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1.
Nat Prod Res ; 34(8): 1097-1104, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30616378

RESUMO

A new 22,26-seco physalin, physalin XI (1) together with 5 known compounds, were isolated from the dichloromethane extract of Physalis angulata L. The structure of isolated compounds was elucidated by spectroscopic analysis. The effects of isolated compounds on in vitro cytotoxicity were investigated. Compound 1 was assessed for its cytotoxicity against cancer cell lines (HepG2, HeLa, HuCCA-1, T47-D and A-549) and a normal cell line (MRC-5), and the result showed that it has no activity. Compounds 2 and 4 are highly toxic to H69AR and MDA-MB-23 cell lines. This property appears to be related to the presence of their conjugated double bond or epoxy groups and is a more reliable indication of toxicity than substitution on C(5)-C(6).


Assuntos
Physalis/química , Secoesteroides/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Extratos Vegetais/química , Secoesteroides/química , Esteroides/química , Esteroides/isolamento & purificação , Relação Estrutura-Atividade
2.
Drug Dev Res ; 80(8): 1013-1030, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31823411

RESUMO

It is now firmly established that an important event in the formation of reperfusion injury of the heart is the opening of mitochondrial permeability transition pores (mPTPs), which changes the permeability of the mitochondria. mPTP opening results in the death of cardiomyocytes through activation of apoptosis and necroptosis. Experimental studies have shown that pharmacological inhibition of mPTP opening promotes the reduction in the infarct size and the suppression of apoptosis. Indeed, studies have shown the efficacy of mPTP inhibitors in animal models of myocardial reperfusion and isolated human myocardial trabeculae. However, clinical trials of cyclosporin A and TRO40303 have not provided a clear answer to the question of the effectiveness of mPTP inhibitors in patients with acute myocardial infarction. This article presents an analysis of possible approaches for the pharmacological regulation of mPTP during reperfusion injury of the heart.


Assuntos
Ciclosporina/uso terapêutico , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Oximas/uso terapêutico , Secoesteroides/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Ensaios Clínicos como Assunto , Ciclosporina/farmacologia , Humanos , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Oximas/farmacologia , Secoesteroides/farmacologia
3.
Medicina (Kaunas) ; 55(7)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284484

RESUMO

Vitamin D is a secosteroid hormone regulating the expression of almost 900 genes, and it is involved in the regulation of calcium and phosphate metabolism, immune response, and brain development. Low blood vitamin D levels have been reported in patients affected by various diseases. Despite a large amount of literature data, there is uncertainty surrounding the role of vitamin D as a serum biomarker in Alzheimer's disease (AD) and Parkinson's disease (PD). Indeed, the lack of internationally recognized 25(OH)D3 reference measurement procedures and standard materials in the past led to unstandardized serum total 25(OH)D3 results among research and clinical care laboratories. Thus, most of the literature studies reported unstandardized data, which are of little use and make it difficult to draw conclusions of the role of vitamin D in AD and PD. This review summarizes the extra-skeletal actions of vitamin D, focusing its role in immunomodulation and brain function, and reports the issue of lacking standardized literature data concerning the usefulness of vitamin D as a biomarker in AD and PD.


Assuntos
Vitamina D/fisiologia , Doença de Alzheimer/sangue , Doença de Alzheimer/etiologia , Biomarcadores/análise , Biomarcadores/sangue , Humanos , Doença de Parkinson/sangue , Doença de Parkinson/etiologia , Secoesteroides/metabolismo , Vitamina D/imunologia , Vitamina D/metabolismo , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/fisiopatologia
4.
Mol Cell Biochem ; 450(1-2): 75-85, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29876765

RESUMO

Calcitriol, vitamin D3 (VD3), and structurally related VD3 analogues are inhibitors of Hh signaling in multiple contexts and are promising anti-cancer agents in Hh-dependent forms of cancer; however, the cellular mechanisms through which these compounds regulate Hh signal transmission are not clearly defined. Previous studies in this area have implicated both Smoothened, a key mediator of Hh signaling, and the vitamin D receptor (VDR) as potential mediators of Hh inhibition for this class of seco-steroids. We have performed a series of in vitro studies to more fully probe the cellular mechanisms that govern seco-steroid-mediated inhibition of Hh signaling. Our results support a role for both the Hh and VDR pathways in this process, as well as the possibility that other, as yet unidentified proteins, are also central to seco-steroid-mediated inhibition of Hh signaling.


