Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 12.885
Filtrar
1.
Acta Gastroenterol Belg ; 84(3): 429-434, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34599567

RESUMO

Background: Intestinal pseudo obstruction both acute and chronic is an uncommon severe motility disorder that affect both children and adults, can lead to significant morbidity burden and have no standard management strategy. Prucalopride a highly selective serotonin receptor agonist is an effective laxative with reported extra colon action. We aim to report our experience in children with acute and chronic intestinal pseudo obstruction who responded to prucalopride and systemically review the use of prucalopride in intestinal pseudo obstruction. Methods: A report of clinical experience and systemic review of the relevant medical databases to identify the outcome of usage of prucalopride in patients with acute and chronic intestinal pseudo obstruction. Studies meeting the selection criteria were reviewed including abstract only and case reports. Results: All reported cases showed clinical response to prucalopride. There were three full text, two abstracts only and three case reports all reporting clinical improvement with prucalopride. Conclusion: Prucalopride appears to show promising results in children and adults with acute and chronic intestinal pseudo obstruction.


Assuntos
Benzofuranos , Pseudo-Obstrução Intestinal , Adulto , Benzofuranos/uso terapêutico , Criança , Colo , Humanos , Laxantes/uso terapêutico
2.
Transl Psychiatry ; 11(1): 497, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34602607

RESUMO

Cognitive deficits commonly accompany psychiatric disorders but are often underrecognised, and difficult to treat. The 5-HT4 receptor is a promising potential treatment target for cognitive impairment because in animal studies 5-HT4 receptor agonists enhance hippocampal-dependent memory processes. To date, there has been little work translating these effects to humans. We tested whether short-term administration of the 5-HT4 partial agonist, prucalopride, modified behavioural and neural (fMRI) memory processing in 44 healthy human volunteers using an experimental medicine model. We found that participants who had received six days of prucalopride treatment were significantly better at recalling previously seen neutral images and distinguishing them from new images. At a neural level, prucalopride bilaterally increased hippocampal activity and activity in the right angular gyrus compared with placebo. Taken together, these findings demonstrate the potential of 5-HT4-receptor activation for cognitive enhancement in humans, and support the potential of this receptor as a treatment target for cognitive impairment.


Assuntos
Agonistas do Receptor 5-HT4 de Serotonina , Serotonina , Animais , Benzofuranos , Hipocampo/metabolismo , Humanos , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia
3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(5): 759-766, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34622589

RESUMO

Objective: To explore the efficacy and mechanism of using 3-n-butylphthalide (NBP) in combination with bone marrow mesenchymal stem cells (BMSCs) in the treatment of experimental autoimmune encephalomyelitis (EAE) in mice. Methods: Myelin oligodendrocyte glycoprotein (MOG35-55) was used for the induction and establishment of the EAE model in C57BL/6 mice. The mice were randomly assigned to the EAE group, which received intraperitoneal injection of phosphate-buffered saline (PBS), the NBP-treated EAE group, or the NBP group, which received intraperitoneal injection of NBP, the BMSCs transplantion EAE group, or the BMSCs group, which received BMSCs injected into the lateral ventricle and intraperitoneal injection of PBS, and the BMSCs and NBP combination treatment EAE group, or the BMSCs+NBP group, which received BMSCs injected into the lateral ventricle and intraperitoneal injection of NBP. Each group had 10 mice, while ten normal mice were used as the blank control group receiving intraperitoneal injection of PBS. The neurological function scores were documented daily. The mice were sacrificed 22 days after EAE induction, and the demyelination state of of the spinal cords was observed through Luxol fast blue (LFB) staining. In addition, the levels of serum interleukin-6 (IL-6), IL-10, IL-17, IL-22 and transforming growth factor-ß (TGF-ß) were examined with ELISA. The levels of glial fibrillary acidic protein (GFAP), microtubule associated protein-2 (MAP-2) and myelin basic protein (MBP) in the brain were examined with immunofluorescence staining. Western blot was used to check the expressions of nuclear factor (NF)-κB pathway, phosphoinositide-3 kinase (PI3K)/protein kinase B (PKB or Akt) pathway, IL-17 and forkhead box P3 (Foxp3) in the spinal cords. Results: The neurological function scores and average scores of each treatment group were significantly lower than those of the EAE group ( P<0.05). The scores of the BMSCs+NBP group decreased more significantly than those of the single treatment groups (the NBP group and the BMSCs group) ( P<0.05). LFB staining results of the spinal cords were consistent with the neurological function scores and the average scores. Compared with the EAE group, the levels of pro-inflammatory cytokines, including IL-6, IL-17 and IL-22, significantly decreased ( P<0.05), and the levels of anti-inflammatory cytokines IL-10 and TGF-ß significantly increased ( P<0.05). The change in cytokine expression was more significant in the BMSCs+NBP group ( P<0.05). The expressions of GFAP, MAP-2 and MBP in the BMSCs+NBP group were significantly higher than those of the BMSCs group ( P<0.05). Compared with the EAE group, the p-NF-κB/NF-κB ratio and the IL-17/Foxp3 ratio in NBP group, BMSCs group and BMSCs+NBP group decreased, while P-IκBα/IκBα, p-pI3k/PI3K and P-Akt/Akt ratios increased, especially in the BMSCs+NBP group( P<0.05). Conclusion: The combined treatment of NBP and BMSCs can help alleviate the symptoms of EAE model mice, showing better efficacy than treatment with NBP or BMSCs alone. The mechanism is related to the inhibition of the NF-κB pathway to regulate Th17/Foxp3 ratio and the activation of the PI3K/Akt pathway to promote the neurogenic differentiation of BMSCs.


