RESUMO
Effective screening and early detection are critical to improve the prognosis of gastric cancer (GC). Our study aims to explore noninvasive multianalytical biomarkers and construct integrative models for preliminary risk assessment and GC detection. Whole genomewide methylation marker discovery was conducted with CpG tandems target amplification (CTTA) in cfDNA from large asymptomatic screening participants in a high-risk area of GC. The methylation and mutation candidates were validated simultaneously using one plasma from patients at various gastric lesion stages by multiplex profiling with Mutation Capsule Plus (MCP). Helicobacter pylori specific antibodies were detected with a recomLine assay. Integrated models were constructed and validated by the combination of multianalytical biomarkers. A total of 146 and 120 novel methylation markers were found in CpG islands and promoter regions across the genome with CTTA. The methylation markers together with the candidate mutations were validated with MCP and used to establish a 133-methylation-marker panel for risk assessment of suspicious precancerous lesions and GC cases and a 49-methylation-marker panel as well as a 144-amplicon-mutation panel for GC detection. An integrated model comprising both methylation and specific antibody panels performed better for risk assessment than a traditional model (AUC, 0.83 and 0.63, P < .001). A second model for GC detection integrating methylation and mutation panels also outperformed the traditional model (AUC, 0.82 and 0.68, P = .005). Our study established methylation, mutation and H. pylori-specific antibody panels and constructed two integrated models for risk assessment and GC screening. Our findings provide new insights for a more precise GC screening strategy in the future.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Metilação de DNA , Detecção Precoce de Câncer , Biomarcadores , Medição de Risco , Helicobacter pylori/genética , Biomarcadores Tumorais/genética , Ilhas de CpG , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/genética , Infecções por Helicobacter/patologiaRESUMO
The pursuit of highly efficient electrocatalysts for the alkaline hydrogen evolution reaction (HER) is of paramount importance for water splitting. However, it is still a formidable task in Mo2C-based materials because of the agglomeration and strong Mo-H binding of Mo2C units. Herein, a novel CeOCl-CeO2/Mo2C heterostructure nesting within a three-dimensional porous nitrogen-doped carbon matrix has been designed and used for catalyzing HER via simultaneous morphology and heterointerface engineering. As expected, the optimal CeOCl-CeO2(0.2)/Mo2C@3DNC exhibits impressive HER activity, with a low overpotential of 156 mV at a current density of 10 mA cm-2 coupled with a slight Tafel slope of 62.20 mV dec-1. Introducing a Ce promoter, that is CeOCl and CeO2, would endow the interface with an internal electric field and electron redistribution between CeOCl-CeO2 and Mo2C induced by the heterogeneous work function difference. Moreover, experimental investigation and density functional calculations confirm that the CeOCl-CeO2/Mo2C heterointerface can downshift the d-band center of the active Mo center, weakening the strength of the Mo-H coupling. This proposed concept, engineering Ce-based promoters into active entities involved in the heterostructure to modulate intermediate adsorption, offers a great opportunity for the design of superior electrocatalysts for energy conversion.
RESUMO
It is a challenging task to utilize efficient electrocatalytic metal hydroxide-based materials for the oxygen evolution reaction (OER) in order to produce clean hydrogen energy through water splitting, primarily due to the restricted availability of active sites and the undesirably high adsorption energies of oxygenated species. To address these challenges simultaneously, we intentionally engineer a hollow star-shaped Ag/CoMo-LDH heterostructure as a highly efficient electrocatalytic system. This design incorporates a considerable number of heterointerfaces between evenly dispersed Ag nanoparticles and CoMo-LDH nanosheets. The heterojunction materials have been prepared using self-assembly, in situ transformation, and spontaneous redox processes. The nanosheet-integrated hollow architecture can prevent active entities from agglomeration and facilitate mass transportation, enabling the constant exposure of active sites. Specifically, the powerful electronic interaction within the heterojunction can successfully regulate the Co3+/Co2+ ratio and the d-band center, resulting in rational optimization of the adsorption and desorption of the intermediates on the site. Benefiting from its well-defined multifunctional structures, the Ag0.4/CoMo-LDH with optimal Ag loading exhibits impressive OER activity, the overpotential being 290 mV to reach a 10 mA cm-2 current density. The present study sheds some new insights into the electron structure modulation of hollow heterostructures toward rationally designing electrocatalytic materials for the OER.
