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1.
ACS Appl Mater Interfaces ; 13(33): 39126-39134, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34383476

RESUMO

The usage of exogenous antioxidant materials to relieve oxidative stress offers an important strategy for the therapy of oxidative stress-induced injuries. However, the fabrication processes toward the antioxidant materials usually require the involvement of extra metal ions and organic agents, as well as sophisticated purification steps, which might cause tremendous environmental stress and induce unpredictable side effects in vivo. To address these issues, herein, we proposed a novel strategy to fabricate green nanoparticles for efficiently modulating oxidative stress, which was facilely prepared from tea polyphenol extracts (originated from green tea) via a green enzymatic polymerization-based chemistry method. The resulting nanoparticles possessed a uniform spherical morphology and good stability in water and biomedium and demonstrated excellent radical scavenging properties. These nanoparticle scavengers could effectively prevent intracellular oxidative damage, accelerate wound recovery, and protect the kidneys from reactive oxygen species damaging in the acute kidney injury model. We hope this work will inspire the further development of more types of green nanoparticles for antioxidant therapies via similar synthetic strategies using green biomass materials.


Assuntos
Injúria Renal Aguda/prevenção & controle , Antioxidantes/química , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/química , Chá/química , Células 3T3 , Células A549 , Animais , Antioxidantes/farmacologia , Catecóis/química , Sobrevivência Celular/efeitos dos fármacos , Feminino , Sequestradores de Radicais Livres/metabolismo , Química Verde , Peroxidase do Rábano Silvestre/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio/química , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Nanomedicina Teranóstica , Cicatrização/efeitos dos fármacos
2.
Transl Psychiatry ; 11(1): 343, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083506

RESUMO

BACKGROUND: Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). METHODS: A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). RESULTS: The authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10-8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10-8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. CONCLUSIONS: The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.


Assuntos
Antipsicóticos , Clozapina , Neutropenia , Esquizofrenia , Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Estudo de Associação Genômica Ampla , Humanos , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Neutropenia/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética
3.
Comput Biol Med ; 134: 104452, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33984751

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is prevalent in patients receiving atypical antipsychotic drugs (AADs), but there are few effective interventions. The Traditional Chinese herbal decoction Liu-Yu-Tang (LYT) has achieved clinical improvement for AAD-induced MetS, but its pharmacological mechanism remains unclear. METHOD: A network pharmacology-based method was utilized in this study. First, the TCMSP and SwissTargetPrediction database were used to acquire plasma-absorbed components and putative targets of LYT, respectively. Second, an interaction network between shared targets of LYT and MetS was constructed using STRING online tool. Topological analyses were performed to extract hub gene targets. Finally, we did a pathway analysis of gene targets using the Kyoto Encyclopedia of Genes and Genomes (KEGG) to find biological pathways of LYT. RESULTS: We obtained 655 putative targets of LYT, 434 known targets of AADs, and 1577 MetS-related gene targets. There are 232 shared targets between LYT and MetS. Interaction network construction and topological analysis yielded 60 hub targets, of which 18 were major hub targets, among which IL-6, IL-8, TNF, PI3K, MAPK, and NF-κB (RELA) are the most important in LYT's treatment of AAD-induced MetS. Pathway enrichment analysis revealed a statistically high significance of the AGE-RAGE signaling pathway in diabetic complications, lipid and atherosclerosis and the insulin resistance pathway. CONCLUSIONS: LYT may control activities of the pro-inflammatory cytokines IL-6, IL-8, TNF and the important signal transduction molecules PI3K, MAPKs, and NF-κB (RELA), regulating metabolic disturbance-related pathways like the AGE-RAGE signaling pathway in diabetic complications, lipid and atherosclerosis, and the insulin resistance pathway, generating therapeutic effects for AAD-induced MetS.


