RESUMO
Alzheimer's disease (AD) is one of the leading causes of dementia. As the first common neurodegenerative disease, there are no effective drugs that can reverse the progression. The present study is to report the anti-AD effect of cryptotanshinone (CTS), a natural product isolated from Salvia castanea. It is found that it can alleviate AD-like features associated with Aß1-42 toxicity in muscle cells as well as neuronal cells of Caenorhabditis elegans (C. elegans). Further studies showed that CTS reduced the level of reactive oxygen species (ROS) in nematodes, up-regulated the expression of sod-3, and enhanced superoxide dismutase activity. Cryptotanshinone reduced the level of Aß monomers and highly toxic oligomers in C. elegans while inhibiting the abnormal aggregation of polyglutamine protein. In addition, CTS upregulated the expression of hsp-16.2 and downregulated the expression of ace-2. These results suggested that CTS could alleviate oxidative stress and reduce the level of abnormally aggregated proteins and has the potential to be developed as an anti-AD drug candidate.
Assuntos
Doença de Alzheimer , Proteínas de Caenorhabditis elegans , Doenças Neurodegenerativas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Estresse Oxidativo , Fenantrenos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the world. However, there is no effective drug to cure it. Caesalmin C is a cassane-type diterpenoid abundant in Caesalpinia bonduc (Linn.) Roxb. In this study, we investigated the effect of caesalmin C on Aß-induced toxicity and possible mechanisms in the transgenic Caenorhabditis elegans AD model. Our results showed that caesalmin C significantly alleviated the Aß-induced paralysis phenotype in transgenic CL4176 strain C. elegans. Caesalmin C dramatically reduced the content of Aß monomers, oligomers, and deposited spots in AD C. elegans. In addition, mRNA levels of sod-3, gst-4, and rpt-3 were up-regulated, and mRNA levels of ace-1 were down-regulated in nematodes treated with caesalmin C. The results of the RNAi assay showed that the inhibitory effect of caesalmin C on the nematode paralysis phenotype required the DAF-16 signaling pathway, but not SKN-1 and HSF-1. Further evidence suggested that caesalmin C may also have the effect of inhibiting acetylcholinesterase (AchE) and upregulating proteasome activity. These findings suggest that caesalmin C delays the progression of AD in C. elegans via the DAF-16 signaling pathway and that it could be developed into a promising medication to treat AD.
Assuntos
Doença de Alzheimer , Proteínas de Caenorhabditis elegans , Diterpenos , Doenças Neurodegenerativas , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Diterpenos/farmacologia , Fatores de Transcrição Forkhead/genética , Paralisia/induzido quimicamente , RNA Mensageiro/metabolismoRESUMO
Salvia castanea (Family Labiatae), a perennial fragrant herb with castaneous flowers, is mainly distributed in areas with an altitude of 2500-3750 m. The roots of this plant were used as a tea drink by local residents to strengthen physical health. The aim of present study was to acquire secondary metabolites of the ethanol extract obtained from the whole plant of S. castanea and to evaluate their potential anti-Alzheimer's disease. Six new sesquiterpene lactones, salcastanins A-F (1-6), together with three known guaiane-type sesquiterpenoids nubiol (7), nubdienolide (8), and nubenolide (9), were separated from the whole plant of S. castanea. The structures of these compounds were determined by HRESIMS and NMR experiments. The absolute configurations of 1-6 were ascertained by electronic circular dichroism (ECD) experiments. The humanized Caenorhabditis elegans AD pathological model was used to evaluate anti-Alzheimer's disease (AD) activities of 1-9. The results showed the compounds 1-3 and 7 significantly delayed AD-like symptoms of worm paralysis phenotype, which could be used as novel anti-AD candidates.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Extratos Vegetais/química , Salvia/química , Sesquiterpenos/farmacologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , China , Modelos Animais de Doenças , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Sesquiterpenos/isolamento & purificaçãoRESUMO
One new bisabolane-type sesquiterpenoid, together with four known bisabolane-type sesquiterpenoid derivatives and seven phenolics, was isolated from the rhizomes of Curcuma longa. Their structures were elucidated by extensive spectroscopic (IR, HR-ESI-MS, and NMR) data analysis. The possible anti-Alzheimer's disease (AD) activities of the isolated compounds were also evaluated using Caenorhabditis elegans AD pathological model, and 1ß-hydroxybisabola-2,10-dien-4-one had the highest possible anti-AD activity.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Curcuma/química , Sesquiterpenos Monocíclicos/farmacologia , Fenóis/farmacologia , Rizoma/química , Animais , Caenorhabditis elegans , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estrutura Molecular , Sesquiterpenos Monocíclicos/química , Sesquiterpenos Monocíclicos/isolamento & purificação , Fenóis/química , Fenóis/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Commiphoins A-C (1-3), three new cadinane-type sesquiterpenes, together with two known cadinane-type sesquiterpenes (4 and 5) were isolated from the resinous exudates of Commiphora myrrha. Their structures and relative configurations were established on the basis of comprehensive spectroscopic methods, including HRESIMS, 1D and 2D NMR analyses. Compounds 1 and 3-5 were screened for anti-Alzheimer's disease (AD) activities using the AD pathological model in Caenorhabditis elegans. The results showed that they all had significant anti-AD activities.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Commiphora/química , Sesquiterpenos Policíclicos/isolamento & purificação , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Avaliação Pré-Clínica de Medicamentos , Sesquiterpenos Policíclicos/química , Sesquiterpenos Policíclicos/uso terapêutico , Resinas Vegetais/químicaRESUMO
