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1.
J Alzheimers Dis ; 99(4): 1361-1374, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38788079

RESUMO

Background: The aging population and high rates of Alzheimer's disease (AD) create significant medical burdens, prompting a need for early prevention. Targeting modifiable risk factors like vascular risk factors (VRFs), closely linked to AD, may provide a promising strategy for intervention. Objective: This study investigates how VRFs influence cognitive performance and brain structures in a community-based cohort. Methods: In this cross-sectional study, 4,667 participants over 50 years old, drawn from the Beijing Ageing Brain Rejuvenation Initiative project, were meticulously examined. Cognitive function and VRFs (diabetes mellitus, hypertension, hyperlipidemia, obesity, and smoking), were comprehensively assessed through one-to-one interviews. Additionally, a subset of participants (n = 719) underwent MRI, encompassing T1-weighted and diffusion-weighted scans, to elucidate gray matter volume and white matter structural network organization. Results: The findings unveil diabetes as a potent detriment to memory, manifesting in atrophy within the right supramarginal gyrus and diminished nodal efficiency and degree centrality in the right inferior parietal lobe. Hypertension solely impaired memory without significant structural changes. Intriguingly, individuals with comorbid diabetes and hypertension exhibited the most pronounced deficits in both brain structure and cognitive performance. Remarkably, hyperlipidemia emerged as a factor associated with enhanced cognition, and preservation of brain structure. Conclusions: This study illuminates the intricate associations between VRFs and the varied patterns of cognitive and brain structural damage. Notably, the synergistic effect of diabetes and hypertension emerges as particularly deleterious. These findings underscore the imperative to tailor interventions for patients with distinct VRF comorbidities, especially when addressing cognitive decline and structural brain changes.


Assuntos
Envelhecimento , Encéfalo , Imageamento por Ressonância Magnética , Humanos , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Fatores de Risco , Envelhecimento/patologia , Envelhecimento/fisiologia , Estudos Transversais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos de Coortes , Hipertensão/epidemiologia , Diabetes Mellitus/epidemiologia , Cognição/fisiologia
2.
Bioorg Med Chem ; 93: 117454, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37659218

RESUMO

Bacterial infection, which is still one of the leading causes of death in humans, poses an enormous threat to the worldwide public health system. Antibiotics are the primary medications used to treat bacterial diseases. Currently, the discovery of antibiotics has reached an impasse, and due to the abuse of antibiotics resulting in bacterial antibiotic resistance, researchers have a critical desire to develop new antibacterial agents in order to combat the deteriorating antibacterial situation. Natural chalcones, the flavonoids consisting of two phenolic rings and a three-carbon α, ß-unsaturated carbonyl system, possess a variety of biological and pharmacological properties, including anti-cancer, anti-inflammatory, antibacterial, and so on. Due to their potent antibacterial properties, natural chalcones possess the potential to become a new treatment for infectious diseases that circumvents existing antibiotic resistance. Currently, the majority of research on natural chalcones focuses on their synthesis, biological and pharmacological activities, etc. A few studies have been conducted on their antibacterial activity and mechanism. Therefore, this review focuses on the antibacterial activity and mechanisms of seventeen natural chalcones. Firstly, seventeen natural chalcones have been classified based on differences in antibacterial mechanisms. Secondly, a summary of the isolation and biological activity of seventeen natural chalcones was provided, with a focus on their antibacterial activity. Thirdly, the antibacterial mechanisms of natural chalcones were summarized, including those that act on bacterial cell membranes, biological macromolecules, biofilms, and quorum sensing systems. This review aims to lay the groundwork for the discovery of novel antibacterial agents based on chalcones.