Assuntos
Proteínas Hedgehog/metabolismo , Receptores de Calcitriol/metabolismo , Secoesteroides/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Camundongos
5.
J Cell Physiol ; 234(6): 8788-8796, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30317606

RESUMO

The in vitro and in vivo effects of physalin D on macrophage M1/M2 polarization were investigated. In silico analysis was first performed for biological function prediction of different physalins. The results suggest physalins have similar predicted biological functions due to their similarities in chemical structures. The cytotoxicity of physalins was then analyzed based on cell apoptosis rate and cell viability evaluation. Physalin D was chosen for further study due to its minimal cytotoxicity. Bone marrow macrophages were isolated and induced with lipopolysaccharide/interferon (IFN)-γ for M1 polarization and interleukin (IL)-4/IL-13 for M2 polarization. The results showed that physalin D can repolarize M1 phenotype cells toward M2 phenotype. In addition, physalin D is protective in M2 macrophages to maintain the M2 phenotype in the presence of IFN-γ. On the molecular level, we found that physalin D suppressed the signal transducers and activators of transcription (STAT)1 activation and blocked STAT1 nuclear translocation. Conversely, physalin D can also activate STAT6 and enhance STAT6 nuclear translocation for M2 polarization. Taken together, these results suggested that physalin D regulates macrophage M1/M2 polarization via the STAT1/6 pathway.


Assuntos
Macrófagos/efeitos dos fármacos , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT6/metabolismo , Secoesteroides/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Imunossupressão , Inflamação , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT6/genética , Secoesteroides/química
6.
Org Lett ; 20(24): 7957-7960, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30512956

RESUMO

Two 11(9 → 10)- abeo-5,10-secosteroids possessing an unprecedented dioxatetraheterocyclic ring system, aspersecosteroids A (1) and B (2), and a new ergosteroid, asperflosterol (3), were isolated from the sponge-derived fungus Aspergillus flocculosus 16D-1. Their structures were determined by spectroscopic analysis, X-ray diffraction, and computational methods. Compounds 1-3 demonstrated inhibitory effects on key pro-inflammatory cytokine production in THP-1 cells. A biogenetic pathway with oxidative cleavage, Wagner-Meerwein rearrangement, and sequential acetalization as key steps is proposed for 1 and 2.


Assuntos
Aspergillus/química , Secoesteroides/isolamento & purificação , Modelos Moleculares , Conformação Molecular , Secoesteroides/química
7.
J Am Chem Soc ; 140(29): 9211-9218, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-29939021

RESUMO

Aplysiasecosterol A (1) is a structurally unusual 9,11-secosteroid isolated from the sea hare Aplysia kurodai. We have accomplished the first and asymmetric total synthesis of 1 in a convergent fashion. The left-hand segment bearing three adjacent stereocenters was constructed through desymmetrizing reduction, ketalization, and radical cyclization. A strategy of asymmetric 2-bromoallylation followed by spontaneous desymmetrizing lactolization enabled a more expeditious access to this segment. The right-hand segment was prepared through two different approaches: one featuring Myers alkylation and Suzuki-Miyaura coupling and the other relying upon Aggarwal lithiation-borylation and Zweifel-Evans olefination. The two fragments were coupled by a Reformatsky type reaction. The three consecutive stereocenters embedded in the central domain of 1 were generated by an iron-mediated, hydrogen atom transfer based radical cyclization reaction.


Assuntos
Secoesteroides/síntese química , Alquilação , Ciclização , Oxirredução , Estereoisomerismo
8.
Cell Death Dis ; 9(6): 591, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789528

