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1.
Virus Res ; : 198593, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34637814

RESUMO

Zika virus (ZIKV) is a typical mosquito-borne flavivirus known to cause severe fetal microcephaly and adult Guillain-Barré syndrome. Currently, there are no specific drugs or licensed vaccines available for ZIKV infection, and further research is required to identify host cell proteins involved in the virus's life cycle. Viruses are known to use host cell membrane skeletal proteins, such as actin and spectrin, to complete cell entry, transportation, and release. Here, based on immunoprecipitation, the Axl and ZIKV envelope (E) protein were shown to interact with the cell membrane skeleton protein 4.1R. Furthermore, deletion of 4.1R significantly reduced virus titer and viral protein synthesis. Our study showed that 4.1R is an important host cell protein during ZIKV infection and may be involved in the process of viral entry into host cells.

2.
Zool Res ; 42(5): 633-636, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34423606

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression. In the present study, we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-CoV-2. Results revealed that SARS-CoV-2 replication was delayed in hypertensive mouse lungs. In contrast, SARS-CoV-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-CoV-2-infected normotensive mice. Furthermore, antihypertensive treatment alleviated lung inflammation induced by SARS-CoV-2 replication (interleukin (IL)-1ß up-regulation and increased immune cell infiltration). No differences in lung inflammation were observed between the SARS-CoV-2-infected normotensive mice and hypertensive mice. Our findings suggest that captopril treatment may alleviate COVID-19 progression but not affect viral replication.


Assuntos
Anti-Hipertensivos/uso terapêutico , COVID-19/complicações , Captopril/uso terapêutico , Hipertensão/complicações , Pneumopatias/tratamento farmacológico , SARS-CoV-2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Captopril/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pneumopatias/etiologia , Pneumopatias/virologia , Camundongos , Replicação Viral/efeitos dos fármacos
3.
Bioorg Chem ; 116: 105303, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34464815

RESUMO

Eucalyptus is a large genus of the Myrtaceae family with high value in various fields of industry. Recently, attention has been focused on the functional properties of Eucalyptus extracts. These extracts have been traditionally used to combat various infectious diseases, and volatile oils are usually considered to play a major role. But the positive effects of non-volatile acylphloroglucinols, a class of specialized metabolites with relatively high content in Eucalyptus, should not be neglected. Herein, non-volatile acylphloroglucinols from leaves of Eucalyptus robusta were evaluated for their abilities to inhibit Zika virus (ZIKV) which is associated with severe neurological damage and complications. The results showed eucalyprobusone G, a new symmetrical acylphloroglucinol dimer, possessed the significant ability to inhibit ZIKV without inducing cytotoxicity. The EC50 values of eucalyprobusone G against the African lineage (MR766) and Asian lineage (SZ-WIV01) of ZIKV were 0.43 ± 0.08 and 10.10 ± 3.84 µM which were 110 times and 5.8 times better than those of the reference compound ribavirin, respectively. Further action mode research showed that eucalyprobusone G impairs the viral binding and RdRp activity of NS5. The results broaden the functional properties of Eucalyptus robusta and indicate acylphloroglucinol dimers could be developed as anti-ZIKV agents.

4.
Bioorg Med Chem Lett ; 36: 127785, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33444740

RESUMO

An array of novel 7-methoxyl-2,3-disubstituted quinoxaline derivatives was designed, synthesized and their potential antihypertensive activities were examined, in an attempt to discover potent small molecules with vasorelaxant effects. The vasoactivities of these compounds on vascular tone, as well as underlying mechanisms were hereby explored. Results showed that five compounds (7s, 7t, 7v, 7w, 7γ) could induce endothelium-independent relaxation in high extracellular K+- and phenylephrine-precontracted C57 mice aortic rings. These five compounds, unlike other commonly used vasodilators, could slowly but effectively inhibit vasoconstriction.


