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1.
Medicine (Baltimore) ; 99(28): e21036, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664111

RESUMO

BACKGROUND: Liver fibrosis is a pathological change existing in most chronic liver diseases, which leads to abnormal changes in liver tissue structure and affects the normal physiological function of liver. Without effectively control, liver fibrosis can develop into cirrhosis and increase the risk of liver cancer. Salvianolic acid B (Sal B) is the main active component in the water-soluble extract from Salvia miltiorrhiza, which is a traditional Chinese medicine usually used for treating cardiovascular and liver diseases. It is reported that Sal B shown a good action against liver fibrosis via numerous signaling pathways, which indicate that Sal B is a potential candidate drug for the treatment of liver fibrosis. METHODS: We searched the related researches from the following electronic databases: PubMed, EMBASE, Web of science, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Wan fang Database for Chinese Technical Periodicals and VIP Database. All the databases were searched from inception to December 2019. No restriction of language, publication date, or publication status. PICO of this systematic review are shown as flowing: P, preclinical studies which evaluated the effects of Sal B on the animal models of liver fibrosis with controlled studies; I, received Sal B as only treat in any dose; C, received normal saline, distilled water, or no treatment; O, the primary outcome include measure will be the decrease in liver fibrosis score, and the secondary outcomes include the index of liver fibrosis. All the included data will be analyzed with the software of Review Manager 5.2 and STATA 14.2. DISCUSSION: The purpose of this study is to conduct a systematic review and meta-analysis to assess the effects on anti-liver fibrosis of Sal B, and this will be contribute to drug development and pathological mechanisms of clinical research. TRIAL REGISTRATION: INPLASY202050101, registered on 28/5/2020.


Assuntos
Benzofuranos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Cirrose Hepática/tratamento farmacológico , Projetos de Pesquisa , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Índice de Gravidade de Doença
2.
Arterioscler Thromb Vasc Biol ; 40(8): 1891-1904, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32493172

RESUMO

OBJECTIVE: Platelets are critical to the formation of a hemostatic plug and the pathogenesis of atherothrombosis. Preclinical animal models, especially the mouse, provide an important platform to assess the efficacy and safety of antiplatelet drugs. However, these studies are limited by inherent differences between human and mouse platelets and the species-selectivity of many drugs. To circumvent these limitations, we developed a new protocol for the adoptive transfer of human platelets into thrombocytopenic nonobese diabetic/severe combined immune deficiency mice, that is, a model where all endogenous platelets are replaced by human platelets in mice accepting xenogeneic tissues. Approach and Results: To demonstrate the power of this new model, we visualized and quantified hemostatic plug formation and stability by intravital spinning disk confocal microscopy following laser ablation injury to the saphenous vein. Integrin αIIbß3-dependent hemostatic platelet plug formation was achieved within ≈30 seconds after laser ablation injury in humanized platelet mice. Pretreatment of mice with standard dual antiplatelet therapy (Aspirin+Ticagrelor) or PAR1 inhibitor, L-003959712 (an analog of vorapaxar), mildly prolonged the bleeding time and significantly reduced platelet adhesion to the site of injury. Consistent with findings from clinical trials, inhibition of PAR1 in combination with dual antiplatelet therapy markedly prolonged bleeding time in humanized platelet mice. CONCLUSIONS: We propose that this novel mouse model will provide a robust platform to test and predict the safety and efficacy of experimental antiplatelet drugs and to characterize the hemostatic function of synthetic, stored and patient platelets.