Assuntos
Chalconas , Humanos , Chalconas/farmacologia , Flavonoides , Antibacterianos/farmacologia , Biofilmes , Carbono
3.
Talanta ; 257: 124343, 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-36791596

RESUMO

Prostate cancer is one of the most common cancers in the world, and its early diagnosis can effectively reduce mortality. A new label-free photoelectrochemical (PEC) immunosensor on the basis of Bi2WO6/BiOBr nanocomposite materials has been successfully prepared for the test of prostate-specific antigen (PSA) in human serum in this work. The Ag2S-sensitized Bi2WO6/BiOBr heterojunction was used as a photosensitive material, which effectively improved the photocurrent response. On Bi2WO6/BiOBr surface, dopamine immobilized PSA antibody by self-polymerizing to form polydopamine membrane. Antigen and antibody are specifically combined to achieve quantitative detection of PSA according to the current changes at different concentrations of antigen. Under the optimal experimental conditions, the PEC immunosensor has an ideal linear relationship between 1 pg/mL - 50 ng/mL, and the detection limit is 0.084 pg/mL. In addition, the prepared immunosensor has good stability, reproducibility and selectivity, providing a new method for the detection of PSA in actual sample analysis.


Assuntos
Técnicas Biossensoriais , Antígeno Prostático Específico , Humanos , Masculino , Técnicas Biossensoriais/métodos , Reprodutibilidade dos Testes , Imunoensaio/métodos , Técnicas Eletroquímicas/métodos , Anticorpos , Limite de Detecção
4.
Bioorg Med Chem Lett ; 78: 129041, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36332882

RESUMO

Proteolysis Targeting Chimeras (PROTACs) based on multi-target inhibitors have been reported several times recently. The advantages of PROTACs technology and the synergistic mechanism of multi-target drugs endow this class of protein degraders with special research significance. Herein, twelve new PROTACs based on Sunitinib and VHL-ligand were synthesized and evaluated for their in vitro anticancer activities. Among them, PROTACs 5 (IC50 = 2.9 ± 1.5 µM) exhibited the most significant antiproliferative activity against HL-60 cells. Western blot results showed that PROTAC 5 reduced the protein levels of FLT-3 and c-KIT in HL-60 cells, and induced the degradation of FLT-3 via the ubiquitin-proteasome system. Moreover, PROTACs 5 and 6 reduced the protein levels of FLT-3 in K562 cells. These results suggest that PROTAC 5 has the potential for further research, especially in combination with small molecule kinase inhibitors to study multidrug resistance of tyrosine kinase inhibitors in cancer treatment.


Assuntos
Leucemia , Humanos , Sunitinibe/farmacologia , Proteólise , Leucemia/tratamento farmacológico , Células HL-60 , Complexo de Endopeptidases do Proteassoma
5.
Front Pharmacol ; 13: 1035882, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339566

RESUMO

Glycolysis is a complex metabolic process that occurs to convert glucose into pyruvate to produce energy for living cells. Normal cells oxidized pyruvate into adenosine triphosphate and carbon dioxide in the presence of oxygen in mitochondria while cancer cells preferentially metabolize pyruvate to lactate even in the presence of oxygen in order to maintain a slightly acidic micro-environment of PH 6.5 and 6.9, which is beneficial for cancer cell growth and metastasis. Therefore targeting glycolytic signaling pathways provided new strategy for anti-cancer therapy. Natural products are important sources for the treatment of diseases with a variety of pharmacologic activities. Accumulated studies suggested that natural products exhibited remarkable anti-cancer properties both in vitro and in vivo. Plenty of studies suggested natural products like flavonoids, terpenoids and quinones played anti-cancer properties via inhibiting glucose metabolism targets in glycolytic pathways. This study provided an updated overview of natural products controlling glycolytic pathways, which also provide insight into druggable mediators discovery targeting cancer glucose metabolism.