Assuntos
Encefalomielite Autoimune Experimental , Células-Tronco Mesenquimais , Animais , Benzofuranos , Encefalomielite Autoimune Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases
4.
J Biomed Nanotechnol ; 17(8): 1699-1710, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34544546

RESUMO

The present study describes the use of fucoidan, a negative sulfated polysaccharide, as a coating material for the development of liposomes targeted to macrophages infected with Mycobacterium tuberculosis. First, fucoidan was chemically modified to obtain a hydrophobized-fucoidan derivative (cholesteryl-fucoidan) using a two-step microwave-assisted (µW) method. The total reaction time was decreased from 14 hours to 1 hour while maintaining the overall yield. Cholesterylfucoidan was then used to prepare surface-modified liposomes containing usnic acid (UA-LipoFuc), an antimicrobial lichen derivative. UA-LipoFuc was evaluated for mean particle size, polydispersity index (PDI), surface charge (ζ), and UA encapsulation efficiency. In addition, a cytotoxicity study, competition assay and an evaluation of antimycobacterial activity against macrophages infected with M. tuberculosis (H37Ra) were performed. When the amount of fucoidan was increased (from 5 to 20 mg), vesicle size increased (from 168 ± 2.82 nm to 1.18 ± 0.01 µm). Changes in from +20 ± 0.41 mV for uncoated liposomes to -5.41 ± 0.23 mV for UA-LipoFuc suggested that the fucoidan was placed on the surface of the liposomes. UA-LipoFuc exhibited a lower IC50 (8.26 ± 1.11 µM) than uncoated liposomes (18.37 ± 3.34 µM), probably due to its higher uptake. UA-LipoFuc5 was internalized through the C-type carbohydrate recognition domain of the cell membrane. Finally, usnic acid, both in its free form and encapsulated in fucoidan-coated liposomes (UA-LipoFuc5), was effective against infected macrophages. Hence, this preliminary investigation suggests that encapsulated usnic acid will aid in further studies related to infected macrophages and may be a potential option for tuberculosis treatment.


Assuntos
Anti-Infecciosos , Mycobacterium tuberculosis , Benzofuranos , Lipossomos , Macrófagos , Polissacarídeos
5.
J Hazard Mater ; 416: 126216, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492973

RESUMO

Thermal treatment of municipal solid waste incineration fly ash (FA) is an effective method to detoxicate FA and produce secondary material with good utilization properties, but the high temperature induced migration of carbon, chlorine, and catalytic metals from FA to flue gases can result in a considerable reformation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). Herein, two typical fly ashes were thermally cotreated with sewage sludge (SS), respectively, and the decomposition and reformation of PCDD/Fs were systematically investigated. Thermal treatment effectively decomposed PCDD/Fs in all samples to a low level well meeting the reutilization criterion of 50 ng WHO-TEQ g-1. Cleavage of the oxygen bridge was identified as the primary decomposition pathway. Compared to mono-treating FA, cotreating FA with SS resulted in a better CaO-Al2O3-SiO2 ternary system for vitrification and effectively suppressed the reformation of PCDD/Fs in off-gases with inhibition efficiencies up to 96%. Based on the variation of chemical speciation of N, P, and S in SS after thermal treatment, SS appeared to be a S-N-containing inhibitor which passivated catalytic metals to suppress PCDD/Fs synthesis. The better suppression on de novo pathway than on chlorophenol-route identified by monitoring PCDD/F-fingerprints evolution further verified the suppression mechanism of passivating catalytic metals.