RESUMO

Aberrant activation of Wnt/ß-catenin signalling is critical in the progression of human cancers, especially colorectal cancer (CRC). Therefore, inhibition of Wnt/ß-catenin signalling is a significant potential target for CRC therapy. Here, we identified for the first time that Physalin F (PF), a steroid derivative isolated from Physalis angulate, acts as an antagonist of Wnt/ß-catenin signalling. In vitro, PF decreased Wnt3a-induced TOPFlash reporter activity in HEK293T cells and promoted the formation of the ß-catenin destruction complex. Importantly, PF also inhibited Wnt/ß-catenin signalling and accelerated the degradation of ß-catenin in CRC cells. However, PF did not affect the stabilization of Axin or the interaction of ß-catenin with E-cadherin. Interestingly, we further found that PF promoted YAP binding to the ß-catenin destruction complex, which facilitated the ubiquitination and degradation of ß-catenin. Silencing and pharmacological inhibition of YAP reversed the formation of the ß-catenin destruction complex induced by PF, implying that YAP binding to the ß-catenin destruction complex was responsible for PF-mediated inhibition of Wnt/ß-catenin signalling. Furthermore, PF observably inhibited tumour growth by down-regulating ß-catenin in tumour-bearing mice. Collectively, our findings indicated that PF inhibited Wnt/ß-catenin signalling by accelerating the ubiquitination and degradation of ß-catenin in a YAP-dependent manner and therefore PF could be a novel potential candidate for CRC therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Colorretais/metabolismo , Fosfoproteínas/metabolismo , Proteólise/efeitos dos fármacos , Secoesteroides/farmacologia , Ubiquitinação , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Secoesteroides/química , Fatores de Transcrição , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Contendo Repetições de beta-Transducina/metabolismo
9.
Biomed Pharmacother ; 101: 334-341, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29499407

RESUMO

Physalin B (PB), one of the major active steroidal constituents of Cape gooseberry (Physalis alkekengi L.), possesses a wide spectrum of biological activities. Although the anticancer activity of PB was reported in previous studies, the underlying mechanisms are still not well stated. In this study, the anticancer effect and the underlying mechanisms of PB were investigated in breast cancer cells. PB significantly reduced the viability of three human breast cancer cell lines, MCF-7, MDA-MB-231 and T-47D, in a concentration- and time-dependent manner. PB induced cell cycle arrest at G2/M phase and promoted cleavage of PARP (poly (ADP-ribose) polymerase), caspases 3, caspase 7 and caspase 9 to stimulate cell apoptosis. Further studies showed that PB induced breast cancer cells apoptosis in a p53-dependent manner in MCF-7 cells. PB also suppressed the phosphorylation of Akt (protein kinase B) and PI3K (phosphoinositide 3-kinase), and increased the phosphorylation of GSK-3ß (glycogen synthase kinase 3ß). Taken together, our results indicated that PB might serve as a potential therapeutic agent for breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Secoesteroides/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Células MCF-7 , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Secoesteroides/administração & dosagem , Fatores de Tempo , Proteína Supressora de Tumor p53/metabolismo
10.
J Sep Sci ; 41(8): 1781-1790, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29331063

RESUMO

Physalins are the major steroidal constituent of Physalis plants and display a range of biological activities. For this study, a rapid and sensitive high-performance liquid chromatography with triple quadrupole mass spectrometry method was developed for the simultaneous quantification of six physalins. Specifically, it was for the quantification of physalin A, physalin B, physalin D, physalin G, 4,7-didehydroneophysalin B, and isophysalin B in rat plasma and rat intestinal bacteria. After a solid-phase extraction, analytes and internal standards (prednisolone) were separated on a Shield reverse-phase C18 column (measuring 3 mm × 150 mm with an internal diameter of 3.5 µm) and determined using multiple reactions in a monitoring mode with a positive-ion electrospray ionization source. The mobile phase was a mixture of 0.1% formic acid in water (A) and acetonitrile (B) and was used at a flow rate of 0.6 mL/min. The intra- and interday precisions were within 15% with accuracies ranging from 86.2 to 114%. The method was validated and successfully applied to pharmacokinetics and stability studies of six physalins in rat plasma and rat intestinal bacteria, respectively. The results showed that physalin B and isophysalin B could not be absorbed by rats, and rat intestinal bacteria could quickly transform physalins.