RESUMO
BACKGROUND: Karat (Musa troglodytarum L.) is an autotriploid Fe'i banana of the Australimusa section. Karat was domesticated independently in the Pacific region, and karat fruit are characterized by a pink sap, a deep yellow-orange flesh colour, and an abundance of ß-carotene. Karat fruit showed non-climacteric behaviour, with an approximately 215-day bunch filling time. These features make karat a valuable genetic resource for studying the mechanisms underlying fruit development and ripening and carotenoid biosynthesis. RESULTS: Here, we report the genome of M. troglodytarum, which has a total length of 603 Mb and contains 37,577 predicted protein-coding genes. After divergence from the most recent common ancestors, M. troglodytarum (T genome) has experienced fusion of ancestral chromosomes 8 and 9 and multiple translocations and inversions, unlike the high synteny with few rearrangements found among M. schizocarpa (S genome), M. acuminata (A genome) and M. balbisiana (B genome). Genome microsynteny analysis showed that the triplication of MtSSUIIs due to chromosome rearrangement may lead to the accumulation of carotenoids and ABA in the fruit. The expression of duplicated MtCCD4s is repressed during ripening, leading to the accumulation of α-carotene, ß-carotene and phytoene. Due to a long terminal repeat (LTR)-like fragment insertion upstream of MtERF11, karat cannot produce large amounts of ethylene but can produce ABA during ripening. These lead to non-climacteric behaviour and prolonged shelf-life, which contributes to an enrichment of carotenoids and riboflavin. CONCLUSIONS: The high-quality genome of M. troglodytarum revealed the genomic basis of non-climacteric behaviour and enrichment of carotenoids, riboflavin, flavonoids and free galactose and provides valuable resources for further research on banana domestication and breeding and the improvement of nutritional and bioactive qualities.
Assuntos
Musa , Carotenoides/metabolismo , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica de Plantas , Musa/genética , Musa/metabolismo , Melhoramento Vegetal , Riboflavina/genética , Riboflavina/metabolismo , beta Caroteno/metabolismoRESUMO
Ciliatasecones A-C (1-3), three rearranged limonoids with a novel ring-seco model and an unprecedented cycle system, were isolated from the root bark of Toona ciliata var. yunnanensis. Ciliatasecones A-B (1-2) share a novel cyclopenta[b]furan ring C/D system through C-9/11-seco and C-11/14 ether linkage. Ciliatasecone C (3) was found to possess a rare rearranged six-membered lactone ring B between C-7 and C-9. Plausible biogenetic pathway speculation indicated that C-9/11 cleavage and oxygen bridge formation played the key roles in the framework rearrangement of 1-3.
RESUMO
A synthesis-inspired chemical investigation of the leaves of Melicope ptelefolia led to the isolation of evodialones A-D (1-4), four rearranged acetophenone stereoisomers possessing a prenylated acylcyclopentenone skeleton with three stereogenic carbons. Evodialones C and D (3 and 4) are new minor constituents. The chiral-phase HPLC resolution gave (+)-1-4 and (-)-1-4, eight enantiomers forming a complete stereoisomer library. Their absolute configurations were elucidated via extensive spectroscopic data and a modified Mosher's method. The relationship between the chiral structures and their NMR and ECD data is discussed. Compounds (±)-1, -2, and -4 have significant protective effects on high-glucose-induced oxidative stress in human vein endothelial cells.
Assuntos
Acetofenonas/química , Células Endoteliais/química , Folhas de Planta/química , Rutaceae/química , Cromatografia Líquida de Alta Pressão , Humanos , Espectroscopia de Ressonância Magnética , Prenilação , EstereoisomerismoRESUMO
Artemisianins A-D (1-4), four stereoisomers of sesquiterpenoid dimers, forming via [4+2] cycloaddition from a 1, 10-seco-guaianolide dienophile and a guaianolide diene, along with two biosynthetically related precurors 5 and 6, were isolated from the famous traditional Chinese medicine Artemisia argyi. The structures of 1-4, including their absolute configurations, were elucidated by extensive spectroscopic data and ECD/TDDFT calculation analysis. Compounds 1-4 exhibited cytotoxicity with IC50 values ranging from 7.2 to 23.3⯵M. The accumulation of Ca2+ in cytoplasm and enlarged endoplasmic reticulum (ER) indicated that 1 mediated HT-29 cancer cell apoptosis through improvement of ER-stress, which was further proved by unfolded protein response (UPR) pathway on basis of the upregulation of IRE1α, p-PERK, ATF6, and CHOP.