Eupulcherol A (1), a novel triterpenoid with an unprecedented carbon skeleton, was isolated from Euphorbia pulcherrima. Its structure was determined by comprehensive analysis of spectroscopic data, including HRESIMS and 1D and 2D NMR, and the absolute configuration was defined by single crystal X-ray diffraction analysis. Biological studies showed that compound 1 possessed anti-Alzheimer's disease (AD) bioactivity, which could delay paralysis of transgenic AD Caenorhabditis elegans. A plausible biogenetic pathway for eupulcherol A (1) was also proposed.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antiprotozoários/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Euphorbia/química , Triterpenos/farmacologia , Doença de Alzheimer/parasitologia , Animais , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
Narjatamanins A (1) and B (2), a pair of epimers possessing a novel 2,3-seco-iridoid skeleton with an unusual 1,10-oxygen bridge, were isolated from the whole plants of Nardostachys jatamansi. Their structures were elucidated by a combination of various spectroscopic methods, including HRESIMS, IR and 1D and 2D NMR techniques. The absolute configurations of 1 and 2 were established by electronic circular dichroism (ECD) calculations. The pharmacological activities of 1 and 2 to alleviate AD-like symptoms were also evaluated using the Caenorhabditis elegans Alzheimer's disease (AD) pathological model, and narjatamanins A (1) and B (2) showed statistically significant delay in the worm paralysis phenotype of AD-like symptoms.
RESUMO
Nardochinins A-D (1-4), four novel sesquiterpenoids, along with four known ones were isolated from the underground parts of Nardostachys chinensis Batal in ethanol. Their structures were determined by extensive spectroscopic methods and single-crystal X-ray diffraction. Nardochinin A (1) possessed a norsesquiterpene skeleton with an unusual 3/6/5/5 tetracyclic ring system, which had not appeared in natural products. Nardochinins B (2) and C (3) were the first time found naturally occurring sesquiterpenoids with a 4,5-seco-nardosinane skeleton. Besides, compound 3 represented an unprecedented 4,5-seco-nardosinane type norsesquiterpenoid with losing an isopropenyl at C-6 compared with 2 in the structural framework. Nardochinin D (4) was a novel, highly oxygenated valerenane-type sesquiterpenoid possessing a rare 3,12-epoxy group and an unusual 9,11-epoxy group. The anti-Alzheimer's disease (AD) activities of 1-4 were also evaluated using the Caenorhabditis elegans AD pathological model, and nardochinin B (2) had the highest anti-AD activity.
RESUMO
Parasite infections of humans and animals remain a major global health problem, with limited choice of drugs being available to the treatment of parasitosis in the clinic. Sophora moorcroftiana (S. moorcroftiana) is a shrub that grows in Tibet Plateau of China. Decoction of the seeds has been used as a traditional Tibetan medicine to treat parasitosis for years. But the anti-parasitic effects of water-soluble fractions in the seeds need further investigation. In the present study, the water-soluble alkaloid fractions (E2) were obtained from S. moorcroftiana seeds by refluxing extraction with 60% ethanol and low polarity fraction (E2-a) and high polarity fraction (E2-b) were subsequently isolated from E2 using column chromatography. As a parasite model, Caenorhabditis elegans (C. elegans) were treated with different fractions and their survivals were recorded. The results showed that that E2-a induced a lower survival rate in C. elegans than E2-b and E2. The protoscoleces of Echinococcus granulosus (E. granulosus) were cultured in the presence of E2-a. Compared with E2-b and E2, protoscoleces exhibited decreased survival rate following E2-a treatment. Furtherly, the effects of E2-a on the behavior, brood size, and lifespan of the worms were investigated. Body bend frequencies of the worms treated with the high concentration of E2-a were reduced by two-thirds compared with the control group (P < 0.01). Compared with non-E2-a-treated group, exposure of nematodes to E2-a led to a decrease in head thrashes and pharyngeal pumps frequency (P < 0.01). E2-a treatment resulted in a significantly lower brood size (P < 0.01). Additional E2-a treatment induced a significantly shortened lifespan, compared with the control (P < 0.05). These findings indicated that water-soluble fraction E2-a from S. moorcroftiana seeds was a potential helminthic agent.
Assuntos
Anti-Helmínticos/administração & dosagem , Caenorhabditis elegans/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Equinococose/tratamento farmacológico , Echinococcus granulosus/efeitos dos fármacos , Sophora/química , Animais , Anti-Helmínticos/isolamento & purificação , Caenorhabditis elegans/fisiologia , China , Medicamentos de Ervas Chinesas/isolamento & purificação , Equinococose/parasitologia , Echinococcus granulosus/fisiologia , Humanos , Sementes/químicaRESUMO
A new succinate derivative, ethyl (5-formylfuran-2-yl)methyl succinate (1), along with three known compounds (2-4) have been isolated from the whole plants of Ajuga decumbens Thunb. Their structures were elucidated by extensive spectroscopic (1D and 2D NMR) and HR-ESI-MS data analysis, and literature values. Compound 1 was isolated as a new succinate derivative, and compounds 2 and 3 were for the first time separated from A. decumbens.