Assuntos
Antipsicóticos , Aterosclerose , Medicamentos de Ervas Chinesas , Síndrome Metabólica , Antipsicóticos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Medicina Tradicional Chinesa , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/tratamento farmacológico
4.
Chembiochem ; 22(11): 1936-1939, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-33779011

RESUMO

DNA N6 -methyladenine (6mA) has recently received notable attention due to an increased finding of its functional roles in higher eukaryotes. Here we report an enzyme-assisted chemical labeling method to pinpoint the DNA 6mA methyltransferase (MTase) substrate modification site at single base resolution. A designed allyl-substituted MTase cofactor was applied in the catalytic transfer reaction, and the allyl group was installed to the N6 -position of adenine within a specific DNA sequence to form N6 -allyladenine (6aA). The iodination of 6aA allyl group induced the formation of 1, N6 -cyclized adenine which caused mutations during DNA replication by a polymerase. Thus the modification site could be precisely detected by a mutation signal. We synthesized 6aA deoxynucleoside and deoxynucleotide model compounds and a 6aA-containing DNA probe, and screened nine DNA polymerases to define an optimal system capable of detecting the substrate modification site of a DNA 6mA MTase at single-base resolution.

5.
Chem Commun (Camb) ; 57(20): 2499-2502, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33586715

RESUMO

Here we report a simple and nonradioactive biochemical assay which is capable of accurately determining the substrate methylation sites of human RNA N6-methyladenosine methyltransferases METTL3/METTL14 and METTL16. This method employs enzyme-assisted chemical labelling of a specific base in an RNA substrate with the assistance of an allyl-substituted methyltransferase cofactor, and enables precise identification of the labelling site by a mutation signal from standard nucleic acid sequencing. Our method provides a platform to investigate the enzymatic methylations of long and structurally complex RNA substrates, and facilitates the discovery of new methyltransferases.


Assuntos
Metiltransferases/química , Adenosina/química , Sequência de Bases , Sítios de Ligação , Técnicas Biossensoriais , Humanos , Metilação , Ligação Proteica , RNA/química , Processamento Pós-Transcricional do RNA , Imagem Individual de Molécula
6.
Br J Psychiatry ; 218(2): 98-103, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32552923

RESUMO

BACKGROUND: The link between schizophrenia and cigarette smoking has been well established through observational studies. However, the cause-effect relationship remains unclear. AIMS: We conducted Mendelian randomisation analyses to assess any causal relationship between genetic variants related to four smoking-related traits and the risk of schizophrenia. METHOD: We performed a two-sample Mendelian randomisation using summary statistics from genome-wide association studies (GWAS) of smoking-related traits and schizophrenia (7711 cases, 18 327 controls) in East Asian populations. Single nucleotide polymorphisms (SNPs) correlated with smoking behaviours (smoking initiation, smoking cessation, age at smoking initiation and quantity of smoking) were investigated in relation to schizophrenia using the inverse-variance weighted (IVW) method. Further sensitivity analyses, including Mendelian randomisation-Egger (MR-Egger), weighted median estimates and leave-one-out analysis, were used to test the consistency of the results. RESULTS: The associated SNPs for the four smoking behaviours were not significantly associated with schizophrenia status. Pleiotropy did not inappropriately affect the results. CONCLUSIONS: Cigarette smoking is a complex behaviour in people with schizophrenia. Understanding factors underlying the observed association remains important; however, our findings do not support a causal role of smoking in influencing risk of schizophrenia.


Assuntos
Fumar Cigarros , Esquizofrenia , Fumar Cigarros/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Esquizofrenia/etiologia , Esquizofrenia/genética
7.
World J Biol Psychiatry ; : 1-9, 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33143498