Assuntos
Plaquetas/fisiologia , Hemostasia/efeitos dos fármacos , Transferência Adotiva , Animais , Benzofuranos/farmacologia , Carbamatos/farmacologia , Terapia Antiplaquetária Dupla/efeitos adversos , Humanos , Masculino , Camundongos , Modelos Animais , Receptor PAR-1/antagonistas & inibidores
3.
Medicine (Baltimore) ; 99(20): e20151, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443330

RESUMO

BACKGROUND: This study will specifically investigate the effect of butylphthalide on hemodynamics in patients with watershed stroke (WS). METHODS: We will search the following databases from their inceptions to the March 1, 2020: Cochrane Library, MEDLINE, EMBASE, PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature, and China National Knowledge Infrastructure. All relevant randomized controlled trials on exploring the effect of butylphthalide on hemodynamics in patients with WS will be considered for inclusion. No language limitation will be imposed to this study. All study quality will be checked using Cochrane risk of bias tool. RevMan 5.3 software will be utilized for data analysis. RESULTS: This study will summarize the latest evidence to investigate the effect of butylphthalide on hemodynamics in patients with WS. CONCLUSION: Findings from this study will provide theoretical basis of butylphthalide on hemodynamics in patients with WS for clinician and future research. DISSEMINATION AND ETHICS: This study is carried out based on the published data, thus, no ethical approval is required. We will submit this study to a peer-reviewed journal for publication. SYSTEMATIC REVIEW REGISTRATION: INPLASY 202030006.


Assuntos
Benzofuranos/farmacologia , Hemodinâmica/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Benzofuranos/administração & dosagem , Benzofuranos/efeitos adversos , China/epidemiologia , Humanos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Resultado do Tratamento
4.
Zhongguo Zhong Yao Za Zhi ; 45(4): 896-898, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32237491

RESUMO

A new isobenzoisofuran(1) has been isolated from the whole plant of Cassia pumila using various chromatographic techniques, including silica gel, Sephadex, MCI-gel resin, and RP-HPLC, and its structure was determined as 9-(2-hydroxyethyl)-2,2-dimethyl-2H-furo[3,4-g]chromen-6(8H)-one. This compound was also evaluated for its antibacterial activity. The results showed that it had prominent antibacterial activity with MIC_(90) value of(45.2±4.2) µg·mL~(-1) for methicillin resistant Staphylococcus aureus(MRSA) strain. This value was closed to that of levofloxacin [with MIC_(90) value(48.5±4.3) µg·mL~(-1)].


Assuntos
Antibacterianos/farmacologia , Benzofuranos/farmacologia , Cassia/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/isolamento & purificação , Benzofuranos/isolamento & purificação , Levofloxacino , Testes de Sensibilidade Microbiana , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química
5.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(1): 30-36, 2020 Feb 28.
Artigo em Chinês | MEDLINE | ID: mdl-32131937

RESUMO

Objective To investigate the protective effect of salvianolic acid B(SAB)on the intestinal tract of rats after intestinal ischemia-reperfusion injury(IIRI). Methods Forty-eight healthy male SD rats were equally randomized into IIRI group,SAB+IIRI group,sham control group,and SAB+sham control group. The malonyldialdehyde(MDA)level and superoxide dismutase(SOD)activity in the ileum were measured in each group according to the kit instructions,the transcription levels of inflammatory factors in the ileum of rats were detected by real-time fluorescence quantitative RT-PCR,the secretion level of inflammatory factors was detected by ELISA,and the effects of intestinal ischemia-reperfusion on intestinal permeability and histological lesions were measured by histopathology. Results The MDA level in IIRI group was significantly higher than those in negative control group(P=0.005)and SAB+IIRI group(P=0.012). SOD activity of IIRI group was significantly lower than those of negative control group(P=0.006)and SAB+IIRI group(P=0.017). The optical densities of tumor necrosis factor-α(TNF-α)(P=0.003,P=0.009),interleukin(IL)-1ß(P=0.026,P=0.005),IL-6(P=0.015,P=0.003),and nuclear factor kappa-B(NF-κB)(P=0.007,P=0.015)in IIRI group were significantly higher than those in sham control group and SAB+IIRI group. The TNF-α(P=0.002,P=0.006),IL-1ß(P=0.002,P=0.006),IL-6(P=0.008,P=0.002),and NF-κB(P=0.026,P=0.005)levels in IIRI group were significantly higher than those in sham control group and SAB+IIRI group. The inulin level in IIRI group was significantly lower than that in negative control group(P=0.015)and significantly higher than that in SAB+IIRI group(P=0.011). The dextran level in IIRI group was significantly lower than those in sham control group(P=0.011)and SAB+IIRI group(P=0.012). The dextran gel level in IIRI group was significantly higher than those in sham control group(P=0.031)and SAB+IIRI group(P=0.020). SAB pretreatment remarkably improved the edema,necrosis,and villus stripping of the intestinal mucosa in the ileum of rats. The Chiu score was significantly higher in SAB+sham control group than in sham control group(P=0.001)and was significantly lower in SAB+IIRI group than in IIRI group(P=0.001). Conclusion SAB pretreatment can alleviate IIRI in rat models,and this protective effect may be achieved by alleviating oxidative stress and inflammation in the intestinal tract.


