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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.
Mol Neurobiol ; 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33095414

RESUMO

Prostaglandin (PG) A1 is a metabolic product of cyclooxygenase 2 (COX-2) that is potentially involved in regulating the development and progression of Alzheimer's disease (AD). PGA1 is a cyclopentenone (cy) PG characterized by the presence of a chemically reactive α,ß-unsaturated carbonyl. PGA1 is potentially involved in the regulation of multiple biological processes via Michael addition; however, the specific roles of PGA1 in AD remain unclear. TauP301S transgenic (Tg) mice were used as in vivo AD models, and neuroblastoma (N) 2a cells were used as an in vitro neuronal model. The PGA1-binding proteins were identified by HPLC-MS-MS after intracerebroventricular injection (i.c.v) of PGA1. Western blotting was used to determine tau phosphorylation in PGA1-treated Tg mice in the absence or in the presence of okadaic acid (OA), an inhibitor of protein phosphatase (PP) 2A. A combination of pull-down assay, immunoprecipitation, western blotting, and HPLC-MS-MS was used to determine that the PP2A scaffold subunit A alpha (PPP2R1A) is activated by the direct binding of PGA1 to cysteine 377. The effect of inhibiting tau hyperphosphorylation was tested in the Morris maze to determine the inhibitory effects of PGA1 on cognitive decline in tauP301S Tg mice. Incubation with N2a cells, pull-down assay, and mass spectrometry (MS) analysis revealed and indicated that PGA1 binds to more than 1000 proteins; some of these proteins are associated with AD and especially with tauopathies. Moreover, short-term administration of PGA1 in tauP301S Tg mice significantly decreased tau phosphorylation at Thr181, Ser202, and Ser404 in a dose-dependent manner. This effect was caused by the activation of PPP2R1A in tauP301S Tg mice. Importantly, PGA1 can form a Michael adduct with cysteine 377 of PPP2R1A, which is critical for the enzymatic activity of PP2A. Long-term treatment of tauP301S Tg mice with PGA1 activated PP2A and significantly reduced tau phosphorylation resulting in improvements in cognitive decline in tauP301S Tg mice. Our data provided new insight into the mechanisms of the ameliorating effects of PGA1 on cognitive decline in tauP301S Tg mice by activating PP2A via a mechanism involving the formation of a Michael adduct with cysteine 377 of PPP2R1A.

3.
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.

4.
Front Neurosci ; 14: 817, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903591

RESUMO

Cyclooxygenase-2 (COX-2) is reported to be activated during the course of amyotrophic lateral sclerosis (ALS) development and progression. However, the roles of COX-2 in aggravating ALS and the underlying mechanism have been largely overlooked. To reveal the mechanisms, the canonical SOD1G93A mouse model was used as an experimental model for ALS in the current study. In addition, a specific inhibitor of COX-2 activity, rofecoxib, was orally administered to SOD1G93A mice. With this in vivo approach, we revealed that COX-2 proinflammatory signaling cascades were inhibited by rofecoxib in SOD1G93A mice. Specifically, the protein levels of COX-2, interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α were elevated as a result of activation of astrocytes and microglia during the course of ALS development and progression. These proinflammatory reactions may contribute to the death of neurons by triggering the movement of astrocytes and microglia to neurons in the context of ALS. Treatment with rofecoxib alleviated this close association between glial cells and neurons and significantly decreased the density of inflammatory cells, which helped to restore the number of motor neurons in SOD1G93A mice. Mechanistically, rofecoxib treatment decreased the expression of COX-2 and its downstream signaling targets, including IL-1ß and TNF-α, by deactivating glial cells, which in turn ameliorated the progression of SOD1G93A mice by postponing disease onset and modestly prolonging survival. Collectively, these results provide novel insights into the mechanisms of ALS and aid in the development of new drugs to improve the clinical treatment of ALS.

5.
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.

6.
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.

7.
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
9.
Neurotherapeutics ; 16(4): 1255-1268, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31392591

