Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 99
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Nat Prod ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33216556

RESUMO

Eleven metabolites, six echinosporins (1-6), four dibenzoyls (7-10), and an aromatic compound (11), were isolated from the fermentation broth of lichen-associated Amycolatopsis hippodromi. The structures of the new compounds (1-5, 8-11) were elucidated by comprehensive spectroscopic analysis including data from experimental and calculated ECD spectra. Amycolasporins A-C (1-3) demonstrated antibacterial activities against Bacillus subtilis, Staphylococcus aureus, and Escherichia coli with MIC values of 25 or 100 µg/mL. Amycolasporin C (3) and the known dibenzoyl (7) attenuated the production of NO due to the suppression of the expression of nitric oxide synthase (iNOS) in LPS-induced RAW 264.7 cells in a dose-dependent manner.

2.
Neurotherapeutics ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33034847

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease characterized by ß-amyloid (Aß) protein deposition, neurofibrillary tangle (NFT) formation, and neuronal loss in the brain. The current study was designed to investigate the potential mechanisms by which levistolide A affects the pathogenesis of AD in an amyloid precursor protein/presenilin 1 (APP/PS1) transgenic (Tg) mouse model of AD and N2a/APP695swe cells. Specifically, behavioral changes in levistolide A-treated APP/PS1 Tg mice were assessed by the nest-building and Morris water maze (MWM) tests. Levistolide A treatment clearly ameliorated memory deficits and cognitive decline in APP/PS1 Tg mice. Aß generation and the inflammatory response in APP/PS1 Tg mouse brains were clearly reduced after long-term levistolide A application. Mechanistically, levistolide A concurrently stimulated the expression of α-secretase and decreased the generation of ß- and γ-secretases. In addition, levistolide A inhibited the phosphorylation of tau in the brains of the Tg mice. Furthermore, in vitro and in vivo experiments suggested that peroxisome proliferator-activated receptor γ (PPARγ) is the key transcription factor that mediates the regulatory effects of levistolide A on the expression of α-, ß-, and γ-secretases and phosphorylation of tau. Collectively, these findings show that levistolide A may be a candidate for the treatment of AD.

3.
Bioorg Chem ; 103: 104242, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32916541

RESUMO

Six new terpenoids (1-6) and two new phloroglucinol glucosides (7 and 8) were isolated from the extract of Syzygium szemaoense leaves. Among the isolates, compounds 1 and 2 (named syzygiumursanolides A and B) were unusual 28-norursane type triterpenoids with 19(18→17)-abeo spirocyclic skeleton. And syzygiumone B (8) was rare ascorbyl-modified phloroglucinol glucoside. Their structures were elucidated on the basis of comprehensive 1D and 2D NMR, HRESIMS spectroscopic data analysis, as well as experimental and calculated ECD spectra and acid hydrolysis. Antimicrobial bioassay revealed that syzygiumursanolide D (4) displayed the most potent antifungal activities with MIC values ranging from 6.25 to 25 µg/mL against a panel of fungi.

4.
Food Funct ; 11(9): 8297-8308, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32909594

RESUMO

Benzophenone glycosides are a major type of polyphenols present in guava. To date, there is still poor understanding of the relationship between benzophenone glycosides and the hepatoprotective effects attributed to this edible fruit. Herein, the protective effects of guavinoside B (GUB), a main benzophenone glycoside present in guava fruit, against acetaminophen (APAP)-induced liver injury were investigated in vitro and in vivo. Fluorescence measurement demonstrated that GUB (at a concentration of 30 µM) significantly reduced the intracellular ROS levels in APAP-treated HepG2 cells. In addition, GUB (100 mg kg-1 d-1) pretreatment markedly alleviated APAP-induced hepatocyte infiltration and necrosis in C57BL/6 mice, and improved serum and hepatic biochemical parameters, such as ALT, AST, SOD, GSH, ROS, MDA, and TNF-α levels. RT-PCR and western blot experiments revealed that GUB up-regulated Nrf2, GCLC and NQO1, while reducing p-JNK gene expression in the liver. The fermentation experiment further revealed that the displayed beneficial effects of GUB in vivo might be related to the gut microbial metabolite gallic acid. These promising data suggested that GUB showed potent hepatoprotective effects through regulating the Nrf2 and JNK signaling pathways. Further investigation of the absorption and metabolism of benzophenones would be warranted to promote the utilization of these phenolics as functional food ingredients against oxidative stress-induced chronic diseases.