Assuntos
Anti-Hipertensivos/farmacologia , Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Quinoxalinas/farmacologia , Vasodilatadores/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Aorta Torácica/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fenilefrina , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade , Vasodilatadores/síntese química , Vasodilatadores/química
5.
Clin Exp Pharmacol Physiol ; 47(10): 1731-1739, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32424975

RESUMO

Vascular dementia (VaD), caused by stroke or small vessel disease, is the second-most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris water maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Aß1-42 in BCCAO rats by enzyme-linked immunosorbent assay. Post-translational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlights the importance of PTMs in neurodegenerative diseases. In this study, we used western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl-PTMs.

6.
Biosci Rep ; 40(4)2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32285918

RESUMO

Radiation-induced brain edema is a serious adverse effect of radiotherapy. Although there are many causes of radiation-induced brain edema, the pathogenesis is not clear and clinical treatment is not ideal. Therefore, knowing the differential expression of the brain microvascular endothelial cell (BMEC) transcriptome after brain radiotherapy may shed light on the pathogenesis of radiation-induced brain edema. The present study used RNA-Seq technique to identify 383 BMEC transcripts differentially expressed (many 2-fold or higher; P < 0.05) between control and X-ray-treated primary cultured rat BMECs. Compared with controls, X-ray-treated BMECs had 183 significantly up-regulated transcripts and 200 significantly down-regulated transcripts. The differentially expressed genes were associated with the biological processes of the cell cycle, apoptosis, vascular permeability, and extracellular junctions. The functional changes identified in the X-ray-treated BMECs included Ca2+ signaling, phosphoinositide 3-kinase-Akt signaling, and methionine degradation. These results indicated that transcript expression was substantially affected by radiation exposure and the proteins encoded by these differentially expressed genes may play a significant role in radiotherapy-induced brain edema. Our findings provide additional insight into the molecular mechanisms of radiation-induced brain edema and may be helpful in the development of clinical treatment of this adverse reaction to radiotherapy.


Assuntos
Edema Encefálico/patologia , Encéfalo/patologia , Sinalização do Cálcio/efeitos da radiação , Endotélio Vascular/efeitos da radiação , Lesões Experimentais por Radiação/patologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/efeitos da radiação , Edema Encefálico/etiologia , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/efeitos da radiação , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Feminino , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Microvasos/citologia , Microvasos/patologia , Microvasos/efeitos da radiação , Cultura Primária de Células , RNA-Seq , Lesões Experimentais por Radiação/etiologia , Ratos , Raios X/efeitos adversos
7.
Biosci Rep ; 134(2): 155-167, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31934723

RESUMO

Colorectal cancer (CRC) is the third most common malignancies in adults. Similar to other solid tumors, CRC cells show increased proliferation and suppressed apoptosis during the development and progression of the disease. Previous studies have shown that a novel tumor oncogene, spermatogenic basic helix-loop-helix transcription factor zip 1 (SPZ1), can promote proliferation. However, it is unclear whether SPZ1 plays a role in suppressing apoptosis, and the molecular mechanism behind SPZ1's suppression of apoptosis in CRC remains unclear. Here, we found that silencing endogenous SPZ1 inhibits cell growth and induces apoptosis, and overexpression of SPZ1 promotes cell growth. These findings were corroborated by in vitro and in vivo studies. Interestingly, SPZ1 overexpressing cells were resistant to 5-fluorouracil, a drug commonly used to treat cancer. Moreover, knocking down SPZ1 led to the activation of caspase through the deregulation of Bim by ERK1/2, we found that CRC tissues had significantly higher SPZ1 and lower Bim expression, and SPZ1HBimL were associated with advanced clinical stage of CRC. Collectively, our findings demonstrate that SPZ1 contributes to tumor progression by limiting apoptosis. SPZ1 reduces apoptosis by altering the stability of Bim, suggesting SPZ1 may serve as a biomarker and therapeutic target for CRC.