6.
Artigo em Inglês | MEDLINE | ID: mdl-35990823

RESUMO

Background: Biejiajian pill (BJJP), a classical traditional Chinese formula, has been reported that it has an effective treatment for diabetic atherosclerosis in recent years, but its underlying mechanisms remain elusive. The study aimed to explore the potential mechanisms of BJJP on diabetic atherosclerosis by integrating network pharmacology, molecular docking, and molecular dynamics simulation. Methods: The active components of BJJP were collected by TCMSP and TCMID, and then the potential targets were obtained from the SwissTargetPrediction database. The targets related to diabetic atherosclerosis were identified from the GeneCards and OMIM databases. The intersection of the potential targets regulated by active components of BJJP and the targets of diabetic atherosclerosis were common targets, which were visualized by the Venn diagram. The common targets were imported into the STRING database to construct a protein-protein interaction (PPI) network. The network of "Medicine-Compound-Target" was constructed with Cytoscape 3.7.1 software. GO functional enrichment analysis and KEGG pathway enrichment analysis were performed using the DAVID database and visualized through bioinformatics. The intersecting targets were input into Cytoscape 3.7.1 software, and the Network Analyzer tool was employed to screen out the key targets. Then molecular docking was used to verify the binding affinity between the active compounds and the key targets, and molecular dynamics simulation was used to investigate the stability of the binding models. Results: A total of 81 active components, 186 targets of BJJP, and 4041 targets of diabetic atherosclerosis were obtained. Furthermore, 121 overlapping targets were identified. GO functional enrichment analysis revealed that these targets were correlated with the oxidation-reduction process, negative regulation of apoptotic process, inflammatory response, and other biological processes. The results of the KEGG pathway enrichment analysis showed that the common targets mainly participated in proteoglycans in cancer, PPAR signaling pathway, adherens junction, insulin resistance, HIF-1 signaling pathway, PI3K-Akt signaling pathway, etc. The results of molecular docking confirmed that the core active components in BJJP could bind well to the key targets. Results from molecular dynamics simulation showed that the binding energies of AKT1-Luteolin, MMP9-quercetin, and MMP9-luteolin complexes were -28.93 kJ·mol-1, -37.12 kJ·mol-1, and -62.91 kJ·mol-1, respectively. Conclusion: The study revealed that BJJP is characterized as multicomponent, multitarget, and multipathway to treat diabetic atherosclerosis, which is helpful to provide ideas and a basis for pharmacological research and clinical application in the future.

7.
Drug Des Devel Ther ; 16: 2731-2753, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36003311

RESUMO

Purpose: This study was the first to screen the active compounds of Jian Aikang Concentrated Pill (JAKCP) with network pharmacology, predict its potential targets, screen the signaling pathways, and combine with cellular experimental validation to explore the potential mechanism of JAKCP for the treatment of acquired immunodeficiency syndrome (AIDS). Methods: The main compounds and targets of Chinese herbs in JAKCP were identified by TCMSP; the targets of AIDS were collected from Genecards, Online Mendelian Inheritance in Man (OMIM), Disgenet, Therapeutic Target Database (TTD) and Drugbank; the network of "Chinese herbs-active compounds-targets" for JAKCP was constructed by Cytoscape, and protein-protein interaction (PPI) network was constructed using STRING to generate the intersection targets, Metascape was conducted to analyze the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and the network of "main active compounds-core targets-pathways" was constructed by Cytoscape. Finally, the effect of JAKCP on the survival rate of HIV pseudovirus-infected MT-4 cells was investigated by CCK-8 assay, and the predicted targets were verified by ELISA, qPCR and Western blot. Results: A total of 147 active compounds of JAKCP were screened covering 351 targets and 416 AIDS disease targets were obtained, besides 140 intersection targets and 321 KEGG pathways were collected. Ultimately, quercetin, kaempferol, stigmasterol, beta-sitosterol, epigallocatechin gallate were identified as the important compounds, the core targets are HSP90AA1, IL-10, IL-6, TNF, IL-1ß, TP53, and IL-1ɑ, and the biological pathways and processes mainly include T cell activation, regulation of DNA-binding transcription factor activity and apoptotic signaling pathway. Experiments on the targets of "T cell activation" demonstrated that JAKCP promotes the survival of HIV pseudovirus-infected MT-4 cells. Also, JAKCP down-regulated mRNA and protein levels of IL-1ɑ, IL-1ß, and IL-6 while up-regulated mRNA and protein levels of IL-2, IL-6ST, and IL-10 in vitro. Conclusion: JAKCP exerted regulatory immune functions through multi-component, multi-target and multi-pathway, thereby providing novel ideas and clues for the treatment of AIDS.