Assuntos
Benzofuranos/farmacologia , Intestinos/lesões , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Citocinas/metabolismo , Inflamação , Masculino , Estresse Oxidativo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
6.
Arch Oral Biol ; 113: 104693, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32179247

RESUMO

BACKGROUND: Osteogenic differentiation of human periodontal ligament cells (hPDLCs) is crucial for regenerate periodontal tissues. In this study, we investigated the function of salvianolic acid B (Sal B) in osteogenesis of hPDLCs. METHODS: HPDLCs were isolated from healthy third molar roots. HPDLCs at passage 3 were identified by morphological observation and immunohistochemistry of vimentin. The viability of hPDLCs incubated with Sal B at concentrations of 0µM, 0.1µM, 0.5µM, 1µM and 5µM were measured by CCK-8 assay. To evaluate the effect of Sal B on osteogenic differentiation of hPDLCs, the alkaline phosphatase (ALP) activity, osteogenic differentiation markers, and mineralized nodules were determined by ALP kit, qRT-PCR and alizarin red S staining, respectively. To confirm the function of Sal B in hPDLCs involved in Wnt/ß-catenin signaling pathway, hPDLCs were incubated with Sal B or co-incubated with Sal B and DKK-1 (a inhibitor of Wnt/ß-catenin). The levels of Wnt/ß-catenin signaling pathway and osteogenic differentiation-associated indicators were then determined. RESULTS: HPDLCs showed a typical fibroblast-like and spindle-shaped, with vimentin-positive. The viability of hPDLCs had no obvious change with stimulation of Sal B at various doses. Sal B promoted the increase of ALP activity, osteogenic differentiation markers levels, mineralized nodules and activation of Wnt/ß-catenin signaling pathway, and DKK-1 could block those effects of Sal B on hPDLCs. CONCLUSION: Sal B promoted osteogenesis of hPDLCs through Wnt/ß-catenin signaling pathway, which providing a potential drug for periodontitis treatment.


Assuntos
Benzofuranos/farmacologia , Diferenciação Celular , Osteogênese , Ligamento Periodontal/citologia , Via de Sinalização Wnt , Células Cultivadas , Humanos
7.
BMC Complement Med Ther ; 20(1): 73, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143619

RESUMO

BACKGROUND: Recent studies indicated that seeded fibril formation and toxicity of α-synuclein (α-syn) play a main role in the pathogenesis of certain diseases including Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy bodies. Therefore, examination of compounds that abolish the process of seeding is considered a key step towards therapy of several synucleinopathies. METHODS: Using biophysical, biochemical and cell-culture-based assays, assessment of eleven compounds, extracted from Chinese medicinal herbs, was performed in this study for their effect on α-syn fibril formation and toxicity caused by the seeding process. RESULTS: Salvianolic acid B and dihydromyricetin were the two compounds that strongly inhibited the fibril growth and neurotoxicity of α-syn. In an in-vitro cell model, these compounds decreased the insoluble phosphorylated α-syn and aggregation. Also, in primary neuronal cells, these compounds showed a reduction in α-syn aggregates. Both compounds inhibited the seeded fibril growth with dihydromyricetin having the ability to disaggregate preformed α-syn fibrils. In order to investigate the inhibitory mechanisms of these two compounds towards fibril formation, we demonstrated that salvianolic acid B binds predominantly to monomers, while dihydromyricetin binds to oligomeric species and to a lower extent to monomers. Remarkably, these two compounds stabilized the soluble non-toxic oligomers lacking ß-sheet content after subjecting them to proteinase K digestion. CONCLUSIONS: Eleven compounds were tested but only two showed inhibition of α-syn aggregation, seeded fibril formation and toxicity in vitro. These findings highlight an essential beginning for development of new molecules in the field of synucleinopathies treatment.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , alfa-Sinucleína/antagonistas & inibidores , Animais , Benzofuranos/farmacologia , Benzofuranos/toxicidade , Flavonóis/farmacologia , Flavonóis/toxicidade , Células HEK293 , Humanos , Camundongos , Estrutura Molecular , Agregação Patológica de Proteínas , Sinucleinopatias/tratamento farmacológico
8.
Food Chem ; 314: 126166, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972406