Assuntos
Apoptose , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteína 11 Semelhante a Bcl-2/metabolismo , Neoplasias Colorretais/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/efeitos dos fármacos , Proteína 11 Semelhante a Bcl-2/genética , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos/crescimento & desenvolvimento , Xenoenxertos/metabolismo , Humanos , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , RNA Interferente Pequeno , Regulação para Cima
8.
Pharmacology ; 105(7-8): 386-396, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31752010

RESUMO

Vascular dementia (VaD) is the second most common type of dementia and has become a major public health challenge as the global population ages. VaD is caused by cerebrovascular disease, and most patients with VaD have been reported to also have Alzheimer's pathologies, which is the formation of neurofibrillary tangles and amyloid plaques that are mainly composed of hyperphosphorylated Tau and amyloid ß (Aß) respectively. However, the mechanisms of VaD are not completely understood, and very few drugs are available to treat this condition. Gastrodin (Gas) is the main bioactive component of the traditional Chinese herbal plant named Tian Ma (Gastrodia elata), and it has been used to treat neurasthenia in the clinical practice of Chinese Medicine for many years. Here, we hypothesize that Gas alleviates VaD in a rat model of permanent bilateral common carotid artery occlusion (2-VO)-induced VaD. Based on the results of the Morris water maze test and attention set shift test, either 22.5 or 90 mg/kg/day Gas improved the executive dysfunction and memory impairment of 2-VO rats following an intragastric administration for 4 weeks. Both 22.5 and 90 mg/kg/day Gas reduced Aß1-40 and Aß1-42 plaques in plasma and hippocampus of 2-VO rats. Mechanistically, in 2-VO rats, treatment with Gas (90 mg/kg/day) suppressed Aß plaque deposition by decreasing the hippocampus levels of phosphorylated Tau. Thus, Gas ameliorated the cognitive deficits of 2-VO rats by inhibiting the abnormal phosphorylation of Aß and Tau.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Álcoois Benzílicos/farmacologia , Demência Vascular/tratamento farmacológico , Glucosídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Proteínas tau/metabolismo , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Estenose das Carótidas/complicações , Demência Vascular/etiologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Sprague-Dawley
9.
Chin J Nat Med ; 12(3): 186-93, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24702804

RESUMO

AIM: To evaluate the anti-HIV activity and mechanism of action of wikstroelide M, a daphnane diterpene from Daphne acutiloba Rehder (Thymelaeaceae). METHODS: The anti-HIV activities of wikstroelide M against different HIV strains were evaluated by cytopathic effect assay and p24 quantification assay with ELISA. The inhibitory effect of wikstroelide M on HIV reverse transcription was analyzed by real-time PCR and ELISA. The effect of wikstroelide M on HIV-1 integrase nuclear translocation was observed with a cell-based imaging assay. The effect of wikstroelide M on LEDGF/p75-IN interaction was assayed by molecular docking. RESULTS: Wikstroelide M potently inhibited different HIV-1 strains, including HIV-1IIIB, HIV-1A17, and HIV-19495, induced a cytopathic effect, with EC50 values ranging from 3.81 to 15.65 ng·mL⁻¹. Wikstroelide M also had high inhibitory activities against HIV-2ROD and HIV-2CBL-20-induced cytopathic effects with EC50 values of 18.88 and 31.90 ng·mL⁻¹. The inhibitory activities of wikstroelide M on the three HIV-1 strains were further confirmed by p24 quantification assay, with EC50 values ranging from 15.16 to 35.57 ng·mL⁻¹. Wikstroelide M also potently inhibited HIV-1IIIB induced cytolysis in MT-4 cells, with an EC50 value of 9.60 ng·mL⁻¹. The mechanistic assay showed that wikstroelide M targeted HIV-1 reverse transcriptase and nuclear translocation of integrase through disrupting the interaction between integrase and LEDGF/p75. CONCLUSION: Wikstroelide M may be a potent HIV-1 and HIV-2 inhibitor, the mechanisms of action may include inhibition of reverse trascriptase activity and inhibition of integrase nuclear translocation through disrupting the interaction between integrase and LEDGF/p75.