Assuntos
Síndrome da Imunodeficiência Adquirida , Medicamentos de Ervas Chinesas , Farmacologia em Rede , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Imunidade , Interleucina-10 , Interleucina-6 , Simulação de Acoplamento Molecular , Farmacologia em Rede/métodos , RNA Mensageiro
8.
Bioelectrochemistry ; 142: 107928, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34428614

RESUMO

Prostate cancer is one of the most common cancers in the world, and its early detection is vital to saving the lives of patients. In this research, a novel label-free photoelectrochemical immunosensor was designed for sensitive detection of prostate specific antigen (PSA). Ag2S sensitized on Ag/AgBr/BiOBr heterojunction could effectively inhibit photogenic holes recombination and improve photocurrent response and sensitivity. Ascorbic acid was an effective electron donor, which can effectively eliminate photo-generated holes. The photocurrent reduced linearly with the logarithm of PSA concentration ranged from 0.001 to 50 ng·mL-1 and the limit of detection was 0.25 pg·mL-1. The designed sensor had the advantages of wide linear range, good stability, high reproducibility, and good selectivity. This study not only provided a method for efficient and sensitive detection of PSA, but also provided valuable reference ideas for the detection of other tumor markers.


Assuntos
Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Calicreínas/sangue , Nanocompostos/química , Antígeno Prostático Específico/sangue , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo
9.
J Biomol Struct Dyn ; 39(10): 3721-3732, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32425109

RESUMO

Phosphatidylinositol 3-kinase alpha (PI3Kα) is among the most important PI3K isoforms and has been associated with multiple human cancers. Therefore, PI3Kα has garnered considerable attention as a viable target for anticancer drug discovery, and thus the identification and development of highly potent inhibitors of this isoform has become an important line of research. Here, structure-based virtual screening, bioassays, and molecular dynamics simulations were performed to discover novel potential PI3Kα inhibitors. TCM-N1 (ZINC13382850) was identified as a possible PI3Kα inhibitor. Particularly, fluorescence quenching assays determined that the binding affinity of the aforementioned compound was superior to that of a reference ligand (BYL719; i.e. a known PI3Kα inhibitor). Moreover, enzymatic activity and cell proliferation inhibition assays indicated that TCM-N1 possessed a moderate inhibition activity against PI3Kα and a relatively high anti-tumor proliferation ability in gastric, colorectal, and cervical cancer cells. The binding model and related thermodynamic parameters further demonstrated that TCM-N1 was tightly embedded into the ATP-binding pocket via hydrogen bonds, van der Waals interactions, and hydrophobic interactions. Therefore, this study provides promising insights into the development and design of more potent PI3Kα-inhibiting analogs. Communicated by Ramaswamy H. Sarma.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase
10.
Front Aging Neurosci ; 13: 632217, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34987373

RESUMO

The role of the right hemisphere (RH) in post-stroke aphasia (PSA) has not been completely understood. In general, the language alterations in PSA are normally evaluated from the perspective of the language processing models developed from Western languages such as English. However, the successful application of the models for assessing Chinese-language functions in patients with PSA has not been reported. In this study, the features of specific language-related lesion distribution and early variations of structure in RH in Chinese patients with PSA were investigated. Forty-two aphasic patients (female: 13, male: 29, mean age: 58 ± 12 years) with left hemisphere (LH) injury between 1 and 6 months after stroke were included. The morphological characteristics, both at the levels of gray matter (GM) and white matter (WM), were quantified by 3T multiparametric brain MRI. The Fridriksson et al.'s dual-stream model was used to compare language-related lesion regions. Voxel-based lesion-symptom mapping (VLSM) analysis has been performed. Our results showed that lesions in the precentral, superior frontal, middle frontal, and postcentral gyri were responsible for both the production and comprehension dysfunction of Chinese patients with PSA and were quite different from the lesions described by using the dual-stream model of Fridriksson et al. Furthermore, gray matter volume (GMV) was found significantly decreased in RH, and WM integrity was disturbed in RH after LH injury in Chinese patients with PSA. The different lesion patterns between Chinese patients with PSA and English-speaking patients with PSA may indicate that the dual-stream model of Fridriksson et al. is not suitable for the assessment of Chinese-language functions in Chinese patients with PSA in subacute phase of recovery. Moreover, decreased structural integrity in RH was found in Chinese patients with PSA.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33275090

