified synthetic route involves the De Mayo reaction to rapidly generate the bicyclo[3.2.1]-octane moiety of ent-kaurane. The key reactions also include bioinspired nucleophilic cyclopropanation generating the [3.2.1.02,7 ]-tricyclic core of ent-trachylobane and regioselective cyclopropane fragmentation furnishing ent-beyerane and ent-atisane through the nucleophilic attack and protonation of the cyclopropane ring. This strategy enables the asymmetric total syntheses of six diterpenoids from the commercially available geraniol.
RESUMEN
Tacrolimus, an immunosuppressive drug, was recommended by the 2012 KDIGO guidelines to treat nephrotic syndrome (NS) in children and adults. However, it has high interpatient pharmacokinetic variability and exposure levels should be monitored, although there are no specified target concentrations. This retrospective study aimed to review efficacy and safety after concomitant treatment with tacrolimus and prednisone, and to identify factors that contribute to the variable blood-trough-concentration-to-dose (C0/Dose) ratio in children with refractory NS (RNS). A 6-month therapy induced complete or partial remission in 95% of patients. One-year follow-up indicated a high remission rate and low nephrotoxicity. Under maintenance dosages, approximately 95% of the C0 values were 2-7 ng/mL. Body weight (BW), age, CYP3A5 polymorphisms were the factors affecting the C0/Dose ratio. The C0/Dose ratio in patients with a BW of <20 kg was 1.5-fold than that in patients with BW of ≥40 kg. Moreover, the C0/Dose ratio in patients aged 1-≤6 and 6-≤12 years was significantly lower than that in patients aged 12-≤18 years, by 25% and 48%, respectively. There were no significant association between CYP3A5 genotyping and C0/Dose ratio in younger children (1-≤6 years), rather than older children (6-≤18 years). In conclusion, routine CYP3A5 genotyping should be considered in children aged over 6 years and exposure levels (C0) of 2-7 ng/mL may be feasible when tacrolimus is combined with low-dose prednisone to treat childhood RNS.
Asunto(s)
Citocromo P-450 CYP3A/genética , Genotipo , Inmunosupresores/uso terapéutico , Síndrome Nefrótico/tratamiento farmacológico , Tacrolimus/uso terapéutico , Adolescente , Niño , Preescolar , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Monitoreo Fisiológico , Polimorfismo Genético , Prednisona/uso terapéutico , Estudios Retrospectivos , Tacrolimus/sangreRESUMEN
Objective: This study was conducted to evaluate the potential genetic and non-genetic factors contributing to plasma trough concentration-to-dose (C 0/D) ratio of valproic acid (VPA) in pediatric patients with epilepsy. Study Design: A single-center, retrospective cohort study was performed by collecting data from 194 children aged 1-14 years between May 2018 and November 2018. The oral solution (n = 135) group and the sustained-release (SR) tablet group (n = 59) were defined, and the plasma VPA C 0 was measured. Twenty-six single-nucleotide polymorphisms (SNPs) were chosen for genotyping with the MassARRAY system. A multiple logistic regression model was used for data analysis. Results: Body weight (BW) and age were positively correlated with the C 0/D ratio in 194 patients, but the positive correlation disappeared after the patients were divided into oral solution and SR tablet subgroups. The average C 0/D ratio was significantly increased by 2.11-fold (P = 0.000) in children who took VPA SR tablets compared with children who were administered VPA oral solutions. No significant association between genetic variants and the C 0/D ratio was found, even for the five well-studied SNPs, namely UGT2B7 G211T, C802T, C161T, T125C, and CYP2C9 * 3 A1075C. However, a significant association between the C 0/D ratio and UGT1A6/9 Del>A (rs144486213) was observed in the VPA oral solution group, but not in the VPA SR tablet group. Conclusions: The dosage forms of sodium valproate, rather than BW, age, or genetic polymorphisms, significantly affected the VPA C 0/D ratios in pediatric patients with epilepsy. Based on our findings, switching the dosage form between solution and SR tablet should be performed cautiously. Total daily dose adjustment should be considered, and the plasma concentration, seizure-control effect, and adverse drug reaction should also be monitored very closely.
RESUMEN
BACKGROUND: Valproic acid (VPA) as a widely used primary medication in the treatment of epilepsy is associated with reversible or irreversible hepatotoxicity. Long-term VPA therapy is also related to increased risk for the development of non-alcoholic fatty liver disease (NAFLD). In this review, metabolic elimination pathways of VPA in the liver and underlying mechanisms of VPA-induced hepatotoxicity are discussed. METHODS: We searched in PubMed for manuscripts published in English, combining terms such as "Valproic acid", "hepatotoxicity", "liver injury", and "mechanisms". The data of screened papers were analyzed and summarized. RESULTS: The formation of VPA reactive metabolites, inhibition of fatty acid ß-oxidation, excessive oxidative stress and genetic variants of some enzymes, such as CPS1, POLG, GSTs, SOD2, UGTs and CYPs genes, have been reported to be associated with VPA hepatotoxicity. Furthermore, carnitine supplementation and antioxidants administration proved to be positive treatment strategies for VPA-induced hepatotoxicity. CONCLUSION: Therapeutic drug monitoring (TDM) and routine liver biochemistry monitoring during VPA-therapy, as well as genotype screening for certain patients before VPA administration, could improve the safety profile of this antiepileptic drug.