Assuntos
Meios de Cultura/química , Intestinos/química , Secoesteroides/farmacocinética , Vitanolídeos/farmacocinética , Animais , Cromatografia Líquida , Feminino , Intestinos/microbiologia , Masculino , Espectrometria de Massas , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Secoesteroides/sangue , Extração em Fase Sólida , Vitanolídeos/sangue
11.
Pancreas ; 47(1): 18-24, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29200128

RESUMO

OBJECTIVES: Mitochondrial permeability transition pore inhibition is a promising approach to treat acute pancreatitis (AP). We sought to determine (i) the effects of the mitochondrial permeability transition pore inhibitor 3,5-seco-4-nor-cholestan-5-one oxime-3-ol (TRO40303) on murine and human pancreatic acinar cell (PAC) injury induced by fatty acid ethyl esters (FAEEs) or taurolithocholic acid-3-sulfate and (ii) TRO40303 pharmacokinetics and efficacy in experimental alcoholic AP (FAEE-AP). METHODS: Changes in mitochondrial membrane potential (Δψm), cytosolic Ca ([Ca]c), and cell fate were examined in freshly isolated murine or human PACs by confocal microscopy. TRO40303 pharmacokinetics were assessed in cerulein-induced AP and therapeutic efficacy in FAEE-AP induced with palmitoleic acid and ethanol. Severity of AP was assessed by standard biomarkers and blinded histopathology. RESULTS: TRO40303 prevented loss of Δψm and necrosis induced by 100 µM palmitoleic acid ethyl ester or 500 µM taurolithocholic acid-3-sulfate in murine and human PACs. Pharmacokinetic analysis found TRO40303 accumulated in the pancreas. A single dose of 3 mg/kg TRO40303 significantly reduced serum amylase (P = 0.043), pancreatic trypsin (P = 0.018), and histopathology scores (P = 0.0058) in FAEE-AP. CONCLUSIONS: TRO40303 protects mitochondria and prevents necrotic cell death pathway activation in murine and human PACs, ameliorates the severity of FAEE-AP, and is a candidate drug for human AP.


Assuntos
Ésteres/farmacologia , Ácidos Graxos/farmacologia , Mitocôndrias/efeitos dos fármacos , Oximas/farmacologia , Pancreatite Alcoólica/prevenção & controle , Secoesteroides/farmacologia , Células Acinares/efeitos dos fármacos , Células Acinares/metabolismo , Doença Aguda , Animais , Ceruletídeo , Ésteres/metabolismo , Ácidos Graxos/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Necrose/prevenção & controle , Oximas/farmacocinética , Pancreatite/induzido quimicamente , Pancreatite/prevenção & controle , Pancreatite Alcoólica/metabolismo , Pancreatite Alcoólica/patologia , Secoesteroides/farmacocinética , Ácido Taurolitocólico/análogos & derivados , Ácido Taurolitocólico/farmacologia
12.
Biomed Chromatogr ; 32(3)2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29055030

RESUMO

The calyces of Physalis alkekengi var. franchetii (Chinese Lantern, JDL) are well-known as traditional Chinese medicine owing to its various therapeutic effects. However, the bioactive constituents responsible for the pharmacological effects of JDL and their metabolites in vivo are still unclear to date. In this paper, an ultra-high-pressure liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS/MS) method was established to identify absorbed constituents and in vivo metabolites in rat biological fluids after oral administration of JDL. Based on the proposed strategy, 33 compounds were observed in dosed rat biosamples. Twelve of 33 compounds were indicated as prototype components of JDL, and 21 compounds were predicted to be metabolites of JDL. Finally, the metabolic pathways were proposed, which were glucuronidation, sulfation, methylation and dehydroxylation for flavonoid constituents and sulfonation and hydroxylation for physalin consitituents. This is the first systematic study on the absorbed constituents and metabolic profiling of JDL and will provide a useful template for screening and characterizing the ingredients and metabolites of traditional Chinese medicine.


Assuntos
Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/farmacocinética , Physalis/química , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Flavonoides/sangue , Flavonoides/farmacocinética , Flavonoides/urina , Masculino , Ratos , Ratos Sprague-Dawley , Secoesteroides/sangue , Secoesteroides/farmacocinética , Secoesteroides/urina , Espectrometria de Massas em Tandem/métodos
13.
Chem Biol Interact ; 279: 187-195, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29113806