RESUMO

A Gram-stain-negative, rod-shaped, mesophilic, milky white-pigmented, aerobic, non-spore-forming and non-flagellated bacterium, designated strain X16T, was isolated from urban soil of Zibo, Shandong, China. According to 16S rRNA gene sequence analysis, the isolate showed highest similarities with Paraflavitalea soli 5GH32-13T (97.6 %), Pseudoflavitalea soli KIS20-3T (96.2 %), Pseudobacter ginsenosidimutans Gsoil 221T (96.0 %) and Pseudoflavitalea rhizosphaerae T16R-265T (95.8 %). The neighbour-joining tree based on 16S rRNA gene sequences showed that strain X16T formed a subcluster with Paraflavitalea soli 5GH32-13T, and the subcluster was closely related to Pseudoflavitalea soli KIS20-3T, Pseudobacter ginsenosidimutans Gsoil 221T and Pseudoflavitalea rhizosphaerae T16R-265T. Strain X16T also formed a subcluster with Paraflavitalea soli 5GH32-13T in phylogenetic tree based on genomic sequences. The polar lipids are phosphatidylethanolamine, two unknown aminolipids, two unknown aminophospholipids, two unknown lipids and two unknown phospholipids. The major quinone of strain X16T is menaquinone-7 and the main fatty acids (>10 % of total fatty acids) of strain X16T are iso-C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 1 G. The genome length of strain X16T is 8.7 Mb with a DNA G+C content of 47.4 %. ANI values among strain X16T and strain Paraflavitalea soli 5GH32-13T, Pseudobacter ginsenosidimutans Gsoil 221T, and Pseudoflavitalea rhizosphaerae T16R-265T are 78.1, 70.7, 70.6 %, respectively. On the basis of the results of the polyphasic characterization presented in this study, it is concluded that strain X16T represents a novel species. Besides, strain X16T can detoxify high toxicity selenite [Se(IV)] to low toxicity elemental selenium [Se(0)], for which the name Paraflavitale devenefica sp. nov. is proposed. The type strain is X16T (=KACC 21698T=GDMCC1.1757T).


Assuntos
Bacteroidetes/classificação , Filogenia , Microbiologia do Solo , Técnicas de Tipagem Bacteriana , Bacteroidetes/isolamento & purificação , Composição de Bases , China , Cidades , DNA Bacteriano/genética , Ácidos Graxos/química , Fosfatidiletanolaminas/química , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2/análogos & derivados , Vitamina K 2/química
12.
Bioorg Med Chem Lett ; 29(2): 326-328, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30472027

RESUMO

Sanjuanolide, psorachalcone A and its seven new analogues were synthesized via a combinatorial strategy by aldol reaction. In order to investigate the effect between electron density in π-conjugated systems and biological activities, several electron-withdrawing and electron-donating groups were introduced at C-4 and the phenolic hydroxyl groups of sanjuanolide. The two natural products and its seven new analogues were investigated for their inhibitory effects against five cancer cell lines. Moreover, the hydroxyisoprenyl group may be important to maintain the biological activities of sanjuanolide.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Chalconas/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
13.
Onco Targets Ther ; 9: 3555-63, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27366092

RESUMO

miR-135a was downregulated in the majority of human primary gastric cancer (GC) tissues and GC cell lines. Kinesin family member C1 (KIFC1) was significantly upregulated in GC tissues and cell lines and promoted GC development and progression. We searched for miR-135a targets by using MiRanda, TargetScan, and PicTar tools, and found that KIFC1 was a potential target of miR-135a. Based on these findings, we speculated that miR-135a might target KIFC1 to inhibit GC growth. We determined the expression of miR-135a and KIFC1 by quantitative real-time polymerase chain reaction and Western blot assays, respectively, and found downregulation of miR-135a and upregulation of KIFC1 in GC tissues and cell lines. Cell proliferation and apoptosis assays showed that knockdown of KIFC1 inhibited proliferation and promoted apoptosis of GC cells, and miR-135a mimics had similar effects on GC cell proliferation and apoptosis. Furthermore, we verified that KIFC1 was a direct target of miR-135a, which confirmed our speculation that the functional effect of miR-135a on GC cells, at least, in part, depends on KIFC1. These findings suggest that miR-135a has an important role in the suppression of GC and presents a novel mechanism of miRNA-mediated KIFC1 expression in cancer cells.