Assuntos
Benzofuranos , Dibenzodioxinas Policloradas , Cinza de Carvão , Dibenzofuranos , Dibenzofuranos Policlorados , Incineração , Dibenzodioxinas Policloradas/análise , Esgotos , Dióxido de Silício , Resíduos Sólidos/análise
6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(9): 815-820, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34533129

RESUMO

Objective To investigate the effect of salvianolic acid B (SalB) on the proliferation, migration and differentiation of human gingival mesenchymal stem cells (hGMSCs). Methods The hGMSCs were isolated and cultured, and the expressions of CD73, CD90, CD34, and CD45 were detected by flow cytometry; logarithmic phase cells were selected and hGMSCs were treated with 0, 5, 10 µmol/L SalB for 24 hours. The proliferation activity of cells in each group was detected by CCK-8 assay, the migration ability of cells was detected by TranswellTM assay and scratch test, and the osteogenic differentiation ability and the adipogenic differentiation ability were detected by alkaline phosphatase (ALP) staining and oil red O staining, respectively; the mRNA and protein expressions of cell differentiation proteins and genes as well as proteins related to the PI3K/AKT signal pathway were detected by Real-time quantiative PCR and Western blotting. Results The proliferation and migration ability of SalB-treated hGMSCs were significantly increased in a dose-dependent manner; the ability of osteogenic differentiation of hGMSCs and the expressions of osteogenesis associated proteins and PI3K/AKT signal pathway related proteins were up-regulated, while the adipogenic differentiation decreased, and the expression of adipogenesis related proteins was significantly down-regulated. Conclusion SalB promotes the proliferation, migration, and osteogenic differentiation of hGMSCs and inhibits the adipogenic differentiation, which may be related to the activation of PI3K/AKT signal pathway.


Assuntos
Células-Tronco Mesenquimais , Osteogênese , Benzofuranos , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética
7.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4244-4251, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467739

RESUMO

Coumarins are the main active components in Psoraleae Fructus. To study the multi-component pharmacokinetics of Psoraleae Fructus, this study established a sensitive and rapid ultra-pressure liquid chromatography coupled to tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of psoralen, isopsoralen, psoralenoside, and isopsoralenoside in rat plasma. After validation, the method was applied to the investigation of pharmacokinetics of psoralen, isopsoralen, psoralenoside, and isopso-ralenoside in rats after single and multiple administration of Psoraleae Fructus extract. The results revealed that the exposure of psoralen and isopsoralen in rat plasma was high after a single intragastric administration of Psoraleae Fructus extract, with an AUC_(0-∞) of 443 619-582 680 and 167 314-276 903 ng·mL~(-1)·h~(-1), respectively. Compared with these two compounds, the exposure of psoralenoside and isopsoralenoside was lower with marked gender difference. After 7-day administration of Psoraleae Fructus extract to rats, the AUC_(0-∞) of psoralen and isopsoralen was 29 701-81 783 and 39 234-89 914 ng·mL~(-1)·h~(-1), respectively, which was significantly lower than that at the first day(P<0.05), and that of psoralenoside and isopsoralenoside was 7 360-19 342 and 8 823-45 501 ng·mL~(-1)·h~(-1), respectively. There was no significant gender difference in exposure of psoralenoside and isopsoralenoside in male and female rats. However, the exposure of psoralenoside and isopsoralenoside in male rats was reduced(P<0.05), and the t_(1/2) and mean residence time(MRT) were shortened, suggesting that the removal of these two compounds from the body was accelerated.


Assuntos
Medicamentos de Ervas Chinesas , Furocumarinas , Psoralea , Administração Oral , Animais , Benzofuranos , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Ficusina , Furocumarinas/análise , Glicosídeos , Ratos , Espectrometria de Massas em Tandem
8.
Phytochemistry ; 191: 112905, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34392008

RESUMO

(+)-(2S,3S)- and (-)-(2R,3R)-Oxybaphuslactam A glucosides are two undescribed benzofuran ε-caprolactams featuring a unique 7/6/5 fused tricyclic framework with p-glucosyl-O-phenyl unit. They were isolated from the root of Tibetan medicinal plant Oxybaphus himalaicus along with an undescribed sucrose ester, 3-O-feruloyl sucrose, an undescribed lignan glucoside, (7'R,8R,8'S)-3,3',5,5'-tetramethoxy-7',9-epoxylignan-9'-ol-7-one 4,4'-di-O-ß-D-glucopyranoside and ten known amides and phenylpropanoid derivatives. Based on the spectral analyses, X-ray crystallography and comparison of experimental and TD-DFT calculated ECD spectra, the structures of these compounds were determined. The anti-inflammatory assay showed the undescribed compounds had significant inhibitory effects on the formation of NO, TNF-α and IL-6, which were evaluated by LPS induced RAW 264.7 cell model.