RESUMO

The occurrence of the quercetin oxidation metabolite 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone (BZF), whose antioxidant potency is notably higher than the antioxidant potency of quercetin, was investigated in twenty quercetin-rich plant foods. BZF was identified (HPLC-DAD-ESI-MS/MS) only in the dry outer scales of onions and shallots. Aqueous extracts of onions (OAE) and shallots (SAE) were evaluated for their antioxidant and cytoprotective properties. OAE, whose potency did not differ from SAE, protected ROS-exposed Caco2 cells against oxidative (78%) and cellular (90%) damage at a 3 µg/L concentration (corresponding to 0.03 nM of BZF). After chromatographic resolution of OAE, the BZF peak accounted fully and exclusively for its antioxidant effect. The antioxidant effects of OAE and of a pure BZF were described by two perfectly overlapping curves whose concentration-dependence was within the 3 × 10-4 to 102 nM BZF range. Such unprecedented low concentrations place BZF-containing plants on the frontier of the search for novel sources of antioxidants.


Assuntos
Antioxidantes/farmacologia , Benzofuranos/análise , Benzofuranos/farmacologia , Cebolas/química , Quercetina/metabolismo , Antioxidantes/química , Benzofuranos/metabolismo , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Frutas/química , Humanos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Espectrometria de Massas em Tandem , Verduras/química
9.
Biochem Pharmacol ; 174: 113815, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31972167

RESUMO

Diabetes is related to alterations in glucose and lipid metabolism, which are linked to endothelial cell (EC) dysfunction. Salvianolic acid B (Sal B), one of the major ingredient of Danshen (Salvia miltiorrhiza), possesses many of the biological activities. However, protective effect of Sal B against oxLDL induced ECs dysfunction under high glucose condition (high Glu) is not well known. Thus, in this study, we investigated the protective effects of Sal B against EC dysfunction induced by oxLDL and high Glu and examined the associated mechanisms. Our results showed that Sal B significantly and dose-dependently decreased oxLDL- and high Glu-mediated induction of lectin-like oxLDL receptor-1 and significantly decreased oxLDL- and high Glu-induced mitochondrial ROS (mtROS) production and mitochondrial DNA (mtDNA) expression. In addition, oxLDL stimulation under high-Glu conditions activated the intrinsic apoptosis pathway in ECs. These effects were abolished by Sal B through reductions in mtROS and mtDNA. Furthermore, Sal B inhibited oxLDL- and high Glu-induced increases in fission protein (p-DRP 1 and FIS 1) levels. OxLDL and high Glu activated the ROCK1 pathway, which is involved in apoptosis and mitophagy, while Sal B significantly reduced ROCK1 protein levels. The protective effects of Sal B against oxLDL- and high Glu-induced endothelial dysfunction may be mediated by reductions in apoptosis-related proteins and fission proteins through suppression of the ROCK1-mediated pathway.


