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1.
J Chem Phys ; 151(12): 125103, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31575200

RESUMO

This article reports on a frequency domain analysis of quasielastic neutron scattering spectra from free and Huperzine-A-inhibited human acetylcholinesterase, extending a recent time domain analysis of the same experimental data [M. Saouessi et al., J. Chem. Phys. 150, 161104 (2019)]. An important technical point here is the construction of a semianalytical model for the resolution-broadened dynamic structure factor that can be fitted to the experimental spectra. We find comparable parameters as in our previous study and demonstrate that our model is sensitive to subpercent changes in the experimental data, which are caused by reversible binding of the inhibitor Huperzine A.


Assuntos
Acetilcolinesterase/química , Alcaloides/química , Inibidores da Colinesterase/química , Sesquiterpenos/química , Alcaloides/farmacologia , Inibidores da Colinesterase/farmacologia , Humanos , Difração de Nêutrons , Domínios Proteicos , Sesquiterpenos/farmacologia
2.
Expert Opin Drug Metab Toxicol ; 15(10): 849-867, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31566028

RESUMO

Introduction: Piperine, the major bioactive component from black pepper, has gained increasing attention for its beneficial effects in the central nervous system (CNS). However, its related pharmacodynamics and brain pharmacokinetics, as well as its interaction with other CNS drugs are lacking, which may hinder its therapeutic and safe use. Areas covered: The current review provides an updated summary on CNS activities of piperine, including anti-epileptic, anti-depressive and neurodegeneration protection effect. The brain pharmacokinetic properties of piperine together with the approaches to enhance its aqueous solubility were summarized. Considering the wide use of black pepper and the well-reported alteration on CYP and transporters by piperine, interactions between piperine and CNS drugs are also illustrated for the first time. Expert opinion: Although the CNS beneficial effects of piperine have been extensively studied in preclinical models, clinical evidence on its CNS application is barely available, which may be attributed to its limited aqueous solubility, unclear pharmacokinetic properties in humans and potential toxicities during long-term use at higher doses. Although beneficial interactions between piperine and certain CNS drugs were often reported in preclinical studies, more mechanistic studies with clinically relevant doses should be conducted to provide guidance on their clinical combination use.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Piper nigrum/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/farmacocinética , Animais , Benzodioxóis/isolamento & purificação , Benzodioxóis/farmacocinética , Fármacos do Sistema Nervoso Central/isolamento & purificação , Fármacos do Sistema Nervoso Central/farmacocinética , Fármacos do Sistema Nervoso Central/farmacologia , Doenças do Sistema Nervoso Central/fisiopatologia , Relação Dose-Resposta a Droga , Interações de Medicamentos , Humanos , Piperidinas/isolamento & purificação , Piperidinas/farmacocinética , Alcamidas Poli-Insaturadas/isolamento & purificação , Alcamidas Poli-Insaturadas/farmacocinética
3.
Zhongguo Zhong Yao Za Zhi ; 44(14): 2980-2986, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31602843

RESUMO

Pain is one of the problems that seriously affect people's quality of life for thousands of years. The causes of pain are complex and varied,and long-term pain can also lead to depression. It has become a research hotspot to develop analgesic preparations with significant drug effects and small side effects. Recent studies have shown that certain alkaloid monomers have analgesic targets such as γ-aminobutyric acid,cannabinoids,and capsaicin. If their preparation is applied to the analgesic field,they can make up for the defects such as strong addiction and side effects of traditional opioid and non-steroidal analgesic drugs,but there is no relevant literature to summarize the research results in this field. This article first introduces the mechanism of pain production and the target of analgesia. Based on this,the application status of alkaloid monomer analgesic preparations approved by China Food and Drug Administration( CFDA)( number varieties,type of dosage form,drug description,analgesic mechanism and advantages) was analyzed,and the research dynamics of alkaloid monomer analgesic preparations( new formulation and new technology) were reviewed. Finally,some problems in this field were pointed out,such as imperfect medication information,inadequate transformation of research results,and too few kinds of analgesic components in developed alkaloids. The development direction was also pointed out for the above problems,with a view to provide reference for further development and in-depth research.


Assuntos
Alcaloides/farmacologia , Analgésicos/farmacologia , Dor/tratamento farmacológico , Analgesia , China , Humanos , Qualidade de Vida
4.
Bol. latinoam. Caribe plantas med. aromát ; 18(5): 527-532, sept. 2019. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1008292

RESUMO

Chemical constituents and biological activities of the aerial parts of Piper erecticaule C.DC. have been studied for the first time. Fractionation and purification of the extracts afforded aristolactam AII (1), aristolactam BII (2), piperolactam A (3), piperolactam C (4), piperolactam D (5), together with terpenoids of ß-sitosterol, ß-sitostenone, taraxerol, and lupeol. The structures of these compounds were obtained by analysis of their spectroscopic data, as well as the comparison with that of reported data. Acetylcholinesterase inhibitory activity revealed that compounds 1 and 3 showed strong AChE inhibitory effects with the percentage inhibition of 75.8% and 74.8%, respectively.


Se estudiaron por primera vez los constituyentes químicos y actividad biológica de las partes aéreas de Piper erecticaule C.DC. El fraccionamiento y la purificación de los extractos proporcionaron aristolactama AII (1), aristolactama BII (2), piperolactama A (3), piperolactama C (4), piperolactama D (5), junto con terpenoides de ß-sitosterol, ß-sitostenona, taraxerol, y el lupeol. Las estructuras de estos compuestos se obtuvieron mediante el análisis de sus datos espectroscópicos, así como mediante la comparación con datos ya informados. La actividad inhibidora de la acetilcolinesterasa reveló que los compuestos 1 y 3 mostraron un potente efecto inhibidor de la AChE con un porcentaje de inhibición del 75.8% y 74.8%, respectivamente.