Assuntos
Benzofuranos , Caprolactama , Lignanas , Amidas , Anti-Inflamatórios/farmacologia , Benzofuranos/farmacologia , Glucosídeos/farmacologia , Lignanas/farmacologia , Estrutura Molecular
9.
Molecules ; 26(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34361605

RESUMO

A large number of secondary metabolites have been isolated from the filamentous fungus Stachybotrys chartarum and have been described before. Fourteen of these natural compounds were evaluated in vitro in the present study for their inhibitory activity towards the cancer target CK2. Among these compounds, stachybotrychromene C, stachybotrydial acetate and acetoxystachybotrydial acetate turned out to be potent inhibitors with IC50 values of 0.32 µM, 0.69 µM and 1.86 µM, respectively. The effects of these three compounds on cell proliferation, growth and viability of MCF7 cells, representing human breast adenocarcinoma as well as A427 (human lung carcinoma) and A431 (human epidermoid carcinoma) cells, were tested using EdU assay, IncuCyte® live-cell imaging and MTT assay. The most active compound in inhibiting MCF7 cell proliferation was acetoxystachybotrydial acetate with an EC50 value of 0.39 µM. In addition, acetoxystachybotrydial acetate turned out to inhibit the growth of all three cell lines completely at a concentration of 1 µM. In contrast, cell viability was impaired only moderately, to 37%, 14% and 23% in MCF7, A427 and A431 cells, respectively.


Assuntos
Benzofuranos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Compostos de Espiro/farmacologia , Stachybotrys/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
10.
Environ Pollut ; 289: 117869, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34388555

RESUMO

Mycoremediation of unsterilized PCDD/F-contaminated field soil was successfully demonstrated by solid-state fermentation coupled with Pleurotus pulmonarius utilizing a patented incubation approach. The experiments were carried out in four setups with two as controls. The contaminated soil was homogenously mixed with solid inocula, 1:0.5 dry w/w, resulting in an initial concentration of 4432 ± 623 ng WHO-TEQ kg-1. After a 30-day incubation under controlled conditions, the overall removal (approx. 60%) was non-specific. The removal was attributed to degradation by extracellular ligninolytic enzymes and uptake into the fruiting tissue (~110 ng WHO-TEQ kg-1 of mushroom). Furthermore, less recalcitrant chlorinated metabolites were found, implying ether bond cleavage and dechlorination happened during the mycoremediation. These metabolites resulted from the complex interaction between P. pulmonarius and the indigenous microbes from the unsterilized soil. This study provides a new step toward scaling up this mycoremediation technique to treat unsterilized PCDD/F-contaminated field soil.


Assuntos
Benzofuranos , Dibenzodioxinas Policloradas , Poluentes do Solo , Benzofuranos/análise , Dibenzofuranos Policlorados , Pleurotus , Dibenzodioxinas Policloradas/análise , Solo , Poluentes do Solo/análise
11.
Phytomedicine ; 91: 153655, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34388563

RESUMO

BACKGROUND: Potassium usnate (KU), a water-soluble form of usnic acid, shows anticancer activity. However, the underlying mechanisms have not been fully elucidated. PURPOSE: We aimed to identify the pathways involved in anticancer effects of KU in human gastric cancer (GC) and colorectal cancer (CRC) cells using RNA-sequencing (RNA-seq) based transcriptome analysis. STUDY DESIGN: We analyzed the cytotoxic effects of KU to identify the common molecular events in GC and CRC cells upon KU exposure using unbiased approaches. METHODS: Cell viability assays and western blot experiments were used to examine apoptotic changes, cell cycle arrest, and endoplasmic reticulum (ER) stress-induced cellular responses in KU-treated cells. Total RNA from KU-treated human GC and CRC cells was prepared for RNA-seq analysis. Gene ontology term and gene set enrichment analyses were used to identify the key mediators of the cytotoxic effects of KU. The expression of ER stress-induced apoptotic markers was evaluated using quantitative reverse-transcription PCR and western blot analysis. Chromatin immunoprecipitation assays for ATF3 and H3K27ac, and ATF3 knockdown were employed to verify the underlying molecular mechanisms. The inhibitory effect of KU on tumor growth in vivo was validated with metastatic tumor nodule formations in a mouse liver model. RESULTS: KU exerted cytotoxicity in human GC and CRC cells through the activation of the ER stress-induced apoptotic pathway. KU stimulated ATF3 expression, an important mediator of molecular events of apoptosis. ATF3 binds to the promoter region of ATF3, CHOP, GADD34, GADD45A, DR5, and PUMA genes and subsequently promoted apoptotic events. Knockdown of ATF3 significantly reduced the expression of ATF3 target genes and the cytotoxic effects of KU. The intraperitoneal injection of KU induced ATF3 and the apoptosis of implanted colon cancer cells, resulting in reduced metastatic tumor growth in the mouse livers. CONCLUSION: KU exerts cytotoxic effects in human GC and CRC cells by triggering ER stress-induced apoptosis via an ATF3 dependent pathway.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Benzofuranos/farmacologia , Neoplasias do Colo , Estresse do Retículo Endoplasmático , Neoplasias Gástricas , Fator 3 Ativador da Transcrição/genética , Animais , Apoptose , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Perfilação da Expressão Gênica , Humanos , Camundongos , Potássio , Neoplasias Gástricas/tratamento farmacológico
12.
Cell Mol Life Sci ; 78(17-18): 6337-6349, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34398253