RESUMO

The present study was conducted to isolate anti-inflammatory compound from Cynanchum atratum and investigate the molecular mechanisms of active compound against lipopolysaccharide (LPS)-induced mastitis in mice. Bioassay-guided fractionations and isolation (via ex vivo tests) of compounds with anti-inflammatory activity were performed on roots of C. atratum yielding a pure bioactive compound: Cynatratoside-C, identified by comparing spectral data (EI-MS, 1H NMR and 13C NMR) with literature values. Ex vivo tests showed that Cynatratoside-C inhibited the expression of TLR4 and pro-inflammatory cytokine (TNF-α, IL-6 and IL-1ß) production in LPS-stimulated primary mouse mammary epithelial cells. In vivo results indicated that Cynatratoside-C markedly attenuated LPS-induced mammary histopathologic changes and mammary oxidative stress (MDA, SOD, GPx) activity. Besides, Cynatratoside-C blocked the expression of Toll-like receptor 4 (TLR4) and then suppressed the phosphorylation of nuclear transcription factor-kappa B (NF-κB) p65 and degradation inhibitor of NF-κBα (IκBα). Further study showed that Cynatratoside-C could suppress the phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) in mitogen-activated protein kinase (MAPK) signal pathway. In conclusion, our results suggest that Cynatratoside-C played an anti-inflammatory role in LPS-induced mastitis by regulating TLR4 and the NF-κB and MAPK signaling pathways in mammary gland tissues. Cynatratoside-C may be a promising potential therapeutic reagent for the treatment of mastitis.


Assuntos
Anti-Infecciosos/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Secoesteroides/farmacologia , Receptor 4 Toll-Like/metabolismo , Trissacarídeos/farmacologia , Vincetoxicum/química , Animais , Anti-Infecciosos/química , Células Epiteliais/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Glândulas Mamárias Animais/citologia , Mastite/induzido quimicamente , Camundongos , Camundongos Endogâmicos BALB C , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Estrutura Molecular , NF-kappa B/genética , Secoesteroides/química , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Trissacarídeos/química
14.
J Chromatogr A ; 1526: 137-150, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29096922

RESUMO

We developed first HPTLC and HPTLC-MS/MS methods which enable characterization of structurally similar and complex biologically active compounds - physalins - from crude extracts of Chinese lantern (Physalis alkekengi L.). Separation on HPTLC silica gel plates developed with ethyl acetate-toluene-formic acid (7:3:0.2, v/v) enabled densitometric screening of physalins in absorption and, after post-chromatographic derivatization with sulfuric acid reagent, also in fluorescence mode. Compared to existing (U)HPLC methods, in this case TLC provides an alternative selectivity, better sensitivity and higher resolution, which was exemplified by the separation of physalin L standard and its impurity, identified as 2,3,25,27-tetrahydrophysalin A. Strong ion suppression caused by the developing solvent additive - formic acid - was efficiently solved by two successive plate pre-developments with methanol-formic acid (9:1, v/v) and methanol. This significantly improved the sensitivity of HPTLC-MS/MS method, but also required a slightly modified developing solvent ethyl acetate-toluene-formic acid (6:4:0.2, v/v). Simultaneous hyphenation of HPTLC with a triple quadrupole and an ion trap mass analyzer enabled a reliable and straightforward non-targeted characterization of physalins from the same chromatographic zone (band) and determination of physalin types. The performance of developed HPTLC-densitometric and HPTLC-MS/MS methods was demonstrated by the analysis of physalins from the aqueous extracts, prepared by an optimized fast and simple extraction method under reflux. Variations in physalin profiles and abundances in different parts of P. alkekengi L. harvested at different stages of maturity were observed. This indicates that not all parts of the plant, or plant as a whole, are appropriate for specific medicinal applications. Husks are proposed as the most suitable plant part for P. alkekengi L. quality control, because they exhibited the most obvious MS2 fingerprints of physalins with minimal interferences.


Assuntos
Cromatografia em Camada Delgada , Physalis/química , Extratos Vegetais/isolamento & purificação , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/química , Controle de Qualidade , Secoesteroides/química , Secoesteroides/isolamento & purificação , Sílica Gel/química
15.
Korean J Parasitol ; 55(4): 409-416, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28877572