Assuntos
Benzofuranos/farmacologia , Células Endoteliais/metabolismo , Glucose/toxicidade , Lipoproteínas LDL/toxicidade , Mitofagia/fisiologia , Quinases Associadas a rho/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mitofagia/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores
10.
Expert Opin Ther Pat ; 30(1): 27-38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31771391

RESUMO

Introduction: The activation of free fatty acid receptor 1 (FFAR1) induces insulin secretion in a glucose-dependent manner, and thereby is considered as an attractive anti-diabetic target. The clinical studies provided a lot of evidence that FFAR1 agonists improved glucose control in T2DM without the risk of hypoglycemia. The field of FFAR1 agonists is extremely competitive with many patent applications filed in recent years identifying potent candidates.Area covered: The present review summarizes patent applications (2016-2019) filing for FFAR1 modulators, including FFAR1 partial/full agonists, atypical agonists, and multiple target agonists, along with in vitro and in vivo evaluation.Expert opinion: The clinical studies of FFAR1 agonists have proved their potential for the improvement of glucose control. However, there are a few issues still to be solved in this field since TAK-875 terminated in Phase III studies due to liver toxicity. The biggest challenge on the development of FFAR1 agonists may not be the identification of a highly potent compound, but finding out the exact mechanisms of hepatotoxicity and avoid it. Moreover, the further exploration of chemical spaces on FFAR1 full agonists and multi-targeted agonists, as well as corresponding clinical studies, will be expected and might open up new directions in this field.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Benzofuranos/efeitos adversos , Benzofuranos/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Desenvolvimento de Medicamentos , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Patentes como Assunto , Receptores Acoplados a Proteínas-G/metabolismo , Sulfonas/efeitos adversos , Sulfonas/farmacologia
11.
Fitoterapia ; 140: 104440, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31783131

RESUMO

Praxelis clematidea (Asteraceae) is a harmful invasive alien weed, which cause huge destruction of ecological environment and economic losses. In this study, 22 compounds were isolated and purified from the whole plant of P. clematidea, including 4 benzofurans (1-4), 18 lignans (5-22), and five of which were new compounds (1, 3, 4, 9, 10). Various spectroscopic analysis methods were utilized to elucidate their chemical structures. The inhibitory effects of the isolated compounds on NO release from BV-2 microglia cells induced by LPS were investigated. Most of the compounds showed pronounced anti-neuroinflammatory activity. Additionally, the new compounds 3, 4 and 10 exhibited significant anti-neuroinflammatory effects, and the biological activities were further confirmed by immunoblotting, quantitative PCR and immunofluorescence staining assays. As results, this study provided a new idea for the further treatment and utilization of P. clematidea as anti-neuroinflammatory agents in health-benefit products.


Assuntos
Asteraceae/química , Benzofuranos/farmacologia , Lignanas/farmacologia , Microglia/efeitos dos fármacos , Animais , Benzofuranos/isolamento & purificação , Linhagem Celular , China , Lignanas/isolamento & purificação , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
12.
Exp Parasitol ; 208: 107779, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634474

RESUMO

Here, we report enhanced the in vitro effect of potassium usnate on coupled adult Schistosoma mansoni worms at different time intervals and concentrations. The evaluated schistosomicidal parameters were the following: motility, mortality, fecundity and integumentary changes, as viewed in photomicrographs. Potassium usnate was able to cause 100 and 50% mortality at 100 and 50 µM concentrations, respectively, after 24 h of exposure, while 25 and 12.5 µM concentrations caused changes in motility at 48 and 72 h, and lethality at 96 and 120 h respectively. Eggs were not detected at any of the concentrations analyzed. Photomicrographs revealed morphological tegument alterations within all periods of observation, such as swelling, blisters, dorsoventral contraction, short and curved worms. In conclusion, our results indicate that potassium usnate represents a possible candidate for a new drug in the control of schistosomiasis.