RESUMO

Signaling via the B-cell receptor (BCR) is a key driver and therapeutic target in chronic lymphocytic leukemia (CLL). BCR stimulation of CLL cells induces expression of eIF4A, an initiation factor important for translation of multiple oncoproteins, and reduces expression of PDCD4, a natural inhibitor of eIF4A, suggesting that eIF4A may be a critical nexus controlling protein expression downstream of the BCR in these cells. We, therefore, investigated the effect of eIF4A inhibitors (eIF4Ai) on BCR-induced responses. We demonstrated that eIF4Ai (silvestrol and rocaglamide A) reduced anti-IgM-induced global mRNA translation in CLL cells and also inhibited accumulation of MYC and MCL1, key drivers of proliferation and survival, respectively, without effects on upstream signaling responses (ERK1/2 and AKT phosphorylation). Analysis of normal naïve and non-switched memory B cells, likely counterparts of the two main subsets of CLL, demonstrated that basal RNA translation was higher in memory B cells, but was similarly increased and susceptible to eIF4Ai-mediated inhibition in both. We probed the fate of MYC mRNA in eIF4Ai-treated CLL cells and found that eIF4Ai caused a profound accumulation of MYC mRNA in anti-IgM treated cells. This was mediated by MYC mRNA stabilization and was not observed for MCL1 mRNA. Following drug wash-out, MYC mRNA levels declined but without substantial MYC protein accumulation, indicating that stabilized MYC mRNA remained blocked from translation. In conclusion, BCR-induced regulation of eIF4A may be a critical signal-dependent nexus for therapeutic attack in CLL and other B-cell malignancies, especially those dependent on MYC and/or MCL1.


Assuntos
Fator de Iniciação 4A em Eucariotos/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Anticorpos Anti-Idiotípicos/farmacologia , Benzofuranos/farmacologia , Células Cultivadas , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia
13.
Chem Biol Interact ; 347: 109603, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34352274

RESUMO

AIMS: Major depressive disorder (MDD) affects approximately 322 million people worldwide and is a common comorbidity in patients with diabetes mellitus (DM). A possible pathophysiological mechanism correlating both diseases is the increased oxidative stress in brain regions due to hyperglycemia. Myrsine coriacea (Primulaceae) is popularly known as "capororoca" and studies have been shown that this plant exhibits several pharmacological properties attributed to myrsinoic acid A (MAA) and B (MAB). Indeed, previous results have been shown its effects on the central nervous system, leading us to explore possible psychotropic effects. MAIN METHODS: The effects of treatment with hydroalcoholic extract of the barks from Myrsine coriacea (HEBMC, 150 mg/kg, o.g.), MAA (5 mg/kg, o.g.), and MAB (3 mg/kg, o.g.) were evaluated in streptozotocin (75 mg/kg, i.p.)-induced diabetic female rats. After 28 days of treatments, rats were submitted to the forced swim test (FST) and open field test (OFT). Also, superoxide dismutase (SOD) and catalase (CAT) activities, reduced glutathione (GSH) and lipid hydroperoxides (LOOH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC) of these rats. KEY FINDINGS: The treatment with MAA or MAB increased the latency of first immobility in diabetic rats, and the HEBMC administration decreased the immobility time, and increase the climbing in FST. However, only MAB treatment reduces the immobility time, increases the climbing, and swimming in FST, and increases the crossing of diabetic animals in the OFT. Besides, this behavioral improvement promoted by MAB administration was accompanied by reducing in oxidative stress in the HIP and PFC, but not reducing hyperglycemia in diabetic rats. SIGNIFICANCE: The results suggest that MAB's antioxidant effect in the HIP of diabetic animals may be essential to its antidepressant-like effect.