Assuntos
Apoptose , Artemisia/química , Estresse do Retículo Endoplasmático , Sesquiterpenos/química , Apoptose/efeitos dos fármacos , Artemisia/metabolismo , Linhagem Celular Tumoral , Dimerização , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Medicina Tradicional Chinesa , Conformação Molecular , Folhas de Planta/química , Folhas de Planta/metabolismo , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , EstereoisomerismoRESUMO
Nine new spirocyclic acylphloroglucinol derivatives, hyperpatulols A-I (1-9), were characterized from the flowers of Hypericum patulum. Their structures were elucidated by the basic analysis of the obtained spectroscopic data, and their absolute configurations were assigned by both the electronic circular dichroism (ECD) exciton chirality method and ECD calculation. The evaluation of their anti-migration effects on U2-OS human osteosarcoma cells showed that compound 4 exhibited moderate inhibitory activity in a dose-dependent manner. Further pharmacological studies revealed that 4 could regulate the expression of the proteins Vimentin and E-cadherin.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Flores/química , Hypericum/química , Floroglucinol/farmacologia , Compostos de Espiro/farmacologia , Antígenos CD/genética , Antígenos CD/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Floroglucinol/análogos & derivados , Floroglucinol/química , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Relação Estrutura-Atividade , Vimentina/genética , Vimentina/metabolismoRESUMO
BACKGROUND: Centenarians refer to a special group who have outlived most of their fellows. Body shape and abdominal obesity have been identified as cardiovascular disease (CVD) risk factors. Our study aimed to evaluate the relationship between body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) and CVD risk factors among male and female centenarians in Hainan province. METHODS: Five hundred thirty-seven centenarians aged between 100 and 115 (Mage = 107 years old) years participated in this study. Each participant received a standardized questionnaire and physical examination. We measured anthropometric variables (BMI, WC, WHR, WHtR, SBP and DBP) and serum lipid (TC, TG, HDL-C and LDL-C). RESULTS: 76.9% (n = 413) of the study subjects were female. TC, TG, LDL-C and HDL-C were significantly higher in female group than that of male group. BMI, WC and WHtR were well-correlated with the CVD risk factors. The anthropometric measures were negatively related with HDL-C levels and positively related with the other CVD risk factors. CONCLUSIONS: Hainan centenarians were short in stature and underweight. Moreover, female centenarians were often pear-shaped, while male centenarians were often apple-shaped. Further, BMI, WC and WHtR were well-correlated with the serum lipid, and TC, TG, LDL-C and HDL-C were significantly higher in females than males. Also, BMI, WC and WHtR were closely related to the incidence of dyslipidemia in females, including high TG, high LDL-C and low HDL-C.
Assuntos
Antropometria , Doenças Cardiovasculares/epidemiologia , Obesidade/epidemiologia , Fatores Etários , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Pressão Sanguínea , Estatura , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , China/epidemiologia , Feminino , Avaliação Geriátrica , Humanos , Lipídeos/sangue , Masculino , Obesidade/sangue , Obesidade/diagnóstico , Obesidade/fisiopatologia , Fatores de Risco , Fatores Sexuais , Circunferência da Cintura , Razão Cintura-Estatura , Relação Cintura-QuadrilRESUMO
Peyronellones A and B (1 and 2), a pair of rare tetracyclic caged adducts of azaphilone with pyruvic acid, along with four new analogues (3-6), were isolated from solid cultures of the endophytic fungus Peyronellaea glomerata. Their structures were elucidated through spectroscopic analysis, and their absolute configurations were unambiguously determined by a combination of single-crystal X-ray crystallography, Rh2(OCOCF3)4-induced ECD experiments, ECD calculations, and modified Mosher methods. Compound 2 (5 µM) was found to have a significant hypoxia-protective effect that improved the survival rate of hypoxia/reoxygenation-treated human umbilical vein endothelial cells from 35% to 70%, which was equal to the potency of the positive control, verapamil. Flow cytometry analysis suggested 2 could inhibit H/R-induced late-stage apoptosis of this cell line.