5.
Int J Syst Evol Microbiol ; 70(9): 5115-5122, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32809927

RESUMO

A novel Gram-stain-positive, aerobic, non-spore-forming, irregular short rod-shaped actinobacterial strain, designated YIM 102482-1T, was isolated from the faeces of Macaca mulatta. Strain YIM 102482-1T grew optimally at 30-37 °C, at pH 8.0 and in the presence of 1.0-3.0% (w/v) NaCl. Similarly, analysis based on 16S rRNA gene sequences showed that strain YIM 102482-1T was a member of the genus Gulosibacter and most closely related to Gulosibacter feacalis NBRC 15706T (97.6 %), Gulosibacter bifidus NBRC 103089T (97.6 %), Gulosibacter chungangensis KCTC 13959T (96.4 %) and Gulosibacter molinativorax DSM 13485T (96.0 %), respectively. Furthermore, phylogenetic trees based on 16S rRNA gene sequences and genomic sequences demonstrated that strain YIM 102482-1T formed a distinct branch with all type strains of the genus Gulosibacter. The major whole-cell sugars and cellular fatty acids (>10.0 %) were ribose and rhamnose, and anteiso-C15 : 0, iso-C16 : 0 and C16 : 0, respectively. The predominant menaquinone was MK-9, and 2,4-diaminobutyric acid and ornithine were the diagnostic diamino acids in the cell-wall peptidoglycan. The dominant polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol and unidentified glycolipid. The DNA G+C content of YIM 102482-1T was 63.0 mol%. Based on analysis results of physiological, biochemical and chemotaxonomic data, strain YIM 102482-1T represents a novel species of the genus Gulosibacter, for which the name Gulosibacter macacae sp. nov. is proposed. The type strain is YIM 102482-1T(=DSM 102156T=CCTCC AB 2016023T).


Assuntos
Actinobacteria/classificação , Macaca mulatta/microbiologia , Filogenia , Actinobacteria/isolamento & purificação , Animais , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/química , Fezes/microbiologia , Glicolipídeos/química , Peptidoglicano/química , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2/análogos & derivados , Vitamina K 2/química
6.
Arch Microbiol ; 202(10): 2599-2606, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32686033

RESUMO

Strain YIM 102744-1T was isolated from Rhinopithecus roxellanae fecal sample collected at Yunnan Wild Animal Park, Yunnan province, PR China. Cells were Gram-stain-negative, aerobic, non-motile and irregular rods. Optimal growth occurred in the presence of 0-1.0% (w/v) NaCl, at pH 7.0-8.0, and at 30 °C. The predominant ubiquinone was Q-10. The major cellular fatty acids (> 10.0%) were C18:1ω7c and C16:1ω7c/C16:1ω6c. The dominant polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylcholine. The DNA G + C content was 62.4 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that YIM 102744-1T belonged to the family Rhodobacteraceae and shared the highest similarity with the type strain Gemmobacter intermedius 119/4T (96.6%). In addition, phylogenetic trees indicated that strain YIM 102744-1T formed a distinct clade together with the closest relative G. intermedius 119/4T. Based on the results of polyphasic taxonomic analysis, strain YIM 102744-1T is considered to represent a novel species within a new genus Falsigemmobacter, for which the name Falsigemmobacter faecalis gen. nov., sp. nov. is proposed. The type strain of Falsigemmobacter faecalis is YIM 102744-1T(= KCTC 52106T = CCTCC AB 2016031T). Because Gemmobacter intermedius 119/4T formed a branch with YIM 102744-1 in the phylogenetic trees and was clearly separated from the other members within the genus Gemmobacter, it is also proposed to transfer into the genus Falsigemmobacter as Falsigemmobacter intermedius comb. nov. (type strain 119/4T = CIP 110795T = LMG 28215T = CCM 8510T). The type species of the genus Falsigemmobacter is Falsigemmobacter intermedius gen. nov., comb. nov.