RESUMO

The high prevalence of pediculosis capitis, commonly known as head lice (Pediculus humanus capitis) infestation, has led to the preparation of a community-based pediculicidal ointment, which is made of common household items and the extract of Tinospora crispa stem. The present study aimed to evaluate the safety, efficacy, and physicochemical characteristics of the T. crispa pediculicidal ointment. The physicochemical properties of the ointment were characterized, and safety was determined using acute dermal irritation test (OECD 404), while the efficacy was assessed using an in vitro pediculicidal assay. Furthermore, the chemical compounds present in T. crispa were identified using liquid-liquid extraction followed by ultra-performance liquid chromatography quadruple time-of-flight mass spectrometric (UPLC-qTOF/MS) analysis. The community-based ointment formulation was light yellow in color, homogeneous, smooth, with distinct aromatic odor and pH of 6.92±0.09. It has spreadability value of 15.04±0.98 g·cm/sec and has thixotropic behavior. It was also found to be non-irritant, with a primary irritation index value of 0.15. Moreover, it was comparable to the pediculicidal activity of the positive control Kwell®, a commercially available 1% permethrin shampoo (P>0.05), and was significantly different to the activity of the negative control ointment, a mixture of palm oil and candle wax (P<0.05). These findings suggested that the community-based T. crispa pediculicidal ointment is safe and effective, having acceptable physicochemical characteristics. Its activity can be attributed to the presence of compounds moupinamide and physalin I.


Assuntos
Composição de Medicamentos , Infestações por Piolhos/tratamento farmacológico , Infestações por Piolhos/parasitologia , Pediculus , Fitoterapia , Extratos Vegetais , Tinospora/química , Animais , Fenômenos Químicos , Ácidos Cumáricos/análise , Pomadas , Pediculus/efeitos dos fármacos , Praguicidas , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Segurança , Secoesteroides/análise , Testes de Irritação da Pele , Tiramina/análogos & derivados , Tiramina/análise
16.
Eur J Med Chem ; 140: 74-83, 2017 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-28923388

RESUMO

Extremely low content of biologically active triterpenoids with the fragmented or contracted ring A extractable from plants is the main disadvantage of their use in drug discovery and practical pharmacology. Development of new methods for synthesis of these compounds and their structural analogs from bioavailable triterpene precursors gives an opportunity to obtain promising agents for pharmacology with excellent yields. A new approach to synthesis of alkylated A-seco-triterpenoids, including the Beckmann fragmentation of 3-methyl-substituted allobetulin or betulinic acid methyl ester with 2-hydroxyimino group in the ring A was proposed. These compounds were used to prepare a series of 2,3-seco- and five-membered ring A lupane and oleanane derivatives, cytotoxicity of which was screened in vitro against the cancer (HEp-2, HCT 116, A549, RD TE32, MS) and non-cancerous (HEK 293) cell lines. Methyl 3-bromomethyl-1-cyano-3-oxo-2,3-seco-2-norlup-20(29)-en-30-al-28-oate was selected as the most active compound (IC50 3.4-10.4 µM for HEp-2, HCT 116, RD TE32, MS cells) capable of triggering caspase-8-mediated apoptosis in HCT 116 cells accompanied by typical apoptotic chromatin condensation, without any loss of mitochondrial membrane permeability.


Assuntos
Antineoplásicos/farmacologia , Secoesteroides/farmacologia , Alquilação , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Secoesteroides/síntese química , Secoesteroides/química , Relação Estrutura-Atividade
17.
Acta Biol Hung ; 68(3): 300-309, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28901802

RESUMO

Physalin D was isolated from the methanol extract of Physalis alkekengi L. fruits by combination of different chromatographic methods (CPC, TLC, HPLC). The structure was elucidated based on 1H and 13C NMR spectral analysis with the aid of 2D-correlation spectroscopy (1H, 1H-COSY, HSQC and HMBC) and comparison with literature data. The quantity of physalin D in mature and immature fruits and calyces was determined by RP-HPLC-UV method. Among the studied samples, immature calyx showed the highest content of physalin D (0.7880 ± 0.0612%), while mature calyx contained 4 times less amount (0.2028 ± 0.016%). The physalin D content of the fruit was much lower; immature fruits contained 0.0992 ± 0.0083% physalin D and mature fruits 0.0259 ± 0.0021%. The antiproliferative activity of the CHCl3 extract and its fractions was tested on three cancer cell lines (HeLa, MCF-7 and A431). The antiproliferative activity of physalin D is discussed with regard the published data.