RESUMO

OBJECTIVES: Environmental and genetic factors play important roles in the development of schizophrenia (SCZ), bipolar disorder (BPD) or major depressive disorder (MDD). Some risk loci are identified with shared genetic effects on major psychiatric disorders. To investigate whether SNX29 gene played a significant role in these psychiatric disorders in the Han Chinese population. METHODS: We focussed on 11 single-nucleotide polymorphisms (SNPs) harbouring SNX29 gene and carried out case-control studies in patients with SCZ (n = 1248), BPD (n = 1344), or MDD (n = 1056), and 1248 healthy controls (HC) recruited from the Han Chinese population. We constructed weighted gene co-expression network analysis (WGCNA) and extracted significant modules by R package. RESULTS: We found that rs3743592 was significantly associated with MDD and rs6498263 with BPD in both allele and genotype distributions. Before correction, rs3743592 showed allelic and genotypic significance with SCZ, rs6498263 showed allelic significance with SCZ. WGCNA identified top 10 modules of co-expressed genes. Gene Ontology (GO) and pathway analysis were used to examine the functions of SNX29, which revealed that SNX29 was involved in the regulation of a number of biological processes, such as TGF-beta, ErbB, and Wnt signalling pathway, etc. CONCLUSIONS: Our results supported common risk factors in SNX29 might share among these three mental disorders in the Han Chinese population.

8.
Curr HIV Res ; 18(5): 332-341, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32562524

RESUMO

BACKGROUND: Acquired immunodeficiency syndrome can hardly be cured currently and people with human immunodeficiency virus (HIV) need lifelong treatment that may result in the emergence of drug resistance which leads to failed treatment. Thus, the development of new anti- HIV drugs and new treatment regimens are necessary. OBJECTIVE: The aim of this study is to analyze the combined anti-HIV activity of tenofovir disoproxil fumarate, lamivudine and ACC007, a new non-nucleoside reverse transcriptase inhibitor. METHODS: The antiviral activity of tenofovir disoproxil fumarate, lamivudine and ACC007 alone or in combination against different HIV-1 strains was determined by the detection of HIV-1 p24 level through enzyme-linked immunosorbent assay. RESULT: ACC007 showed EC50 of nanomolar range (from 3.03 nM to 252.59 nM) against all HIV-1 strains used in this study except the HIV-1A17, with EC50 of 1.57 µM. The combined antiviral activity of ACC007, lamivudine and tenofovir disoproxil fumarate showed synergy antiviral activity against all HIV-1 strains used in this study. The three-drug combination showed moderate synergism against HIV-1A17, HIV-14755-5, HIV-1K103N and HIV-1V106M, with a combination index value ranging from 0.71 to 0.87, and showed synergism against the other HIV-1 strains with combination index value from 0.35 to 0.67. The combination with ACC007 significantly increases the dose reduction index value of lamivudine and tenofovir disoproxil fumarate, compared with two-drug combination. CONCLUSION: ACC007 exhibits potent antiviral activity alone or with 3TC and TDF, and exerts synergistic effect against all HIV strains used in our investigation in vitro.

9.
Psychiatry Res ; 290: 113026, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32450414

RESUMO

A sequential-recruited clinical trial has been conducted to assess capacity of Patient Health Questionnaire-15 (PHQ-15) in distinguishing bipolar II disorder from major depressive disorder. A total of 73 patients (49 BD-II depression patients) filled sociodemographic characteristics, Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 Questionnaire (GAD-7), and PHQ-15. Sum score of PHQ-15 showed statistically significant difference in the two groups (t-test, P = 0.027). The area under the curve was 0.663 (P = 0.025), and the specificity was 0.75 at sum score of 13. Patients with BD-II depression has more somatic symptoms than MDD, and PHQ-15 might be used for identification.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Questionário de Saúde do Paciente/normas , Transtornos Somatoformes/diagnóstico , Adulto , Transtorno Bipolar/psicologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Sensibilidade e Especificidade , Transtornos Somatoformes/psicologia , Inquéritos e Questionários
10.
Nat Chem Biol ; 16(8): 887-895, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32341503