Assuntos
Filogenia , Presbytini/microbiologia , Rhodobacteraceae/classificação , Animais , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/análise , Fezes/microbiologia , Fosfatidiletanolaminas , RNA Ribossômico 16S/genética , Rhodobacteraceae/genética , Rhodobacteraceae/isolamento & purificação , Especificidade da Espécie
7.
Fitoterapia ; 146: 104692, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32717293

RESUMO

Physalis pubescens L. is a medicinal plant widely cultivated in northeast of China. Investigation on the extract of P. pubescens fruit led to the isolation and identification of four new withanolides, namely, physapubescins J-M (1, 2, 4 and 5), together with four known analogues (3, 6-8) and fifteen other compounds. Their structures were elucidated on the basis of comprehensive NMR, MS, and ECD spectroscopic data analysis. Among isolates, physapubescin J (1) contained an unusual sulphide linkage, and four withanolides (3, 5, 7 and 8) showed anti-inflammatory potential in LPS-induced RAW264.7 cells. This study supports P. pubescens fruit could be a valuable source of withanolides. Further studies to investigate anti-inflammatory activities of isolated withanolides using in vivo models are warranted.

8.
Sci Rep ; 10(1): 5081, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193473

RESUMO

In the process of investigating the antifungal structure-activity relationships (SAR) of borrelidin and discovering antifungal leads, a semisynthetic borrelidin analogue, BN-3b with antifungal activity against Candida albicans, was achieved. In this study, we found that oxidative damage induced by endogenous reactive oxygen species (ROS) plays an important role in the antifungal activity of BN-3b. Further investigation indicated that BN-3b stimulated ROS accumulation, increased malondialdehyde (MDA) levels, and decreased reduced/oxidized glutathione (GSH/GSSG) ratio. Moreover, BN-3b decreased mitochondrial membrane potential (MMP) and ATP generation. Ultrastructure analysis revealed that BN-3b severely damaged the cell membrane of C. albicans. Quantitative PCR (RT-qPCR) analysis revealed that virulence factors of C. albicans SAPs, PLB1, PLB2, HWP1, ALSs, and LIPs were all down-regulated after BN-3b exposure. We also found that BN-3b markedly inhibited the hyphal formation of C. albicans. In addition, in vivo studies revealed that BN-3b significantly prolonged survival and decreased fungal burden in mouse model of disseminated candidiasis.

9.
Int J Syst Evol Microbiol ; 70(1): 51-57, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31584868

RESUMO

A yellow, Gram-stain-negative, aerobic, non-gliding, non-spore-forming, rod-shaped strain, designated YIM 102600T, was isolated from the faeces of Macaca mulatta dwelling in the Yunnan Wild Animal Park, Yunnan Province, South-West PR China. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain YIM 102600T was a member of the genus Flavobacterium, and closely related to Flavobacterium qiangtangense F3T (96.9 % similarity) and Flavobacterium noncentrifugens R-HLS-17T (96.0 % similarity). Phylogenetic trees showed that strain YIM 102600T formed a clade with F. qiangtangense F3T and F. noncentrifugens R-HLS-17T. Growth occurred at 4-30 °C (optimum, 28 °C), pH 7.0-8.0 (pH 7.5) and NaCl concentration 0-2 % (w/v; 0-1 %, w/v). The major fatty acids were iso-C15:0 and summed feature 3 (comprising C16:1 ω7c and/or C16:1 ω6c). The predominant polar lipid was phosphatidylethanolamine and the sole respiratory quinone was menaquinone-6. The DNA G+C content was 36.4 mol%. The calculated digital DNA-DNA hybridization values between strain YIM 102600T and other species of Flavobacterium ranged from 70.0 to 75.0 % and average nucleotide identity values were in a range between 13.7 to 23.5 %. Based above the consensus of phenotypic and phylogenetic analyses as well as whole genome comparisons, strain YIM 102600T (=KCTC 52099T=CCTCC AB 201632T) is proposed to represent type strain of a novel species, Flavobacterium macacae sp. nov.