Assuntos
Alcenos/uso terapêutico , Antidepressivos/uso terapêutico , Benzofuranos/uso terapêutico , Depressão/prevenção & controle , Hipocampo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Catalase/metabolismo , Depressão/etiologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Feminino , Myrsine/química , Teste de Campo Aberto/efeitos dos fármacos , Casca de Planta/química , Extratos Vegetais/uso terapêutico , Caules de Planta/química , Ratos Wistar , Estreptozocina
14.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361791

RESUMO

As a key enzyme regulating postprandial blood glucose, α-Glucosidase is considered to be an effective target for the treatment of diabetes mellitus. In this study, a simple, rapid, and effective method for enzyme inhibitors screening assay was established based on α-glucosidase catalyzes reactions in a personal glucose meter (PGM). α-glucosidase catalyzes the hydrolysis of maltose to produce glucose, which triggers the reduction of ferricyanide (K3[Fe(CN)6]) to ferrocyanide (K4[Fe(CN)6]) and generates the PGM detectable signals. When the α-glucosidase inhibitor (such as acarbose) is added, the yield of glucose and the readout of PGM decreased accordingly. This method can achieve the direct determination of α-glucosidase activity by the PGM as simple as the blood glucose tests. Under the optimal experimental conditions, the developed method was applied to evaluate the inhibitory activity of thirty-four small-molecule compounds and eighteen medicinal plants extracts on α-glucosidase. The results exhibit that lithospermic acid (52.5 ± 3.0%) and protocatechualdehyde (36.8 ± 2.8%) have higher inhibitory activity than that of positive control acarbose (31.5 ± 2.5%) at the same final concentration of 5.0 mM. Besides, the lemon extract has a good inhibitory effect on α-glucosidase with a percentage of inhibition of 43.3 ± 3.5%. Finally, the binding sites and modes of four active small-molecule compounds to α-glucosidase were investigated by molecular docking analysis. These results indicate that the PGM method is feasible to screening inhibitors from natural products with simple and rapid operations.


Assuntos
Benzaldeídos/farmacologia , Benzofuranos/farmacologia , Glicemia/análise , Catecóis/farmacologia , Depsídeos/farmacologia , Diabetes Mellitus Tipo 2/diagnóstico , Inibidores de Glicosídeo Hidrolases/farmacologia , Monitorização Ambulatorial/métodos , alfa-Glucosidases/sangue , Acarbose/química , Acarbose/farmacologia , Benzaldeídos/química , Benzaldeídos/isolamento & purificação , Benzofuranos/química , Benzofuranos/isolamento & purificação , Sítios de Ligação , Técnicas Biossensoriais/instrumentação , Catecóis/química , Catecóis/isolamento & purificação , Depsídeos/química , Depsídeos/isolamento & purificação , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/química , Humanos , Hidrólise , Cinética , Maltose/metabolismo , Simulação de Acoplamento Molecular , Monitorização Ambulatorial/instrumentação , Extratos Vegetais/química , Plantas Medicinais , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Termodinâmica , Dispositivos Eletrônicos Vestíveis , alfa-Glucosidases/química
15.
Zhongguo Zhong Yao Za Zhi ; 46(13): 3410-3421, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34396762

RESUMO

This study aims to investigate metabolic activities of psoralidin in human liver microsomes( HLM) and intestinal microsomes( HIM),and to identify cytochrome P450 enzymes( CYPs) and UDP-glucuronosyl transferases( UGTs) involved in psoralidin metabolism as well as species differences in the in vitro metabolism of psoralen. First,after incubation serial of psoralidin solutions with nicotinamide adenine dinucleotide phosphate( NADPH) or uridine 5'-diphosphate-glucuronic acid( UDPGA)-supplemented HLM or HIM,two oxidic products( M1 and M2) and two conjugated glucuronides( G1 and G2) were produced in HLM-mediated incubation system,while only M1 and G1 were detected in HIM-supplemented system. The CLintfor M1 in HLM and HIM were 104. 3,and57. 6 µL·min~(-1)·mg~(-1),respectively,while those for G1 were 543. 3,and 75. 9 µL·min~(-1)·mg~(-1),respectively. Furthermore,reaction phenotyping was performed to identify the main contributors to psoralidin metabolism after incubation of psoralidin with NADPH-supplemented twelve CYP isozymes( or UDPGA-supplemented twelve UGT enzymes),respectively. The results showed that CYP1 A1( 39. 5 µL·min~(-1)·mg~(-1)),CYP2 C8( 88. 0 µL·min~(-1)·mg~(-1)),CYP2 C19( 166. 7 µL·min~(-1)·mg~(-1)),and CYP2 D6( 9. 1 µL·min~(-1)·mg~(-1)) were identified as the main CYP isoforms for M1,whereas CYP2 C19( 42. 0 µL·min~(-1)·mg~(-1)) participated more in producing M2. In addition,UGT1 A1( 1 184. 4 µL·min~(-1)·mg~(-1)),UGT1 A7( 922. 8 µL·min~(-1)·mg~(-1)),UGT1 A8( 133. 0 µL·min~(-1)·mg~(-1)),UGT1 A9( 348. 6 µL·min~(-1)·mg~(-1)) and UGT2 B7( 118. 7 µL·min~(-1)·mg~(-1)) played important roles in the generation of G1,while UGT1 A9( 111. 3 µL·min~(-1)·mg~(-1)) was regarded as the key UGT isozyme for G2. Moreover,different concentrations of psoralidin were incubated with monkey liver microsomes( MkLM),rat liver microsomes( RLM),mice liver microsomes( MLM),dog liver microsomes( DLM) and mini-pig liver microsomes( MpLM),respectively. The obtained CLintwere used to evaluate the species differences.Phase Ⅰ metabolism and glucuronidation of psoralidinby liver microsomes showed significant species differences. In general,psoralidin underwent efficient hepatic and intestinal metabolisms. CYP1 A1,CYP2 C8,CYP2 C19,CYP2 D6 and UGT1 A1,UGT1 A7,UGT1 A8,UGT1 A9,UGT2 B7 were identified as the main contributors responsible for phase Ⅰ metabolism and glucuronidation,respectively. Rat and mini-pig were considered as the appropriate model animals to investigate phase Ⅰ metabolism and glucuronidation,respectively.