Assuntos
Fármacos Anti-HIV/farmacologia , Daphne/química , Diterpenos/farmacologia , Integrase de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Extratos Vegetais/farmacologia , Fármacos Anti-HIV/uso terapêutico , Linhagem Celular , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/enzimologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fitoterapia , Extratos Vegetais/uso terapêutico , Integração Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
10.
Carbohydr Res ; 380: 64-9, 2013 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-23962762

RESUMO

Fucosylated chondroitin sulfate (FuCS-1) is a nontoxic and water-soluble depolymerized glycosaminoglycan obtained from the sea cucumber Thelenota ananas. Anti-HIV activities of FuCS-1 were evaluated in the present study. FuCS-1 was effective in blocking laboratory strain HIV-1IIIB entry and replication (4.26µg/mL and 0.73µg/mL, respectively), and inhibiting infection by clinic isolate HIV-1KM018 and HIV-1TC-2 (23.75µg/mL and 31.86µg/mL, respectively) as well as suppressing HIV-1 drug-resistant virus. It also inhibited HIV-2ROD and HIV-2CBL-20 replication (100µg/mL). Notably, FuCS-1 showed highly effective antiviral activity against T-20-resistant strains (EC50 values ranging from 0.76µg/mL to 1.13µg/mL). Further studies indicated that FuCS-1 can potently bind the recombinant HIV-1 gp120 protein, but no inhibition of recombinant HIV-1 reverse transcriptase was observed. In conclusion, FuCS-1 inhibited several strains of HIV-1 replication with different potencies. These results suggest that FuCS-1 may possess great potential to be further developed as novel HIV-1 entry inhibitor for treatment of HIV/AIDS patients, particularly for those infected by T-20-resistant variants.


Assuntos
Fármacos Anti-HIV/farmacologia , Sulfatos de Condroitina/farmacologia , Fucose/química , HIV/efeitos dos fármacos , Pepinos-do-Mar/química , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Fármacos Anti-HIV/química , Linhagem Celular , Sulfatos de Condroitina/química , HIV/fisiologia , Humanos , Polimerização
11.
Molecules ; 17(6): 6916-29, 2012 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-22728366

RESUMO

The anti-HIV activities of a pine cone extract (YNS-PY-F) from Pinus yunnanensis have been evaluated, and its mechanisms of action were also explored. The pine cone extract, YNS-PY-F, potently inhibited HIV-1(IIIB), HIV-1(RF), HIV-1(A17), HIV-1(AO18) and HIV-2(ROD) and induced cytopathic effect in C8166 cells with EC50 values of 0.96 µg/mL, 1.53 µg/mL, 0.88 µg/mL, 7.20 µg/mL and 6.17 µg/mL, respectively. The quantification of a p24 production assay showed that YNS-PY-F significantly inhibited the acute replication of HIV-1(IIIB), HIV-1RF, HIV-1(A17) and HIV-1(AO18) in C8166 cells. An MTT assay showed that YNS-PY-F also significantly inhibited the HIV-1(IIIB) induced cytolysis in MT-4 cells with an EC50 value of 2.22 µg/mL. The mechanism assays showed that YNS-PY-F had potent inhibitory effects on the fusion between infected cells and uninfected cells, and the activity of HIV-1 reverse transcriptase, with EC50 values of 7.60 µg/mL and 4.60 µg/mL, respectively. Overall, these data suggest that the pine cone extract from Pinus yunnanensis has potent inhibitory activities against HIV-1(IIIB), HIV-1(RF), RT inhibitor-resistant strains HIV-1(A17) and HIV-1(AO18), and HIV-2(ROD), and its anti-HIV mechanisms include inhibition of HIV entry and inhibition of reverse transcriptase activity.


Assuntos
Fármacos Anti-HIV/farmacologia , Pinus/química , Extratos Vegetais/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/toxicidade , Linhagem Celular , Núcleo Celular/metabolismo , Quimiocina CXCL12/metabolismo , Integrase de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Transporte Proteico , Receptores CXCR4/metabolismo , Internalização do Vírus/efeitos dos fármacos
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