Assuntos
Flavobacterium/classificação , Macaca mulatta/microbiologia , Filogenia , Animais , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/química , Fezes/microbiologia , Flavobacterium/isolamento & purificação , Hibridização de Ácido Nucleico , Fosfatidiletanolaminas/química , Pigmentação , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2/análogos & derivados , Vitamina K 2/química
10.
Planta Med ; 86(1): 70-77, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31671467

RESUMO

Four new barringtogenol C-type triterpenoid saponins, namely acerplatanosides A - D (1: -4: ), along with 22 known compounds (5: -26: ), were isolated from the stem bark of Norway maple (Acer platanoides). Their structures were elucidated on the basis of comprehensive spectroscopic analyses and chemical hydrolysis. This is the first report of triterpenoid saponins isolated from Norway maple. Compounds 1, 3: , and 4: showed cytotoxicity against 4 human cancer cell lines with IC50 values ranging from 9.4 to 39.5 µM.


Assuntos
Acer/química , Antineoplásicos Fitogênicos/isolamento & purificação , Saponinas/isolamento & purificação , Triterpenos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Casca de Planta/química , Saponinas/química , Triterpenos/química
11.
Bioorg Chem ; 95: 103507, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31884136

RESUMO

Three pyrrol-2-aldehyde derivatives, including one new compound, jiangrine G (JG), two known compounds, jiangrine A (JA), and pyrrolezanthine (PZ), were isolated from the fermentation broth of Jiangella alba associated with a traditional Chinese medicinal plant Maytenus austroyunnanensis. The structure of jiangrine G was elucidated by a detailed spectroscopic data analysis including data from CD spectra. The anti-inflammatory activities assay demonstrated that JG and JA suppressed the production of pro-inflammatory cytokines including NO, IL-1ß, and IL-6 as well as inhibited the expression of iNOS in LPS-induced RAW 264.7 cells in a dose-dependent manner. While high concentration of PZ dramatically suppressed the protein expression of TNF-α, but stimulated the release of IL-1ß and IL-6. Western blot results revealed that JG, JA, and PZ modulated the expression of pro-inflammatory cytokines via MAPK p38 and NF-κB signaling pathways. For the unique structure of PZ, difference from JG and JA, the signaling pathway involved in mediating its effects on regulating the synthesis of IL-1ß and IL-6 are probably more complicated than that of JG and JA.

12.
Bioorg Chem ; 94: 103420, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31718890

RESUMO

A concise total synthesis of an exceedingly potent anti-inflammatory agent violacin A as well as the preparation of thirty analogues of this lead from commercially available orcinol are described. Highlights of our synthetic efforts involve Friedel-Crafts acylation, the regioselective etherification and esterification of phenolic hydroxyl groups, and Baker-Venkatamaran rearrangement to form basic skeleton of violacin A. The deprotection reaction with Pd-catalytic was involved to avoid the elimination of the hemiacetal hydroxyl at C2. In addition, all synthetic compounds were screened for anti-inflammatory activity against nitric oxide (NO) production using lipopolysaccharide (LPS)-induced Raw264.7 cells. A range of violacin A derivatives 11b, 11d, 11f, 12e, 12g, 13g, 17d-g exhibited stronger anti-inflammatory effect than that of violacin A. Notably, halogeno-benzyloxy substituent at C-7 were favourable for anti-inflammatory activities of violacin A derivatives. Additionally, Western blot results indicated halogeno-benzyloxy derivatives inhibited pro-inflammatory cytokines releases correlated with the suppression of NF-κB signaling pathway.