Assuntos
Anti-Helmínticos/farmacologia , Benzofuranos/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/prevenção & controle , Análise de Variância , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/química , Benzofuranos/administração & dosagem , Benzofuranos/química , Relação Dose-Resposta a Droga , Feminino , Fertilidade/efeitos dos fármacos , Masculino , Camundongos , Movimento/efeitos dos fármacos , Fotomicrografia , Schistosoma mansoni/fisiologia , Esquistossomose mansoni/tratamento farmacológico , Fatores de Tempo
13.
Chem Biol Interact ; 315: 108898, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31715134

RESUMO

Usnic acid, a dibenzofuran derivative found in many lichen species, is reported to have anticancer activity against human gastric cancer. We investigated the molecular alterations associated with anticancer effects of usnic acid against human gastric adenocarcinoma AGS and gastric carcinoma SNU-1 cells. Usnic acid (10-25 µM) treatment to these cells caused a significant increase in mitochondrial membrane depolarization and apoptotic cells. Apoptosis induction was accompanied by an increase in the ratio of Bax:Bcl-2 expression and cleaved-PARP. Usnic acid increased the comet tail length and tail DNA in alkaline comet assay indicating DNA double-strand breaks which was also evidenced by an increase in γH2A.X (Ser139) phosphorylation. The expression of DNA damage response proteins including DNA-PKcs, pATM (Ser1981), Chk-2 and p53 were increased. Further, N-acetyl cysteine, a known reactive oxygen species (ROS) scavenger, reversed the effects of usnic acid on expression of DNA damage response proteins and γH2A.X (Ser139) phosphorylation. This reversal was also observed in comet assay in a time and dose-dependent manner suggesting that usnic acid-induced DNA damage was caused by ROS. In addition, the non-toxic concentrations (1-10 µM) of usnic acid inhibited colony forming potential of AGS cells indicating its anti-proliferation activity. More importantly, the concentration of usnic acid that caused significant death in gastric cancer cells, did not show any considerable toxicity to normal human embryonic kidney HEK293 cells, human keratinocyte HaCaT cells and mouse primary gastric cells. Collectively, these results for the first time demonstrated the selective apoptotic effect of usnic acid (10-25 µM) through ROS generation and DNA damage on human gastric cancer cells accompanied with upregulation of γH2A.X (Ser139) phosphorylation, DNA-PKcs and p53.


Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Dano ao DNA/efeitos dos fármacos , Proteína Quinase Ativada por DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Histonas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Animais , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Regulação para Cima/efeitos dos fármacos
14.
Chem Biol Interact ; 316: 108913, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31838052

RESUMO

Protein kinases play an indispensable role in signaling pathways that regulate tumor cell functions, which represent potent therapeutic targets in cancers. Dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) as a serine/threonine kinase has recently been reported to be upregulated in pancreatic ductal adenocarcinoma (PDAC) and show protumorigenic effect. By activity-guided phytochemical investigation of the extracts from Glycyrrhiza uralensis Fisch, we expect to find the effective constituents that can suppress pancreatic cancer cell proliferation and/or induce cells apoptotic by inhibiting DYRK1A. Eight isopentenyl-substituted compounds (1-8), including four coumarins (1-4), one benzofuran (5), and three flavonoids (6-8), were isolated and identified from G. uralensis Fisch. Among them, licocoumarone (LC, 5) showed effective inhibitory activity against DYRK1A with an IC50 value of 12.56 µM. Molecular docking analysis suggested that LC completely occupied the whole pocket of DYRK1A and formed obvious hydrophobic interactions and hydrogen bonds with DYRK1A residues. Further in vitro validation, including Microscale Thermophoresis (MST) and drug affinity responsive target stability (DARTS) techniques, demonstrated the specific combining capacity of LC to DYRK1A. Meanwhile, LC induced significant cytotoxicity against DYRK1A-overexpressing BxPC-3 cells with an IC50 value of 50.77 µM. Mechanism studies revealed that LC reduced c-MET protein level by inhibiting DYRK1A. These findings provide preliminary evidences that LC as a natural DYRK1A inhibitor suppresses human pancreatic adenocarcinoma BxPC-3 cell proliferation and induces cell apoptotic, which might present new options and possibilities for targeted therapies in pancreatic cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Resorcinóis/farmacologia , Benzofuranos/química , Benzofuranos/metabolismo , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Glycyrrhiza/química , Glycyrrhiza/metabolismo , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Resorcinóis/química , Resorcinóis/metabolismo
15.
Nat Prod Res ; 34(7): 923-929, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30587038