RESUMO

Transcriptome-wide mapping of N6-methyladenosine (m6A) at base resolution remains an issue, impeding our understanding of m6A roles at the nucleotide level. Here, we report a metabolic labeling method to detect mRNA m6A transcriptome-wide at base resolution, called 'm6A-label-seq'. Human and mouse cells could be fed with a methionine analog, Se-allyl-L-selenohomocysteine, which substitutes the methyl group on the enzyme cofactor SAM with the allyl. Cellular RNAs could therefore be metabolically modified with N6-allyladenosine (a6A) at supposed m6A-generating adenosine sites. We pinpointed the mRNA a6A locations based on iodination-induced misincorporation at the opposite site in complementary DNA during reverse transcription. We identified a few thousand mRNA m6A sites in human HeLa, HEK293T and mouse H2.35 cells, carried out a parallel comparison of m6A-label-seq with available m6A sequencing methods, and validated selected sites by an orthogonal method. This method offers advantages in detecting clustered m6A sites and holds promise to locate nuclear nascent RNA m6A modifications.


Assuntos
Adenosina/análogos & derivados , Perfilação da Expressão Gênica/métodos , Adenosina/análise , Animais , Linhagem Celular , Células HEK293 , Células HeLa , Humanos , Metilação , Camundongos , RNA/genética , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , Transcriptoma/genética
11.
Comput Biol Med ; 110: 1-7, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31085379

RESUMO

BACKGROUND: The metabolic syndrome (MetS) is a common side effect of second-generation antipsychotic drugs (SGAs), leading to poor prognosis in patients with mental illness. The traditional Chinese herbal formula Ling-Gui-Zhu-Gan decoction (LGZGD) is a clinically validated remedy for SGAs-induced MetS, but its underlying mechanism remains unclear. METHODS: A network pharmacology-based analysis was performed to explore predicted plasma-absorbed components, putative therapeutic targets, and main pathways involved in LGZGD bioactivity. We constructed a target interaction network between the predicted targets of LGZGD and the known targets of MetS, after which we extracted major hubs using topological analysis. Thereafter, the maximum value of "edge betweenness" of all interactions was defined as a bottleneck, which suggested its importance in connecting all targets in the network. Finally, a pathway enrichment analysis of major hubs was used to reveal the biological functions of LGZGD. RESULTS: This approach identified 120 compounds and 361 candidate targets of LGZGD. According to the data generated in this study, the interaction between JUN and APOA1 plays a vital role in the treatment of SGAs-induced MetS using LGZGD. Interestingly, JUN was a putative target of LGZGD and APOA1 is one of the known targets of both MetS and SGAs (olanzapine and clozapine). LGZGD was significantly associated with several pathways including PI3K-Akt signaling, insulin resistance, and MAPK signaling pathway. CONCLUSIONS: LGZGD might inhibit JUN and thereby increases the expression of APOA1 to maintain metabolic homeostasis via some vital pathways.


Assuntos
Antipsicóticos/efeitos adversos , Apolipoproteína A-I/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Síndrome Metabólica , Modelos Biológicos , Extratos Vegetais , Proteínas Proto-Oncogênicas c-jun/metabolismo , Antipsicóticos/farmacologia , Humanos , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologia
12.
Metab Brain Dis ; 33(4): 1131-1139, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29564727

RESUMO

Tacrine(10)-hupyridone (A10E) was designed as a dual-binding acetylcholinesterase (AChE) inhibitor from the modification of tacrine and a fragment of huperzine A. We have found that A10E effectively inhibited AChE in a mixed competitive manner, with an IC50 of 26.4 nM, which is more potent than those of tacrine and huperzine A. Most importantly, we have shown, for the first time that A10E attenuated scopolamine-induced cognitive impairments without affecting motor function in mice. A10E effectively attenuated impairments of learning and memory to a similar extent as donepezil, an inhibitor of AChE used for treating Alzheimer's disease (AD). In addition, A10E significantly decreased AChE activity in the brain of mice, suggesting that A10E might cross the brain blood-barrier. Taken together, our results demonstrated that A10E, a designed dual-binding AChE inhibitor, could effectively reverse cognitive impairments, indicating that A10E might provide therapeutic efficacy for AD treatment.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Aprendizagem em Labirinto/efeitos dos fármacos , Tacrina/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/induzido quimicamente , Modelos Animais de Doenças , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Escopolamina , Tacrina/farmacologia
13.
Med Chem ; 14(3): 249-252, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28969577