13.
Bioorg Chem ; 93: 103311, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31586709

RESUMO

Spectinabilin (1), spectinabilin derivative (2), and a new analogue, 2-demethyl-spectinabilin (3) were isolated from the fermentation broth of a soil-borne Streptomyces spectabilis strain. The structure of the new compound was elucidated by a detailed spectroscopic data analysis including data from CD spectra. Spectinabilin (1) demonstrated cytotoxicity against five human cancer cell lines, with IC50 values ranging from 18.7 ±â€¯3.1 to 34.6 ±â€¯4.7 µM, while derivatives 2 and 3 showed weak cytotoxicities. Notably, 1 inhibited the growth and proliferation of the hepatocellular carcinoma cell lines SMMC7721 and HepG2 in a time- and dose-dependent manner. Further study demonstrated that 1 caused G2/M phase cell cycle arrest in SMMC7721 and HepG2 cells through decreasing the protein levels of cyclin B1 and cdc2 as well as increasing that of p21. Compound 1 downregulated the protein expression of Bcl-2, upregulated Bax, and activated the cleavage of caspase-9 and -3 as a result of inducing apoptosis in SMMC7721 and HepG2 cells. Furthermore, the antitumor effect of 1 in SMMC7721 and HepG2 cells was mediated by the PI3K/AKT signaling pathway. In addition, 1 also suppressed tumor growth in vivo though inducing cell cycle arrest and apoptosis.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Pironas/química , Streptomyces/química , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pironas/isolamento & purificação , Pironas/farmacologia , Pironas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Streptomyces/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
14.
J Agric Food Chem ; 67(41): 11403-11407, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31509401

RESUMO

Three new phenazine metabolites, strepphenazine A-C (1-3), along with a known compound baraphenazine E 4 were isolated from the culture broth of a Streptomyces strain YIM PH20095. The structures were elucidated based on the spectral data. Compounds 1-4 showed different antifungal activity against Fusarium oxysporum, Plectosphaerella cucumerina, Alternaria panax, and Phoma herbarum, which caused root-rot disease of Panax notoginseng with minimal inhibitory concentrations (MICs) of 16-64 µg/mL; compared with compound 4, compounds 1-3 showed better antifungal activity against some of these pathogenic fungi with MICs of 16-32 µg/mL, while compound 4 showed antifungal activity against F. oxysporum, P. cucumerina, and A. panax with the same MICs of 64 µg/mL. Thus, strain YIM PH20095 provides new sources for the development of biological control agents to prevent the infection of pathogenic fungi of P. notoginseng.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Panax notoginseng/microbiologia , Fenazinas/química , Fenazinas/farmacologia , Streptomyces/química , Alternaria/efeitos dos fármacos , Alternaria/crescimento & desenvolvimento , Antifúngicos/isolamento & purificação , Antifúngicos/metabolismo , Fusarium/efeitos dos fármacos , Fusarium/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenazinas/isolamento & purificação , Fenazinas/metabolismo , Doenças das Plantas/microbiologia
15.
J Agric Food Chem ; 67(40): 11089-11098, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31509411

RESUMO

Reactive oxygen species and subsequent oxidative stress are reported to play important roles in chronic metabolic diseases. Plant-derived polyphenols, especially food-derived phenolics, have attracted a lot of attention due to their potential usage against oxidative stress-related diseases. The leaf of Psidium guajava (known as guava) is regarded as a good resource of polyphenols and its products are commercially available in Japan as functional foods against multiple chronic metabolism disorders. In the course of finding novel polyphenols with antioxidative activities from guava leaf, 11 acylated phenolic glycosides (1-11), including 5 new oleuropeic acid-conjugated phenolic glycosides, named guajanosides A-E (1, 2, and 5-7), along with 17 known meroterpenoides (12-28), were isolated and identified. Their structures were determined by spectroscopic data analysis, chemical degradation, and acid hydrolysis. Compounds 1, 2, and 5-11 displayed potent reactive oxygen species-scavenging activity in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. Western blot revealed that compound 6 markedly increased the expression levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (NQO1), and the glutamate-cysteine ligase catalytic subunit. The current study revealed the presence of oleuropeic acid-derived phenolic glycosides in guava leaf and highlighted the potential usage of this type of phenolics against oxidative stress-related metabolic diseases via activation of the Nrf2 signaling pathway.