RESUMO

A three-component Strecker-type reactions was applied for the synthesis of benzofuran derivatives through the reaction of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1-ethanone (euparin), primary amines and trimethylsilyl cyanide (TMSCN) in the presence of catalytic amount of ZnO-nanorods (ZnO-NR) and piperidine in acetonitrile at room temperature. The method has proved to be synthetically simple, and effective with high atom economy and yield. The catalyst also revealed significant reusability. Moreover, the antioxidant activity and free radical scavenging capacity of the newly synthesized such as 4a, 4c, 6a and 6c was screened using free radical scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays and compared with hydroxytoluene (BHT) and tert-butylhydroquinone (TBHQ). These compounds exhibit good DPPH radical scavenging and ferric reducing antioxidant power (FRAP) assays.


Assuntos
Antioxidantes/farmacologia , Benzofuranos/síntese química , Antioxidantes/síntese química , Antioxidantes/química , Benzofuranos/química , Benzofuranos/farmacologia , Catálise , Depuradores de Radicais Livres/química , Ferro/química , Óxido de Zinco
16.
Acta Trop ; 201: 105159, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31491401

RESUMO

Currently, the control of schistosomiasis is based on a single drug, praziquantel, which is effective against all species of Schistosoma but only in the adult stage, presenting a schistosomicidal deficit at the other developmental stages of the parasites. Recently our research group has demonstrated that the potassium salt of usnic acid (PS-UA) presented schistosomicidal property against couples of adult worms of S. mansoni. Thus, the present study seeks to report for the first time the in vitro activity of PS-UA against different developmental stages of S. mansoni (schistosomules and young worms). As schistosomicide parameters, we evaluated motility, mortality, cell viability of the worms and tegument changes by scanning electron microscopy (SEM). After 3 h exposure, PS-UA was lethal to schistosomules at concentrations of 100 and 50 µM, whereas for concentrations 25 and 12.5 µM, 38 and 18% of mortality and 62 and 24% changes in motility, respectively, were reached. Yet for schistosomules, concentration of 25 µM caused 90 and 100% of death after 6 and 12 h, respectively. In the concentration of 12.5 µM at intervals of 12 and 24 h mortality was 68 and 100%, respectively. For young worms, after 3 h of exposure at concentrations of 200 and 100 µM caused 57 and 27% mortality, respectively. After 12 and 24 h, these concentrations caused mortality of 90 and 100% and 47 and 60% respectively. After 24 h, concentrations of 50 and 25 µM caused 80 and 30% change in motility, respectively. However, at the 12.5 µM concentration no change was observed. In addition, PS-UA reduced the cellular viability of young worms by 50.98% and 85.87% at concentrations of 100 and 200 µM, respectively. In both stages of worms and at different exposure intervals, PS-UA caused alterations such as: dorsoventral contraction, peeling, swelling, blisters, erosion, exposure of subtegumental tissue and disintegration of tegument. According to the results, changes in motility and mortality caused by PS-UA against schistosomules and young worms were concentration and time-dependents, also PS-UA even at low concentration, was able to cause profound ultrastructural changes in the integument of the worms. PS-UA is a promising candidate as prophylactic agent in the control of schistosomiasis mansoni.


Assuntos
Benzofuranos/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Microscopia Eletrônica de Varredura , Schistosoma mansoni/crescimento & desenvolvimento , Schistosoma mansoni/ultraestrutura
17.
Eur J Med Chem ; 187: 111961, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865017