Assuntos
Ascomicetos/química , Benzopiranos/farmacologia , Hipóxia/tratamento farmacológico , Pigmentos Biológicos/farmacologia , Substâncias Protetoras/farmacologia , Apoptose/efeitos dos fármacos , Benzopiranos/química , Células Cultivadas , Cristalografia por Raios X/métodos , Endófitos/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Pigmentos Biológicos/química , Substâncias Protetoras/química , Ácido Pirúvico/química , Taxa de Sobrevida , Verapamil/farmacologiaRESUMO
Ten new highly oxidized monomeric (1-8) and dimeric guaianolides (9 and 10), along with two known guaianolide derivatives (11 and 12), were isolated from the aerial parts of Chrysanthemum indicum using a bioassay-guided fractionation procedure. The new compounds were characterized by the basic analysis of the spectroscopic data obtained, and the absolute configurations were determined by both empirical approaches and ECD calculations. Inhibitory effects of 1-12 on nitric oxide production were investigated in lipopolysaccaride (LPS)-mediated RAW 264.7 cells, and most of them (1-8 and 11) displayed IC50 values in the range 1.4-9.7 µM. Moreover, a mechanistic study revealed that the potential anti-inflammatory activity of compound 1 appears to be mediated via suppression of an LPS-induced NF-κB pathway and down-regulation of MAPK activation.
Assuntos
Anti-Inflamatórios/química , Chrysanthemum/química , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Lipopolissacarídeos/farmacologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células RAW 264.7RESUMO
BACKGROUND Gremlin has been reported to be up-regulated in glomerular mesangial cells in diabetic nephropathy (DN). However, the regulation of gremlin in podocytes is still rarely reported. This study aimed to investigate the underlying mechanisms by which gremlin mediates the pathogenesis of DN via transforming growth factor-ß (TGF-ß) signaling pathways. MATERIAL AND METHODS Lentiviral and RNAi transfection were performed to increase and decrease gremlin expression in high-glucose conditions. Expression at the mRNA and protein level was detected by RT-qPCR and Western blotting. RESULTS The expression of gremlin was significantly higher in high-glucose (HG, 30mM) than normal-glucose (NG, 5.5 mM) conditions. The gremlin overexpression significantly suppressed the expression of nephrin and synaptopodin. The phosphorylation of canonical TGF-b signaling pathway components, including Smad2/3 and MKK, was increased in the gremlin-overexpressing group. In addition, the expression levels of Bax and cleaved caspase-3 were also higher in the gremlin-overexpressing group. TGF-ß pathway inhibitor (SB505124) significantly inhibited TGF-ß pathway activity and enhanced the expression of nephrin and synaptopodin. CONCLUSIONS These results indicate that gremlin can aggravate podocyte lesions through the TGF-ß signaling pathway, providing a novel therapeutic target for DN.
Assuntos
Apoptose , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Podócitos/citologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzodioxóis/farmacologia , Citocinas , Imidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Lentivirus/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Proteínas dos Microfilamentos/metabolismo , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-ß (Aß) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aß1-42 aggregation (91.3±2.1%, 25µM), inhibition of hMAO-B (IC50, 1.73±0.39µM), antioxidant effects (43.4±2.6µM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Iminas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Salicilatos/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Peróxido de Hidrogênio/farmacologia , Iminas/síntese química , Iminas/química , Ligantes , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Ratos , Salicilatos/síntese química , Salicilatos/química , Relação Estrutura-AtividadeRESUMO
In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of chromone derivatives were designed, synthesized and evaluated. In vitro assay indicated that most of the target compounds have both MAOs inhibition activities, antioxidant activity and biometal chelating ability. Especially, compound s19 exhibits good inhibitory potency for inhibition of MAOs (IC50 value of 5.12µM for hMAO-A and 0.816µM for hMAO-B), moderate inhibition of Aß aggregation (75.1% at 20µM), metal chelation, control of ROS generation and antioxidant activity (ORAC=3.62). In addition, s19 could reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results suggested that s19 might be a promising multitargeted compound for AD treatment.
Assuntos
Cromonas/química , Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Cromonas/farmacologia , Cromonas/uso terapêutico , Cobre/química , Cobre/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Estrutura Terciária de Proteína , Ratos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Three new syncarpic acid-conjugated sesquiterpenoids, tomentodiones E-G (1-3), and six new syncarpic acid-conjugated monoterpenoids, tomentodiones H-M (4-9), were isolated from the leaves of Rhodomyrtus tomentosa. Compounds 1-3 represent the first examples of ß-calacorene-based meroterpenoids. Their structures and absolute configurations were determined by a combination of NMR and ECD spectroscopy and X-ray diffraction analysis. On the basis of ECD data analysis for isolated and synthesized compounds, an empirical rule was proposed to determine the absolute configuration at C-7' of syncarpic acid-conjugated terpenoids. Additionally, a study of the reversal effect of multidrug resistance in doxorubicin-resistant human breast cancer cells showed that the noncytotoxic (+)-4 exerted the strongest potentiation effect of doxorubicin susceptibility, with an enhancement of 16.5-fold at a concentration of 30 µM.