Assuntos
Depuradores de Radicais Livres/farmacologia , Glicosídeos/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Psidium/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Depuradores de Radicais Livres/química , Glicosídeos/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenóis/química , Extratos Vegetais/química , Folhas de Planta/química , Células RAW 264.7
17.
EBioMedicine ; 45: 393-407, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31303501

RESUMO

BACKGROUND: Recent studies have revealed that vitamin D deficiency may increase the risk of Alzheimer's disease, and vitamin D supplementation may be effective strategy to ameliorate the neurodegenerative process in Alzheimer's disease patients. Paricalcitol (PAL), a low-calcemic vitamin D receptor agonist, is clinically used to treat secondary hyperparathyroidism. However, the potential application of PAL for treating neurodegenerative disorders remains unexplored. METHODS: The APP/PS1 mice were intraperitoneally injected with PAL or vehicle every other day for 15 weeks. The ß-amyloid (Aß) production was confirmed using immunostaining and enzyme linked immunosorbent assay. The underlying mechanism was verified by western blot and immunostaining in vivo and in vitro. FINDINGS: Long-term PAL treatment clearly reduced ß-amyloid (Aß) generation and neuronal loss in APP/PS1 transgenic mouse brains. PAL stimulated the expression of low-density lipoprotein receptor-related protein 1 (LRP1) possibly through inhibiting sterol regulatory element binding protein-2 (SREBP2); PAL also promoted LRP1-mediated ß-site APP cleavage enzyme 1 (BACE1) transport to late endosomes, thus increasing the lysosomal degradation of BACE1. Furthermore, PAL diminished 8-hydroxyguanosine (8-OHdG) generation in neuronal mitochondria via enhancing base excision repair (BER), resulting in the attenuation of calpain-1-mediated neuronal loss. INTERPRETATION: The present data demonstrate that PAL can reduce Aß generation through accelerating BACE1 lysosomal degradation and can inhibit neuronal loss through suppressing mitochondrial 8-OHdG generation. Hence, PAL might be a promising agent for treating Alzheimer's disease. FUND: This study was financially supported by the Natural Science Foundation of China (U1608282).


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/genética , Ácido Aspártico Endopeptidases/genética , Ergocalciferóis/farmacologia , Neurônios/efeitos dos fármacos , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Calpaína/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Lisossomos/efeitos dos fármacos , Lisossomos/genética , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Neurônios/patologia , Oligopeptídeos/genética , Presenilina-1/genética , Proteólise/efeitos dos fármacos
18.
Front Aging Neurosci ; 11: 108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143112

RESUMO

Alzheimer's disease (AD) is reportedly associated with the accumulation of calcium ions (Ca2+), and this accumulation is responsible for the phosphorylation of tau. Although several lines of evidence demonstrate the above phenomenon, the inherent mechanisms remain unknown. Using APP/PS1 Tg mice and neuroblastoma (N)2a cells as in vivo and in vitro experimental models, we observed that Ca2+ stimulated the phosphorylation of tau by activating microsomal PGE synthase 1 (mPGES1) in a prostaglandin (PG) E2-dependent EP receptor-activating manner. Specifically, the highly accumulated Ca2+ stimulated the expression of mPGES1 and the synthesis of PGE2. Treatment with the inhibitor of Ca2+ transporter, NMDAR, attenuated the expression of mPGES1 and the production of PGE2 were attenuated in S(+)-ketamine-treated APP/PS1 Tg mice. Elevated levels of PGE2 were responsible for the hyperphosphorylation of tau in an EP-1-, EP-2-, and EP-3-dependent but not EP4-dependent cyclin-dependent kinase (Cdk) 5-activating manner. Reciprocally, the knockdown of the expression of mPGES1 ameliorated the expected cognitive decline by inhibiting the phosphorylation of tau in APP/PS1 Tg mice. Moreover, CDK5 was found to be located downstream of EP1-3 to regulate the phosphorylation of tau though the cleavage of p35 to p25. Finally, the phosphorylation of tau by Ca2+ contributed to the cognitive decline of APP/PS1 Tg mice.