RESUMO

BACKGROUND: The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has always been a global health threat and leading cause of deaths. However, due to the emergence of drug-resistant HIV, an inevitable consequence of increasing use of antiretroviral drugs posed a major threat to antiretroviral therapy success. OBJECTIVE: The discovery of anti-HIV-1 agents will be used for the effective treatment of HIV/AIDS. METHOD: In continuation of our program aimed to discover anti-HIV-1 agents, twelve matrine derivatives, such as 14-formyl-15-aryloxy/methoxymatrines (3a-j) and 14-aryloxymethylidenylmatrines (3k,l), were semi-prepared from matrine, and evaluated against HIV-1 IIIB replication in acutely infected C8166 cells in vitro. RESULTS: Among them, compound 3j showed the most potent anti-HIV-1 activity with EC50 and therapeutic index (TI) values of 1.79 µg/mL, and 98.2, respectively. CONCLUSION: It has been demonstrated that the positions of methyl on the phenyl ring and 14- formylmatrine-15-oxy on the naphthyl ring were very important for the activity. It will lay the foundation for further structural modification and application of matrines as HIV-1 inhibitors.


Assuntos
Alcaloides/farmacologia , Fármacos Anti-HIV/farmacologia , Quinolizinas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular Transformada , Descoberta de Drogas , HIV-1/efeitos dos fármacos , Humanos , Estrutura Molecular , Quinolizinas/síntese química , Quinolizinas/química , Relação Estrutura-Atividade
14.
Macromol Rapid Commun ; 38(23)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28921705

RESUMO

The constant demand for functional nanomaterials from natural biomass polymers usually requires new "green" synthetic strategies without using any foreign additives. Here, the green fabrication of a series of polyphenol nanoparticles (PNs) only from green tea extraction compounds is reported (i.e., tea polyphenols and theophylline). It is found that the nanoparticle formation process involves covalent copolymerization of monomers, as well as noncovalent self-assembly pathways. Additionally, the resulting PNs exhibit better free-radical scavenging activities compared with similar-sized, polydopamine-based synthetic melanin nanoparticles. This class of biomass-based functional nanoparticles is promising as green and effective antioxidant agents in general.


Assuntos
Polifenóis/química , Chá/química , Antioxidantes/química , Química Verde
15.
J Agric Food Chem ; 65(20): 4092-4102, 2017 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-28478680

RESUMO

ß-Amyloid (Aß) can form aggregates through self-assembly and produce neurotoxicity in the early stage of Alzheimer's disease (AD). Therefore, the inhibition of Aß assembly is considered as the primary target for AD therapy. In this study, we reported that fucoxanthin, a marine carotenoid, potently reduced the formation of Aß fibrils and oligomers. Moreover, the fucoxanthin-triggered modification significantly reduced the neurotoxicity of Aß oligomers in vitro. Molecular dynamics simulation analysis further revealed a hydrophobic interaction between fucoxanthin and Aß peptide, which might prevent the conformational transition and self-assembly of Aß. Most importantly, fucoxanthin could attenuate cognitive impairments in Aß oligomer-injected mice. In addition, fucoxanthin significantly inhibited oxidative stress, enhanced the expression of brain-derived neurotrophic factor, and increased ChAT-positive regions in the hippocampus of mice. On the basis of these novel findings, we anticipated that fucoxanthin might ameliorate AD via inhibiting Aß assembly and attenuating Aß neurotoxicity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Cognição/efeitos dos fármacos , Xantofilas/administração & dosagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/química , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
16.
ACS Chem Neurosci ; 7(8): 1047-56, 2016 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-27046396