Assuntos
Glucuronosiltransferase , Microssomos Hepáticos , Animais , Benzofuranos , Cumarínicos , Cães , Glucuronídeos , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Cinética , Camundongos , Microssomos Hepáticos/metabolismo , Fenótipo , Ratos , Especificidade da Espécie , Suínos , Porco Miniatura/metabolismo
16.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360821

RESUMO

Dexamethasone (Dexa), frequently used as an anti-inflammatory agent, paradoxically leads to muscle inflammation and muscle atrophy. Receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) lead to nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome formation through nuclear factor-κB (NF-κB) upregulation. NLRP3 inflammasome results in pyroptosis and is associated with the Murf-1 and atrogin-1 upregulation involved in protein degradation and muscle atrophy. The effects of Ecklonia cava extract (ECE) and dieckol (DK) on attenuating Dexa-induced muscle atrophy were evaluated by decreasing NLRP3 inflammasome formation in the muscles of Dexa-treated animals. The binding of AGE or high mobility group protein 1 to RAGE or TLR4 was increased by Dexa but significantly decreased by ECE or DK. The downstream signaling pathways of RAGE (c-Jun N-terminal kinase or p38) were increased by Dexa but decreased by ECE or DK. NF-κB, downstream of RAGE or TLR4, was increased by Dexa but decreased by ECE or DK. The NLRP3 inflammasome component (NLRP3 and apoptosis-associated speck-like), cleaved caspase -1, and cleaved gasdermin D, markers of pyroptosis, were increased by Dexa but decreased by ECE and DK. Interleukin-1ß/Murf-1/atrogin-1 expression was increased by Dexa but restored by ECE or DK. The mean muscle fiber cross-sectional area and grip strength were decreased by Dexa but restored by ECE or DK. In conclusion, ECE or DK attenuated Dexa-induced muscle atrophy by decreasing NLRP3 inflammasome formation and pyroptosis.


Assuntos
Benzofuranos/farmacologia , Dexametasona/efeitos adversos , Glucocorticoides/efeitos adversos , Inflamassomos/efeitos dos fármacos , Atrofia Muscular , Piroptose/efeitos dos fármacos , Animais , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Extratos Vegetais/farmacologia
17.
Biomolecules ; 11(7)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34356597

RESUMO

Usnic acid (UA) is a secondary metabolite of lichens that exhibits a wide range of biological activities. Previously, we found that UA derivatives are effective inhibitors of tyrosyl-DNA phosphodiesterase 1 (TDP1). It can remove covalent complex DNA-topoisomerase 1 (TOP1) stabilized by the TOP1 inhibitor topotecan, neutralizing the effect of the drugs. TDP1 removes damage at the 3' end of DNA caused by other anticancer agents. Thus, TDP1 is a promising therapeutic target for the development of drug combinations with topotecan, as well as other drugs for cancer treatment. Ten new UA enamino derivatives with variation in the terpene fragment and substituent of the UA backbone were synthesized and tested as TDP1 inhibitors. Four compounds, 11a-d, had IC50 values in the 0.23-0.40 µM range. Molecular modelling showed that 11a-d, with relatively short aliphatic chains, fit to the important binding domains. The intrinsic cytotoxicity of 11a-d was tested on two human cell lines. The compounds had low cytotoxicity with CC50 ≥ 60 µM for both cell lines. 11a and 11c had high inhibition efficacy and low cytotoxicity, and they enhanced topotecan's cytotoxicity in cancerous HeLa cells but reduced it in the non-cancerous HEK293A cells. This "protective" effect from topotecan on non-cancerous cells requires further investigation.