Assuntos
Medicamentos de Ervas Chinesas/isolamento & purificação , Monoterpenos/isolamento & purificação , Myrtaceae/química , Sesquiterpenos/isolamento & purificação , Terpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Estrutura Molecular , Monoterpenos/química , Monoterpenos/farmacologia , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Relação Estrutura-Atividade , Terpenos/química , Terpenos/farmacologiaRESUMO
Nine formyl-phloroglucinolmeroterpenoids (FPMs), namely, eucalrobusonesâ A-I (1-9), were isolated from the leaves of Eucalyptus robusta by tracking the phenolic hydroxyl (1) Hâ NMR peaks. The Snatzke helicity rules for the Cotton effects of twisted benzene rings were applied to elucidate the absolute configurations of the FPMs. These findings, along with NMR spectroscopy, the circular dichroism (CD) exciton chirality method, and CD calculations, allowed complete structures for the FPMs to be assigned. Eucalrobusonesâ A-F (1-6) are novel adducts formed between a formyl-derived carbon atom on the phloroglucinol ring and monoterpene and sesquiterpene components. Eucalrobusonesâ G-I (7-9) are the first examples of FPMs with cubebane part structures connected by an unusual 1-oxaspiro[5.5]undecane subunit. Among these isolates, eucalrobusoneâ C (3) showed significant cytotoxicity against HepG2, MCF-7, and U2OS cancer cell lines, with IC50 values less than 10â µm. Compound 3 significantly blocks cell proliferation in MCF-7 cells and induces MCF-7 cell death through apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Eucalyptus/química , Floroglucinol/química , Folhas de Planta/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Terpenos/química , Terpenos/farmacologia , Dicroísmo Circular , Humanos , Células MCF-7 , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Sesquiterpenos/isolamento & purificação , Terpenos/isolamento & purificaçãoRESUMO
Trichiconlides A (1) and B (2), two novel limonoids, were isolated from the fruits of Trichilia connaroides. Compound 1 is a novel limonoid with a highly rearranged A/B ring system and an intact D ring, which formed an unprecedented 5/6/5/6/5 carbon skeleton. Trichiconlide B (2) possesses a 10-oxatricyclo[3.3.1.(3,8)]decane core and formed a cage-like structure located between rings A and C. Their structures and absolute configurations were elucidated by spectroscopic methods, single crystal X-ray diffraction, the ECD exciton chirality method and TDDFT/ECD calculations. 1 showed a moderate inhibitory effect on nitric oxide (NO) production.
Assuntos
Frutas/química , Limoninas/isolamento & purificação , Meliaceae/química , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Limoninas/química , Limoninas/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Modelos Moleculares , Conformação Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and ß-amyloid (Aß) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Aß aggregation (56.3% at 20µM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Indanos/farmacologia , Indóis/farmacologia , Melatonina/análogos & derivados , Melatonina/farmacologia , Piperidinas/farmacologia , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Antioxidantes/síntese química , Antioxidantes/toxicidade , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/farmacologia , Quelantes/toxicidade , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/toxicidade , Donepezila , Electrophorus , Cavalos , Humanos , Indanos/síntese química , Indanos/toxicidade , Indóis/síntese química , Indóis/toxicidade , Ferro/química , Cinética , Melatonina/síntese química , Melatonina/toxicidade , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Piperidinas/síntese química , Piperidinas/toxicidade , Multimerização Proteica , Ratos , Zinco/químicaRESUMO
The isolation of the new polycyclic polyprenylated acylphloroglucinols uraliones A-K (1-11) together with five known analogues (12-16) from a whole Hypericum uralum plant was reported. The structures of these compounds were established through spectroscopic methods, and a single-crystal X-ray diffraction analysis was used to confirm the absolute configuration of 1. The protective effects of the isolates against corticosterone-induced PC12 cell injury were assessed. Except for compound 9, all tested compounds exhibited significant protective effects against induced injury in PC12 cells. Uralodin A (14), orally administered in doses of 13 and 26 mg/kg, exhibited antidepressant-like activity in the tail suspension and forced-swimming tests in mice.