14.
Mater Sci Eng C Mater Biol Appl ; 67: 599-610, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27287159

RESUMO

To engineer bone tissue, a scaffold with good biological properties should be provided to approximate the hierarchical structure of collagen fibrils in natural bone. In this study, we fabricated a novel scaffold consisting of multilayer nanofiber fabrics (MLNFFs) by weaving nanofiber yarns of polylactic acid (PLA) and Tussah silk fibroin (TSF). The yarns were fabricated by electrospinning, and we found that spinnability, as well as the mechanical properties of the resulting scaffold, was determined by the ratio between polylactic acid and Tussah silk fibroin. In particular, a 9:1 mixture can be spun continuously into nanofiber yarns with narrow diameter distribution and good mechanical properties. Accordingly, woven scaffolds based on this mixture had excellent mechanical properties, with Young's modulus 417.65MPa and tensile strength 180.36MPa. For nonwoven scaffolds fabricated from the same materials, the Young's modulus and tensile strength were 2- and 4-fold lower, respectively. Woven scaffolds also supported adhesion and proliferation of mouse mesenchymal stem cells, and promoted biomineralization via alkaline phosphatase and mineral deposition. Finally, the scaffolds significantly enhanced the formation of new bone in damaged femoral condyle in rabbits. Thus, the scaffolds are potentially suitable for bone tissue engineering because of biomimetic architecture, excellent mechanical properties, and good biocompatibility.


Assuntos
Substitutos Ósseos , Calcificação Fisiológica/efeitos dos fármacos , Fêmur , Fibroínas/química , Nanofibras/química , Poliésteres/química , Engenharia Tecidual , Alicerces Teciduais/química , Animais , Substitutos Ósseos/química , Substitutos Ósseos/farmacologia , Células Cultivadas , Módulo de Elasticidade , Fêmur/lesões , Fêmur/metabolismo , Fêmur/patologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Coelhos
15.
J Med Chem ; 59(3): 1184-96, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26814890

RESUMO

Natural product rakicidin A induces cell death in TKI-resistant chronic myelogenous leukemia (CML) cells. Therefore, 14 rakicidin A analogues were synthesized via a highly efficient combinatorial strategy and were evaluated against CML cell lines. The conjugated diene moiety was found to be crucial for the anti-CML activity of rakicidin A, and the changes in the configuration(s) at C-2, C-3, C-14, C-15, and C-16 resulted in lower levels of anti-CML activity. The most promising compound was 4-methylester rakicidin A (1a). Compared with rakicidin A, 1a exhibited 2.8-fold greater potency against the imatinib-resistant cell line K562/G(+) and approximately 100-fold enhanced potency compared with that of imatinib. Furthermore, compound 1a demonstrated a significantly lower resistance index against Ba/F3 cells expressing BCR-ABL(T315I) than bosutinib, dasatinib, nilotinib, and ponatinib, while 1a exhibited less effect on normal hematopoietic cells. Preliminary results indicated that 1a down-regulated caspase-3 and PARP, which contributes to its K562 cell inhibitory activity.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Lipopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Lipopeptídeos/síntese química , Lipopeptídeos/química , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Relação Estrutura-Atividade
16.
J Am Chem Soc ; 136(44): 15787-91, 2014 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-25286338