RESUMO

Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) have been shown to be involved in the pathogenesis of Alzheimer's disease. Analysis of the underlying mechanisms elucidated a function of sequential PGE2 and PGD2 synthesis in regulating ß-amyloid protein (Aß) deposition by modulating tumor necrosis factor α (TNF-α)-dependent presenilin (PS)1/2 activity in COX-2 and APP/PS1 crossed mice. Specifically, COX-2 overexpression accelerates the expression of microsomal PGE synthase-1 (mPGES-1) and lipocalin-type prostaglandin D synthase (L-PGDS), leading to the synthesis of PGE2 and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) in 6-month-old APP/PS1 mice. Consequently, PGE2 has the ability to increase Aß production by enhancing the expression of PS1/2 in a TNF-α-dependent manner, which accelerates the cognitive decline of COX-2/APP/PS1 mice. More interestingly, low concentrations of 15d-PGJ2 treatment facilitate the effects of PGE2 on the deposition of Aß via TNF-α-dependent PS1/2 mechanisms. In contrast, high concentrations of 15d-PGJ2 treatment inhibit the deposition of Aß via suppressing the expression of TNF-α-dependent PS1/2. In this regard, a high concentration of 15d-PGJ2 appears to be a therapeutic agent against Alzheimer's disease. However, the high 15d-PGJ2 concentration treatment induces neuronal apoptosis via increasing the protein levels of Bax, cleaved caspase-3, and DFF45, which further impairs the learning ability of APP/PS1 mice.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apoptose/fisiologia , Ciclo-Oxigenase 2/biossíntese , Dinoprostona/biossíntese , Neurônios/metabolismo , Prostaglandina D2/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/patologia , Nitrobenzenos/administração & dosagem , Prostaglandina D2/biossíntese , Sulfonamidas/administração & dosagem , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
10.
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.

11.
Front Psychol ; 10: 702, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31024379

RESUMO

In the present study, we applied the forward-looking paradigm to examine how positive beliefs appear in self-deception and to further reveal the influence of negative feedback on positive beliefs to decrease self-deception. In Experiment 1, the answer group (with answer hints provided below the test material) and the control group (without answer hints) completed two tests. Participants estimated their Test 1 scores, predicted their performance on the upcoming Test 2 without answer hints, and completed Test 2. Their actual scores on the two tests were recorded. The results showed that the answer group predicted higher Test 2 scores than the control group, but the two groups did not differ in their actual scores. These results showed that the answer group had positive self-deception. In Experiment 2, the two groups were given negative feedback (vs. no feedback) after Test 1, and the changes between their estimated scores on Test 1 and their predicted score and actual score on Test 2 were measured. The results indicated that there was no significant difference in the estimated scores and the predicted score between the two groups under the feedback condition compared with the negative feedback condition. These findings demonstrated that the effectiveness of the forward-looking paradigm can activate participants' positive beliefs and cheat behaviors by providing the answers to induce self-deception, and negative feedback can decrease the occurrence of self-deception by reducing the positive beliefs of individuals and improving self-awareness to prevent or eliminate the negative impact of self-deception.

12.
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
13.
Neurotherapeutics ; 16(2): 505-522, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30627958

RESUMO

Prostaglandins (PGs) are early and key contributors to chronic neurodegenerative diseases. As one important member of classical PGs, PGA1 has been reported to exert potential neuroprotective effects. However, the mechanisms remain unknown. To this end, we are prompted to investigate whether PGA1 is a useful neurological treatment for Alzheimer's disease (AD) or not. Using high-throughput sequencing, we found that PGA1 potentially regulates cholesterol metabolism and lipid transport. Interestingly, we further found that short-term administration of PGA1 decreased the levels of the monomeric and oligomeric ß-amyloid protein (oAß) in a cholesterol-dependent manner. In detail, PGA1 activated the peroxisome proliferator-activated receptor-gamma (PPARγ) and ATP-binding cassette subfamily A member 1 (ABCA1) signalling pathways, promoting the efflux of cholesterol and decreasing the intracellular cholesterol levels. Through PPARγ/ABCA1/cholesterol-dependent pathway, PGA1 decreased the expression of presenilin enhancer protein 2 (PEN-2), which is responsible for the production of Aß. More importantly, long-term administration of PGA1 remarkably decreased the formation of Aß monomers, oligomers, and fibrils. The actions of PGA1 on the production and deposition of Aß ultimately improved the cognitive decline of the amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , PPAR gama/metabolismo , Prostaglandinas A/farmacologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Disfunção Cognitiva/metabolismo , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Presenilina-1/metabolismo , Prostaglandinas A/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
14.
FASEB J ; 33(1): 13-33, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30020833

RESUMO

Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) are involved in the pathogenesis of Alzheimer's disease (AD), which is characterized by the accumulation of ß-amyloid protein (Aß) and tau hyperphosphorylation. However, the gaps in our knowledge of the roles of COX-2 and PGs in AD have not been filled. Here, we summarized the literature showing that COX-2 dysregulation obviously influences abnormal cleavage of ß-amyloid precursor protein, aggregation and deposition of Aß in ß-amyloid plaques and the inclusion of phosphorylated tau in neurofibrillary tangles. Neuroinflammation, oxidative stress, synaptic plasticity, neurotoxicity, autophagy, and apoptosis have been assessed to elucidate the mechanisms of COX-2 regulation of AD. Notably, an imbalance of these factors ultimately produces cognitive decline. The current review substantiates our understanding of the mechanisms of COX-2-induced AD and establishes foundations for the design of feasible therapeutic strategies to treat AD.-Guan, P.-P., Wang, P. Integrated communications between cyclooxygenase-2 and Alzheimer's disease.


Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/fisiopatologia , Ciclo-Oxigenase 2/metabolismo , Estresse Oxidativo , Animais , Autofagia , Humanos , Plasticidade Neuronal
15.
Artigo em Inglês | MEDLINE | ID: mdl-30510777

RESUMO

Osteoarthritis (OA) was recently identified as being regulated by the induction of cyclooxygenase-2 (COX-2) in response to high fluid shear stress. Although the metabolic products of COX-2, including prostaglandin (PG)E2, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), and PGF2α, have been reported to be effective in regulating the occurrence and development of OA by activating matrix metalloproteinases (MMPs), the roles of PGF2α in OA are largely overlooked. Thus, we showed that high fluid shear stress induced the mRNA expression of MMP-12 via cyclic (c)AMP- and PGF2α-dependent signaling pathways. Specifically, we found that high fluid shear stress (20 dyn/cm2) significantly increased the expression of MMP-12 at 6 h ( > fivefold), which then slightly decreased until 48 h ( > threefold). In addition, shear stress enhanced the rapid synthesis of PGE2 and PGF2α, which generated synergistic effects on the expression of MMP-12 via EP2/EP3-, PGF2α receptor (FPR)-, cAMP- and insulin growth factor-2 (IGF-2)-dependent phosphatidylinositide 3-kinase (PI3-K)/protein kinase B (AKT), c-Jun N-terminal kinase (JNK)/c-Jun, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-activating pathways. Prolonged shear stress induced the synthesis of 15d-PGJ2, which is responsible for suppressing the high levels of MMP-12 at 48 h. These in vitro observations were further validated by in vivo experiments to evaluate the mechanisms of MMP-12 upregulation during the onset of OA by high fluid shear stress. By delineating this signaling pathway, our data provide a targeted therapeutic basis for combating OA.

16.
Aging (Albany NY) ; 10(11): 3117-3135, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30383537

RESUMO

Transferrin (Tf) is an important iron-binding protein postulated to play a key role in iron ion (Fe) absorption via the Tf receptor (TfR), which potentially contributes to the pathogenesis of Alzheimer's disease (AD). However, the role of Tf in AD remains unknown. Using mouse-derived neurons and APP/PS1 transgenic (Tg) mice as model systems, we firstly revealed the mechanisms of APH-1α/1ß and presenilin 1 (PS1) upregulation by Fe in prostaglandin (PG) E2- and PGD2-dependent mechanisms. Specifically, Fe stimulated the expression of mPGES-1 and the production of PGE2 and PGD2 via the Tf and TfR system. Highly accumulated PGE2 markedly induced the expression of anterior pharynx-defective-1α and -1ß (APH-1α/1ß) and PS1 via an EP receptor-dependent mechanism. In contrast, PGD2 suppressed the expression of APH-1α/1ß and PS1 via a prostaglandin D2 (DP) receptor-dependent mechanism. As the natural dehydrated product of PGD2, 15d-PGJ2 exerts inhibitory effects on the expression of APH-1α/1ß and PS1 in a peroxisome proliferator-activated receptor (PPAR) γ-dependent manner. The expression of APH-1α/1ß and PS1 ultimately determined the production and deposition of ß-amyloid protein (Aß), an effect that potentially contributes to the pathogenesis of AD.


Assuntos
Dinoprostona/farmacologia , Endopeptidases/metabolismo , Ferro/farmacologia , Proteínas de Membrana/metabolismo , Presenilina-1/metabolismo , Prostaglandina D2/farmacologia , Transferrina/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo , Linhagem Celular Tumoral , Dinoprostona/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Infusões Intraventriculares , Ferro/metabolismo , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Nitrobenzenos/farmacologia , Presenilina-1/genética , Prostaglandina D2/metabolismo , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Sulfonamidas/farmacologia
17.
Bioorg Med Chem ; 26(23-24): 6035-6049, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442507

RESUMO

Borrelidin, a nitrile containing 18-membered polyketide macrolide, display potent antifungal activity. In this study, a library of borrelidin derivatives were synthesized. Their structures were elucidated by detailed spectroscopic data analysis. The antifungal activity and cytotoxicity of these target compounds were evaluated by broth microdilution and 3-(4,5-dimethylthiazol-2-yl)-3,5-phenytetrazoliumromide (MTT) methods. Among forty-seven prepared analogues, compound 3b had the inhibitory effect on Candida albicans and Candida parapsilosis (MIC: 50 and 12.5 µg/mL, respectively). Furthermore, compounds 4n and 4r presented better antifungal activity against Aspergillus fumigatus with 12.5 µg/mL MIC value, which were insensitive to borrelidin. Preliminary structure-activity relationships (SAR) revealed that the ester analogues containing fragment -OCH2CH2N- had an important effect on the antifungal activity. Meanwhile, the molecular docking study indicated the carboxyl substituents in BN could provide extra interaction with pathogenic fungal threonyl-tRNA synthetase (ThrRS).


Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Candida/efeitos dos fármacos , Desenho de Fármacos , Antifúngicos/síntese química , Antifúngicos/química , Relação Dose-Resposta a Droga , Álcoois Graxos/síntese química , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
18.
Molecules ; 23(9)2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30231581

RESUMO

Six new metabolites, actinofuranones D-I (compounds 1⁻6), were isolated together with three known compounds-JBIR-108 (7), E-975 (8), and E-492 (9)-from a fermentation broth of Streptomyces gramineus derived from the lichen Leptogium trichophorum. The structures of the new compounds 1⁻6 were established using comprehensive NMR spectroscopic data analysis, as well as UV, IR, and MS data. The anti-inflammatory activity of these isolated compounds were evaluated by examining their ability to inhibit nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophage cells. Compounds 4, 5, 8, and 9 attenuated the production of NO due to the suppression of the expression of nitric oxide synthase (iNOS) in LPS-induced RAW 264.7 cells. Moreover, 4, 5, 8, and 9 also inhibited LPS-induced release of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α).


Assuntos
Actinobacteria/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Furanos/química , Furanos/farmacologia , Líquens/microbiologia , Actinobacteria/metabolismo , Animais , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Expressão Gênica , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Óxido Nítrico , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7
19.
Front Mol Neurosci ; 11: 172, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29899688

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. The neuropathological features of AD are the aggregation of extracellular amyloid ß-protein (Aß) and tau phosphorylation. Recently, AD was found to be associated with magnesium ion (Mg2+) deficit and tumor necrosis factor-alpha (TNF-α) elevation in the serum or brains of AD patients. To study the relationship between Mg2+ and TNF-α, we used human- or mouse-derived glial and neuronal cell lines or APP/PS1 transgenic (Tg) mice as in vitro and in vivo experimental models, respectively. Our data demonstrates that magnesium-L-threonate (MgT) can decrease the expression of TNF-α by restoring the levels of Mg2+ in glial cells. In addition, PI3-K/AKT and NF-κB signals play critical roles in mediating the effects of Mg2+ on suppressing the expression of TNF-α. In neurons, Mg2+ elevation showed similar suppressive effects on the expression of presenilin enhancer 2 (PEN2) and nicastrin (NCT) through a PI3-K/AKT and NF-κB-dependent mechanism. As the major components of γ-secretase, overexpression of presenilin 1 (PS1), PEN2 and NCT potentially promote the synthesis of Aß, which in turn activates TNF-α in glial cells. Reciprocally, TNF-α stimulates the expression of PEN2 and NCT in neurons. The crosstalk between TNF-α and Aß in glial cells and neurons could ultimately aggravate the development and progression of AD.

20.
J Antibiot (Tokyo) ; 71(9): 808-817, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29752478

RESUMO

Bafilomycin C1, which was isolated from Streptomyces albolongus in our previous work, exhibited strong cytotoxicity against several cancer cell lines. This study aimed to evaluate its antitumor effect on human hepatocellular cancer SMMC7721 cells and the underlying mechanism in vitro and in vivo. MTT assay revealed that bafilomycin C1 retarded SMMC7721 cell growth and proliferation. Western blot and real-time qPCR analysis revealed that bafilomycin C1 caused partial G0/G1 phase cell-cycle arrest, downregulated the expression of cyclin D3, cyclin E1, CDK2, CDK4, and CDK6 and upregulated the expression of p21. Moreover, bafilomycin C1 caused mitochondrial membrane dysfunction through oxidative stress. Furthermore, bafilomycin C1 decreased the expression of Bcl-2; increased the expression of Bax, p53, and P-p53; and increased cleavage of caspase-9 and caspase-3, thereby inducing the intrinsic caspase-dependent apoptotic pathway. In vivo experiments in mice suggested that bafilomycin C1 suppressed tumor growth with few side effects. Cell-cycle arrest and induced apoptosis in tumor tissues in a mouse model treated with bafilomycin C1 were demonstrated by histological analyses, western blot and TUNEL. These findings indicate that bafilomycin C1 may be a promising candidate for hepatic cellular cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Macrolídeos/farmacologia , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D3/biossíntese , Ciclina E/biossíntese , Quinase 2 Dependente de Ciclina/biossíntese , Quinase 4 Dependente de Ciclina/biossíntese , Quinase 6 Dependente de Ciclina/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Membranas Mitocondriais/patologia , Proteínas Oncogênicas/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Streptomyces/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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