RESUMO

Accumulation of tau protein aggregation plays a crucial role in neurodegenerative diseases, such as Alzheimer's disease (AD). Uncontrollable neuroinflammation and tau pathology form a vicious circle that further aggravates AD progression. Herein, we reported the synthesis of usnic acid derivatives and evaluation of their inhibitory activities against tau-aggregation and neuroinflammation. The inhibitory activity of the derivatives against the self-fibrillation of the hexapeptide AcPHF6 was initially screened by ThT fluorescence assay. Using circular dichroism and transmission electron microscopy, compound 30 showed the most potent inhibitory activity against AcPHF6 self-fibrillation. Compound 30 was further confirmed to inhibit the aggregation of full-length 2N4R tau protein by a heparin-induced mechanism. In addition, we investigated the anti-inflammatory activity of compound 30, and showed that compared with sodium usnate, it reduced NO release in LPS-stimulated mouse microglia BV2 cells. More importantly, 30 showed significant protective effects against okadaic acid-induced memory impairment in rats. Thus, 30 was a novel tau-aggregation and neuroinflammation inhibitor that represented a potential therapeutic candidate for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/farmacologia , Inflamação/tratamento farmacológico , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas tau/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Animais , Benzofuranos/síntese química , Benzofuranos/química , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Agregados Proteicos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Proteínas tau/metabolismo
18.
Talanta ; 206: 120195, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514831

RESUMO

The ability to separate bioactive compounds from herbal medicines, which contain abundant components, is crucial for drug discovery. Conventional Countercurrent chromatography (CCC) methods for separating bioactive compounds are labor intensive and show low efficiency. Here, we present a novel integrative CCC method for separating lysine-specific demethylase 1 (LSD1) inhibitors from the roots of Salvia miltiorrhiza (RSM). The methanol extracts of RSM were separated into hydrosoluble and liposoluble fractions, which were online stored in coils. Subsequently, the targeting LSD1 constituents were isolated using isocratic, gradient, or recycling elution mode. All separation processes could be accomplished using one CCC apparatus. Using our separation strategy, two phenylpropanoids and four tanshinones were isolated, which were determined to be new classes of natural LSD1 inhibitors. Salvianolic acid B, which showed the most potent inhibitory activity with an IC50 of 0.11 µM, exhibiting a considerable potential as an anticancer agent. Promisingly, the integrative CCC could be a crucial tool for the target separation of enzyme inhibitors from herbal medicines.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Raízes de Plantas/química , Salvia miltiorrhiza/química , Benzofuranos/isolamento & purificação , Benzofuranos/metabolismo , Benzofuranos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cinamatos/isolamento & purificação , Cinamatos/metabolismo , Cinamatos/farmacologia , Distribuição Contracorrente/métodos , Depsídeos/isolamento & purificação , Depsídeos/metabolismo , Depsídeos/farmacologia , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/metabolismo , Histona Desmetilases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Fenantrenos/isolamento & purificação , Fenantrenos/metabolismo , Fenantrenos/farmacologia , Ligação Proteica
19.
Biochim Biophys Acta Proteins Proteom ; 1868(1): 140283, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31526870

RESUMO

The abnormal aggregation of human islet amyloid polypeptide (hIAPP) is a crucial pathogenic factor associated with type 2 diabetes (T2D). The development of effective inhibitors to prevent hIAPP aggregation is a common therapeutic strategy against T2D. Lithospermic acid (LA) is a natural compound with diversified biological activities. In this study, electrospray ionization coupled with ion mobility-mass spectrometry, thioflavin T fluorescence assay, Congo red binding assay, Nile red fluorescence assay, circular dichroism spectroscopy, transmission electron microscopy, cell toxicity, lactate dehydrogenase assay (LDH) assay and molecular docking were combined to explore the influence of LA on hIAPP aggregation. Results showed that LA had favorable binding affinity to hIAPP and formed hIAPP-LA complexes, which could alter the relative abundance of the compact and extended conformers and promoted the transition of extended structures to compact conformers. LA also displayed strong inhibitory actions on fibrillation and potential protective effects against hIAPP-induced cell toxicity. Therefore, the obtained results were useful to understand the possible inhibitory mechanism of LA on hIAPP aggregation and provided valuable reference for the screening of potent amyloid inhibitors.


Assuntos
Amiloide/metabolismo , Benzofuranos/farmacologia , Depsídeos/farmacologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Simulação de Acoplamento Molecular , Conformação Proteica , Ratos
20.
J Enzyme Inhib Med Chem ; 35(1): 211-226, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31760822

RESUMO

Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aß aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aß1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Benzofuranos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade , Tacrina/química
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