Assuntos
Flores/química , Frutas/química , Neoplasias Experimentais/tratamento farmacológico , Physalis/química , Secoesteroides/administração & dosagem , Secoesteroides/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Células MCF-7 , Neoplasias Experimentais/patologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química
18.
Cardiology ; 138(2): 122-132, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28651249

RESUMO

OBJECTIVES: In the MITOCARE study, reperfusion injury was not prevented after administration of the mitochondrial permeability transition pore (mPTP) opening inhibitor, TRO40303, in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). The effects of TRO40303 on pro-inflammatory cytokines and acute-phase proteins were assessed. METHODS: STEMI patients (n = 163, mean age 62 years) with chest pain within 6 h before admission for pPCI were randomized to intravenous bolus of TRO40303 (n = 83) or placebo (n = 80) prior to reperfusion. We tested whether the groups differed in levels of IL-1ß, IL-6, IL-10, TNF, and high-sensitive C-reactive protein at various time points (0, 12, and 72 h) after PCI. Further, potential differences between groups in the change of biomarker levels between 0 and 72 h, 0 and 12 h, and 12 and 72 h were tested. RESULTS: There were no statistically significant differences between the two groups, neither in levels of pro-inflammatory cytokines nor in levels of acute-phase proteins, and there were no statistically significant differences in the change of biomarker levels between the groups considering the time intervals from 0 to 72 h, from 0 to 12 h, and from 12 to 72 h. CONCLUSION: The administration of the mPTP, TRO40303, prior to reperfusion does not alter the pharmacokinetics of pro-inflammatory cytokines or acute-phase proteins during the first 72 h after PCI.


Assuntos
Proteínas da Fase Aguda/metabolismo , Citocinas/metabolismo , Oximas/administração & dosagem , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Secoesteroides/administração & dosagem , Idoso , Biomarcadores/metabolismo , Método Duplo-Cego , Europa (Continente) , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Resultado do Tratamento
19.
J Sep Sci ; 40(11): 2355-2365, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28388002

RESUMO

Physalin D is known to show extensive bioactivities. However, no excretion study has elucidated the excretion of physalin D and its metabolites. This study investigates the excretion of physalin D and its metabolites in rats. Metabolites in rat urine and feces were separated and identified by liquid chromatography with triple quadrupole time-of-flight mass spectrometry. Furthermore, a validated high-performance liquid chromatography with tandem mass spectrometry method was developed to quantify physalin D, physalin D glucuronide, and physalin D sulfate in rat feces and urine after the intragastric administration of physalin D. The analyte showed good linearity over a wide concentration range (r > 0.995), and the lower limit of quantification was 0.0532 µg/mL and 0.226 µg/g for urine and feces, respectively. Nine metabolites, including five phase I and four phase II metabolites, were identified and clarified after dosing in vivo. Only 4.0% of the gavaged dose, including physalin D and its phase II metabolites, was excreted in urine, whereas 10.8% was found in feces in the unchanged form. The results indicate that the extensive and rapid metabolism may be the main factors leading to the short half-life of physalin D. These results can provide a basis for further studies on the structural modification and pharmacology of physalin D.


Assuntos
Fezes/química , Secoesteroides/farmacocinética , Secoesteroides/urina , Animais , Cromatografia Líquida de Alta Pressão , Ratos , Espectrometria de Massas em Tandem
20.
Biomed Chromatogr ; 31(10)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28273367

RESUMO

A rapid and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of luteolin, luteolin-7-O-ß-D-glucopyranoside, physalin A, physalin D and physalin L in rat plasma. Scutellarein and dexamethasone were used as the internal standards (IS). Plasma samples were prepared by liquid-liquid extraction with ethyl acetate. The five constituents were separated on an Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 µm). A gradient elution procedure was used with acetonitrile (A)-0.1% aqueous formic acid (B). Mass spectrometric detection was performed in negative ion multiple reaction monitoring mode with an electrospray ionization (ESI) source. This method showed good linearity (r2 > 0.997) over a concentration range of 2.0-500 ng/mL with a lower limit of quantification of 2.0 ng/mL for all five compounds. The inter- and intra-day accuracy ranged from 91.7 to 104%, and precisions (RSD) were <6.46% for all analytes. The extraction recoveries of all analytes were >85%. This validated method was successfully applied for the first time to the pharmacokinetic study of five ingredients after oral administration of 70% ethanol extract of Chinese lantern in rats.


Assuntos
Cromatografia Líquida/métodos , Flavonoides/sangue , Physalis/química , Extratos Vegetais/administração & dosagem , Secoesteroides/sangue , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Estabilidade de Medicamentos , Flavonoides/química , Flavonoides/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Secoesteroides/química , Secoesteroides/farmacocinética
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