Assuntos
Benzofuranos/química , Monoterpenos/química , Inibidores de Fosfodiesterase , Diester Fosfórico Hidrolases/metabolismo , Benzofuranos/farmacologia , Células HEK293 , Humanos , Monoterpenos/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia
18.
Molecules ; 26(16)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34443666

RESUMO

The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p < 0.05); when aromaticity increased, the antifungal activity decreased for series I and increased for series II. To verify the validity of the obtained equations, a new set of 44 benzofuran-4-ones was designed by replacing the nitrogen atom of the five-membered ring with oxygen in indol-4-ones. The NICS(0) and NICS(1) of benzofuran-4-ones were calculated and used to predict their biological activities using the previous equations. A set of 10 benzofuran-4-ones was synthesized and tested in eight human pathogenic fungi, showing the validity of the equations. The minimum inhibitory concentration (MIC) in yeasts was 31.25 µg·mL-1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 µg·mL-1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.


Assuntos
Antifúngicos/farmacologia , Benzofuranos/farmacologia , Fungos/efeitos dos fármacos , Antifúngicos/química , Aspergillus niger/efeitos dos fármacos , Aspergillus niger/patogenicidade , Benzofuranos/química , Candida/efeitos dos fármacos , Candida/patogenicidade , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pichia/efeitos dos fármacos , Pichia/patogenicidade , Hidrocarbonetos Policíclicos Aromáticos/química , Hidrocarbonetos Policíclicos Aromáticos/farmacologia
19.
Ann Clin Lab Sci ; 51(4): 503-511, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452888

RESUMO

OBJECTIVE: To compare the e!cacy and functional outcomes of dl-3-n-Butylphthalide (NBP) and human urinary kallidinogenase (HUK) on ischemic stroke patients and to determine their effects on serum tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF). METHODS: A prospective study was conducted on 57 ischemic stroke patients. Functional outcomes were assessed by the National Institute Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the activities of daily living score (ADL), whereas TNF-α and VEGF expressions were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: TNF-α was significantly down-regulated in the NBP group and upregulated in the control group two weeks after treatment (p=0.017 and p=0.047, respectively). A significant difference in VEGF expressions was observed between the two groups (330.25±120.64 vs. 437.15±137.68, p=0.041) two weeks after treatment. Both groups showed significant improvement in NIHSS and ADL scores three months after treatment (p<0.001), with the NBP group exhibiting improvement in NIHSS scores as early as two weeks after treatment (p=0.008). The three-month NIHSS scores of the two groups were significantly lower than those of the control group (p=0.010 and p=0.008, respectively). Both the NBP and HUK groups showed a significant decline in mRS scores two weeks and three months after treatment (p<0.05). CONCLUSIONS: Both treatments are effective and can significantly promote recovery in stroke patients. Additionally, both options have similar effects in promoting long-term recovery, with NBP exerting a greater impact on serum VEGF and TNF-α expressions.


Assuntos
Benzofuranos/uso terapêutico , Biomarcadores/sangue , Isquemia Encefálica/patologia , AVC Isquêmico/patologia , Calicreínas/administração & dosagem , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/sangue , Isquemia Encefálica/terapia , Estudos de Casos e Controles , Feminino , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/terapia , Calicreínas/urina , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/uso terapêutico , Prognóstico , Adulto Jovem
20.
Mar Pollut Bull ; 171: 112763, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34332355

RESUMO

This study determines the levels of PCDD/Fs and PCBs in Baltic fish caught in ICES areas 24, 25, and 26, and the related risk for fish consumers in relation to the newly established Tolerable Weekly Intake dose (TWI) (2 pg WHO-TEQ kg --1 body weight). The total PCDD/F/DL-PCBs toxic equivalents in the fish muscle ranged from 0.12 to 10.34 pg WHO-TEQ g - -1 wet weight. Salmon muscles contained the highest average concentration and cod the lowest, below 0.5 pg WHO-TEQ g - -1 wet weight of total TEQ. The average intake of PCDD/F/DL-PCBs (portion of fish 200 g) was 91-2420% of the TWI for children, and 30-799% of the TWI for adults. It appears that despite the decreased levels of PCDD/F and PCBs in Baltic fish, in relation to the newly established TWI dose, this decrease is not enough to make the Baltic fish safe for frequent consumers.


Assuntos
Benzofuranos , Dioxinas , Bifenilos Policlorados , Dibenzodioxinas Policloradas , Adulto , Animais , Benzofuranos/análise , Criança , Dibenzofuranos , Dibenzofuranos Policlorados , Dioxinas/análise , Contaminação de Alimentos/análise , Humanos , Bifenilos Policlorados/análise , Dibenzodioxinas Policloradas/análise
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...