RESUMO

Rakicidin A is a cyclic depsipeptide that has exhibited unique growth inhibitory activity against chronic myelogenous leukemia stem cells. Furthermore, rakicidin A has five chiral centers with unknown stereochemical assignment, and thus, can be represented by one of 32 possible stereoisomers. To predict the most probable stereochemistry of rakicidin A, calculations and structural comparison with natural cyclic depsipeptides were applied. A total synthesis of the proposed structure was subsequently completed and highlighted by the creation of a sterically hindered ester bond (C1-C15) through trans-acylation from an easily established isomer (C1-C13). The analytic data of the synthetic target were consistent with that of natural rakicidin A, and then the absolute configuration of rakicidin A was assigned as 2S, 3S, 14S, 15S, 16R. This work suggests strategies for the determination of unknown chiral centers in other cyclic depsipeptides, such as rakicidin B, C, D, BE-43547, and vinylamycin, and facilitates the investigations of rakicidin A as an anticancer stem cell agent.


Assuntos
Lipopeptídeos/química , Peptídeos Cíclicos/química , Lipopeptídeos/síntese química , Estrutura Molecular , Peptídeos Cíclicos/síntese química
17.
Eur J Med Chem ; 68: 321-32, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23994325

RESUMO

Epothilone D (Epo D) and its 9-Methyl conformational analogues were synthesized through a highly efficient combinatorial approach. The fragment E was synthesized in 11 total steps with 6 longest linear steps, and each aldehyde B was prepared via a 3-step sequence. Starting from the common precursor E and a suitable aldehydes B, each target molecule were obtained in only 4 steps. The 9-(S)-epo D and 9-(R)-epo D demonstrated significant difference in inhibition activities against cancer cell lines and in conformational analysis.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Epotilonas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Combinatória , Simulação por Computador , Cristalografia por Raios X , Epotilonas/síntese química , Epotilonas/química , Epotilonas/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Modelos Biológicos , Estrutura Molecular
18.
Onco Targets Ther ; 6: 1129-38, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23990729

RESUMO

OBJECTIVE: Overexpression of the sonic hedgehog (SHH) signaling pathway is an essential characteristic of pancreatic cancer stem cells (PCSCs) and arsenic trioxide (ATO) is described as a SHH inhibitor. This study evaluates whether ATO has the potential to inhibit viability of PCSCs via binding to SHH-Gli proteins. METHODS: Cell counting kit-8 and flow cytometry were used for analyzing apoptosis in cells in vitro. The animal model was an athymic nude mouse model bearing subcutaneous xenografts of SW1990 pancreatic cancer cells. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry were used for tumor tissue analysis. The interaction between Gli1 and ATO was examined by a confocal system and an ultraviolet absorption spectrum assay. RESULTS: ATO induced apoptosis in pancreatic cancer cells, especially CD24(+)CD44(+) cells in vitro. Combination treatment of ATO and low dose gemcitabine inhibited tumor growth by 60.9% (P = 0.004), and decreased the expression of CD24, CD44, and aldehyde dehydrogenase 1 family, member A1 significantly in vivo. ATO changed the structure of the recombinant Gli1 zinc finger peptides in a cell-free condition and the binding action of ATO to recombinant Gli1 was observed in cultured pancreatic cancer cells. CONCLUSION: ATO may have the potential to inhibit viability of PCSCs via binding to SHH-Gli proteins in vitro and in vivo.

19.
Neural Regen Res ; 7(36): 2867-73, 2012 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-25317138

RESUMO

In the present study, a human neuroblastoma cell line (SH-SY5Y) and BV-2 microglia were treated with amyloid-ß peptide (25-35), as a model of Alzheimer's disease, to evaluate the protective effects of 10-3-10-8 g/mL Lingguizhugan decoction and to examine the underlying anti-inflammatory mechanism. Lingguizhugan decoction significantly enhanced the viability of SH-SY5Y cells with amyloid-ß peptide-induced injury, and lowered levels of interleukin-1ß, interleukin-6, tumor necrosis factor-α and nitric oxide in the culture supernatant of activated BV-2 microglia. The effects of 10-3 g/mL Lingguizhugan decoction were more significant. These results suggest that Lingguizhugan decoction can protect SH-SY5Y cells against amyloid-ß peptide (25-35)-induced injury in a dose-dependent manner by inhibiting overexpression of inflammatory factors by activated microglia.

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