19.
Curr Microbiol ; 76(7): 818-823, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31028411

RESUMO

Strains YIM 102796T and YIM 102701-2T were isolated from the feces of Macaca mulatta and Hylobates hoolock, respectively, living in the Yunnan Wild Animal Park, Yunnan province of China. The two strains were Gram-stain-negative, non-gliding, produced flexirubin pigments, non-flagellated and aerobic bacteria. The 16S rRNA gene-based phylogenetic analysis indicate that both YIM 102796T and YIM 102701-2T are members of the genus Flavobacterium, closely related to F. ummariense DS-12T (95.9% similarity) and F. ceti 454-2T (93.8% similarity), respectively. The two strains shared 95.1 % 16S rRNA gene sequence similarity. The average nucleotide identity and digital DNA-DNA hybridization values between the two strains were 76.5% and 22.9%, respectively, indicating that they are separate species. DNA G+C contents of YIM 102796T and YIM 102701-2T were 32.3 mol% and 34.0 mol%, respectively. Strains are able to grow at 4-37 °C, at pH 7.0-8.0 and in 0-2% (w/v) NaCl. Predominant fatty acid constituents (>7 %) were iso-C15:0, summed feature 3 (C16 : 1ω6c and/or C16 : 1ω7c) and summed feature 9 (iso-C17:1ω9c and/or 10-methylC16:0). Menaquinone 6 is major respiratory quinone. The predominant polar lipids were very similar to each other, comprising phosphatidylethanolamine, and multiple unknown aminolipids and unidentified polar lipids, and an unidentified aminophospholipid. On the basis of phenotypic and phylogenetic distinctiveness, it is suggested that the two strains represent two novel Flavobacterium species with strain YIM 102796T (=KCTC 52101T=CCTCC AB 2016015T) as the type strain of Flavobacterium viscosus sp. nov. and strain YIM 102701-2T (=KCTC 52100T=CCTCC AB 2016028T) as the type strain of Flavobacterium tangerina sp. nov.


Assuntos
Fezes/microbiologia , Flavobacterium/classificação , Primatas/microbiologia , Animais , Animais de Zoológico , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/análise , Fezes/química , Flavobacterium/genética , Flavobacterium/fisiologia , Genoma Bacteriano/genética , Hibridização de Ácido Nucleico , Fosfolipídeos/análise , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Especificidade da Espécie , Vitamina K 2/análogos & derivados
20.
J Alzheimers Dis ; 68(3): 1095-1111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30883354

RESUMO

Alzheimer's disease (AD) is reported to be associated with the accumulation of calcium ions (Ca2+), which is responsible for the phosphorylation of tau. Although a series of evidence have demonstrated this phenomenon, the inherent mechanisms remain unknown. Using tauP301S and cyclooxygenase-2 (COX-2) transgenic mice and neuroblastoma (n)2a cells as in vivo and in vitro experimental models, we found that Ca2+ stimulates the phosphorylation of tau by activating COX-2 in a prostaglandin (PG) E2-dependent EP receptor-activating manner. Specifically, Ca2+ incubation stimulated COX-2 and PGE2 synthase activity, microsomal PGE synthase 1 and the synthesis of PGE2 by activating the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in n2a cells. Elevated levels of PGE2 were responsible for phosphorylating tau in an EP-1, -2, and -3 but not EP4-dependent glycogen synthase kinase 3-activating manner. These observations were corroborated by results that showed tau was phosphorylated when it colocalized with activated COX-2 in tauP301S and COX-2 transgenic mice or n2a cells. To further validate these observations, treatment of mice with the COX-2 inhibitor rofecoxib decreased the phosphorylation of tau via EP1-3 but not EP4. Collectively, our observations fill the gaps between Ca2+ and the phosphorylation of tau in a COX-2-dependent mechanism, which potentially provides therapeutic targets for combating AD.


Assuntos
Cálcio/metabolismo , Ciclo-Oxigenase 2/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Animais , Western Blotting , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Lactonas/farmacologia , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Fosforilação , Prostaglandina-E Sintases/metabolismo , Quinazolinas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Serina , Sulfonas/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...