Assuntos
Ajuga/química , Succinatos/isolamento & purificação , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fitol/isolamento & purificação , Succinatos/química , Ácido Vanílico/isolamento & purificaçãoRESUMO
In our searching for novel antioxidants from natural sources, N-trans-Caffeoyldopamine which was from natural product was found to be a potential compound for its remarkable antioxidant activity. Isoniazid (INH) and Rifampicin (RFP) is widely used for the treatment of Tuberculosis (TB) as the first line drugs, have been known to be potentially hepatotoxic and may lead to drug-induced liver injury. Oxidative stress has been regarded as the major mechanism of the hepatotoxicity. Therefore, in this study, the possible protective effects of N-trans-Caffeoyldopamine was investigated in the hepatotoxicity caused by INH and RFP in rats. Results showed that serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and hepatic malondialdehyde (MDA) content were reduced dramatically, and hepatic superoxide dismutase (SOD) activity and glutathione (GSH) content were restored remarkably by N-trans-Caffeoyldopamine co-administration, as compared to the INH-RFP treated rats (p<0.01). Moreover, the histopathological damage of liver and the number of apoptotic hepatocytes were also significantly ameliorated by the treatment. It is therefore suggested that N-trans-Caffeoyldopamine can provide a definite protective effect against acute hepatic injury caused by INH and RFP in rats, which may mainly be associated with its antioxidative effect. Mechanisms studies indicated that it inhibited the lipid peroxidation through the cytochrome P450 2E1 (CYP2E1) downregulation.
Assuntos
Produtos Biológicos/farmacologia , Ácidos Cafeicos/química , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dopamina/análogos & derivados , Isoniazida/toxicidade , Fígado/efeitos dos fármacos , Rifampina/toxicidade , Animais , Produtos Biológicos/química , Ácidos Cafeicos/farmacologia , Dopamina/química , Dopamina/farmacologia , Fígado/patologia , Estrutura Molecular , RatosRESUMO
Iron pyrite, an important component of traditional Chinese medicine, has a poor solubility, bioavailability, and patient compliance due to a high dose required and associated side effects, all of which have limited its clinical applications and experimental studies on its action mechanisms in improving fracture healing. This study investigated Acidithiobacillus ferrooxidans (A.f)-bioleaching of two kinds of pyrites and examined bioactivities of the derived solutions in viability and osteogenic differentiation in rat calvarial osteoblasts. A.f bioleaching improved element contents (Fe, Mn, Zn, Cu, and Se) in the derived solutions and the solutions concentration-dependently affected osteoblast viability and differentiation. While the solutions had no effects at low concentrations and inhibited the osteoblast alkaline phosphatase (ALP) activity at high concentrations, they improved ALP activity at their optimal concentrations. The improved osteoblast differentiation and osteogenic function at optimal concentrations were also revealed by levels of ALP cytochemical staining, calcium deposition, numbers and areas of mineralized nodules formed, mRNA and protein expression levels of osteogenesis-related genes (osteocalcin, Bmp-2, Runx-2, and IGF-1), and Runx-2 nuclear translocation. Data from this study will be useful in offering new strategies for improving pyrite bioavailability and providing a mechanistic explanation for the beneficial effects of pyrite in improving bone healing.
Assuntos
Acidithiobacillus , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ferro/farmacologia , Osteoblastos/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Animais Recém-Nascidos , Calcificação Fisiológica/fisiologia , Diferenciação Celular/fisiologia , Sobrevivência Celular/fisiologia , Células Cultivadas , Osteoblastos/fisiologia , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Soluções Farmacêuticas/farmacologia , Ratos , Ratos WistarRESUMO
Although realgar bioleaching solution (RBS) has been proved to be a potential candidate for cancer therapy, the mechanisms of RBS anticancer are still far from being completely understood. Dosed with RBS in C. elegans, the multivulva phenotype resulting from oncogenic ras gain-of-function was inhibited in a dose dependent manner. It could be abrogated by concurrent treatment C. elegans with RBS and the radical scavenger DMSO. However, RBS could not induce DAF-16 nuclear translocation in TJ356 or the increase of HSP 16.2 expression in CL2070, which both could be aroused visible GFP fluorescent variation to represent for oxidative stress generation. Treatment C. elegans with superoxide anion generator paraquat, similar results were also obtained. Our results indicated that RBS suppress excessive activated ras by increasing reactive oxygen species (ROS) in C. elegans. Secondly, ROS induced by RBS significantly accumulated on a higher level in C. elegans with a mutational ras than that with wild ras, thus leading to oxidative stress on ras gain-of-function background rather than on normal ras context. Our results firstly demonstrated that using C. elegans as a model organism for evaluating prooxidant drug candidates for cancer therapy.