RESUMO

Sunitinib, a tyrosine kinase inhibitor, is clinically used for the treatment of cancer. In this study, we found for the first time that sunitinib inhibits acetylcholinesterase (AChE) at submicromolar concentrations in vitro. In addition, sunitinib dramatically decreased the hippocampal and cortical activity of AChE in a time-dependent manner in mice. Molecular docking analysis further demonstrates that sunitinib might interact with both the catalytic anion and peripheral anionic sites within AChE, which is in accordance with enzymatic activity results showing that sunitinib inhibits AChE in a mixed pattern. Most importantly, we evaluated the effects of sunitinib on scopolamine-induced cognitive impairments in mice by using novel object recognition and Morris water maze tests. Surprisingly, sunitinib could attenuate cognitive impairments to a similar extent as donepezil, a marketed AChE inhibitor used for the treatment of Alzheimer's disease. In summary, our results have shown that sunitinib could potently inhibit AChE and attenuate cognitive impairments in mice.


Assuntos
Acetilcolinesterase/metabolismo , Antineoplásicos/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Indóis/uso terapêutico , Pirróis/uso terapêutico , Animais , Antagonistas Colinérgicos/toxicidade , Inibidores da Colinesterase/uso terapêutico , Modelos Animais de Doenças , Donepezila , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Indanos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Piperidinas/farmacologia , Escopolamina/toxicidade , Sunitinibe
17.
Mar Drugs ; 14(4)2016 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-27023569

RESUMO

Fucoxanthin, a natural carotenoid abundant in edible brown seaweeds, has been shown to possess anti-cancer, anti-oxidant, anti-obesity and anti-diabetic effects. In this study, we report for the first time that fucoxanthin effectively protects against scopolamine-induced cognitive impairments in mice. In addition, fucoxanthin significantly reversed the scopolamine-induced increase of acetylcholinesterase (AChE) activity and decreased both choline acetyltransferase activity and brain-derived neurotrophic factor (BDNF) expression. Using an in vitro AChE activity assay, we discovered that fucoxanthin directly inhibits AChE with an IC50 value of 81.2 µM. Molecular docking analysis suggests that fucoxanthin likely interacts with the peripheral anionic site within AChE, which is in accordance with enzymatic activity results showing that fucoxanthin inhibits AChE in a non-competitive manner. Based on our current findings, we anticipate that fucoxanthin might exhibit great therapeutic efficacy for the treatment of Alzheimer's disease by acting on multiple targets, including inhibiting AChE and increasing BDNF expression.


Assuntos
Acetilcolinesterase/metabolismo , Carotenoides/farmacologia , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Escopolamina/farmacologia , Xantofilas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular/métodos , Alga Marinha/metabolismo
18.
Yao Xue Xue Bao ; 51(11): 1704-10, 2016 11.
Artigo em Chinês | MEDLINE | ID: mdl-29908113

RESUMO

To evaluate the anti-HIV-1 activities of 5 benzophenones non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as DY1203, DY1204, DY1119, DY1208 and DY1209 in vitro, the cytotoxicity of 5 compounds were tested on C8166, MT-4, H9 and PBMC with the MTT assay. The anti-HIV-1 activities of compounds were evaluated on laboratory-adapted strain, drug-resistant strains and primary isolated strains by p24 antigen expression ELISA. The inhibition of HIV-1 recombinant reverse transcriptase activity was assessed by ELISA assay. Among 5 compounds, DY1203 and DY1204 showed low cytotoxicities with CC(50) greater than 200 µg·m L(-1). DY1119, DY1208 and DY1209 showed strong anti-HIV-1 activities against HIV-1(IIIB,) HIV-1(74V,) HIV-1(RF/V82F/184V,) HIV-1(NL4-3) (gp41(36G)N42S,) HIV-1(KM018,) HIV-1(TC-1) and HIV-1(Wan.) However, NNRTIs drug-resistant strain HIV-1(A17) showed different resistance to these compounds. The 5 compounds proved active against HIV-1 recombinant reverse transcriptase. DY1208 is expected to become a new lead compound for its high therapeutic index. The results can provide new information for HIV-1 drug research and promote the development of new HIV-1 drugs.


Assuntos
Fármacos Anti-HIV/farmacologia , Benzofenonas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Linhagem Celular , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Humanos , Leucócitos Mononucleares
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