Assuntos
Aporfinas/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Extratos Vegetais/química , Inibidores da Colinesterase/farmacologia , Piper/química , Alcaloides/farmacologia , Aporfinas/química , Terpenos , Inibidores da Colinesterase/química , Alcaloides Indólicos/química , Alcaloides/química , Lactamas/química
5.
Pestic Biochem Physiol ; 159: 51-58, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400784

RESUMO

Isoquinoline alkaloids possess broad pharmacological activities. In this study, the antifungal activity of twelve isoquinoline alkaloids, including berberine (1), jatrorrhizine (2), coptisine (3), corydaline (4), tetrahydroberberine (5), chelidonine (6), dihydrosanguinarine (7), chelerythrine (8), sanguinarine (9), palmatine (10), tetrahydropalmatine (11) and columbamine (12) were evaluated against eight plant pathogenic fungi in vitro. All the tested compounds showed varying degrees of inhibition against the eight tested plant fungi. Among them, sanguinarine exhibited high antifungal activity (EC50 ranging from 6.96-59.36 µg/mL). It displayed the best inhibitory activity against Magnaporthe oryzae (EC50 = 6.96 µg/mL), compared with azoxystrobin (EC50 = 12.04 µg/mL), and significantly suppressed spore germination of M. oryzae with the inhibition rate reaching 100% (50 µg/mL). The optical microscopy and scanning electron microscopy observations revealed that after treating M. oryzae mycelia with sanguinarine at 10 µg/mL, the mycelia appeared curved, collapsed and the cell membrane integrity was eventually damaged. Furthermore, the reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia had been changed, and the membrane function and cell proliferation of mycelia were destroyed. These results will enrich our insights into action mechanisms of antifungal activity of sanguinarine against M. oryzae.


Assuntos
Alcaloides/farmacologia , Antifúngicos/farmacologia , Benzofenantridinas/farmacologia , Isoquinolinas/farmacologia , Berberina/análogos & derivados , Berberina/farmacologia , Alcaloides de Berberina/farmacologia , Magnaporthe/metabolismo , Magnaporthe/patogenicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Espécies Reativas de Oxigênio/metabolismo
6.
Oncol Rep ; 42(4): 1451-1458, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364732

RESUMO

Epithelial­mesenchymal transition (EMT) is closely related to tumor metastasis, and offers insight into novel strategies for cancer treatment. HMQ­T­F2 (F2) is a taspine derivative, which has excellent anticancer activity in human cervical cancer. The present study aimed to evaluate the effect of F2 on in vitro migration of HeLa cells. The present data demonstrated that F2 inhibited migration of HeLa cells by negatively regulating the Wnt signaling pathway and reversing EMT. F2 not only mediated Frizzled8, p­LRP6 and LRP6 expression, but also downregulated the phosphorylation of GSK3ß, and concurrently decreased the nucleus protein expression of MMP2, MMP3, MMP7, MMP9, and c­Myc. In addition, the expression of N­cadherin, vimentin, Snail and HIF­1α were downregulated and that of E­cadherin was upregulated after F2 treatment. F2 was also associated with the downregulation of the PI3K/Akt/mTOR signaling pathways. Notably, F2 induced HeLa cell accumulation at the S phase and cell apoptosis. These results provide evidence that F2 inhibits HeLa cell migration, proliferation and promotes apoptosis. It also reverses EMT, potentially via the PI3K/Akt signaling pathway. Therefore, F2 may be a potential therapeutic reagent against cervical cancer.


Assuntos
Alcaloides/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Alcaloides/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Fase S/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
7.
Bratisl Lek Listy ; 120(8): 576-580, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379180

RESUMO

AIM: Quinine, a frequently used anti-malaria alkaloid isolated from the Cinchona bark, possesses numerous toxic properties, the majority of which arrive from a dysfunction of the gastrointestinal tract. Similarly, cinchonine, another alkaloid from the Cinchona bark, displays a great potential for treating malaria (especially the resistant forms). METHODS: In this work, we aimed to evaluate the effects of cinchonine on spontaneous and induced Wistar rat ileum contractions in order to uncover potential side effects that might arise after its application. RESULTS: Cinchonine produced a concentration-dependent spasmolytic activity, which was found to be reversible (i.e. disappeared after tissue wash-up), with an IC50 value of 273 µM. Furthermore, the mechanism of action of cinchonine at IC50 elucidated through experiments with acetylcholine and Ca2+-induced ileum contractions. The applied IC50 concentration of cinchonine statistically significantly prevented the occurrence of contractions after the application of specific agonist. The obtained results are in a range with the effects seen with standard receptor antagonists, i.e. atropine and verapamil. CONCLUSIONS: The obtained results showed that cinchonine inhibited both types of induced contractions, suggesting a Ca2+-channels mediated modus operandi (Fig. 4, Ref. 19).


Assuntos
Alcaloides/farmacologia , Alcaloides de Cinchona/farmacologia , Cinchona/química , Íleo/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Animais , Ratos , Ratos Wistar
8.
Planta Med ; 85(13): 1114-1123, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31340396

RESUMO

The fruit from various pepper plants has been employed for the seasoning of food, as perfuming agents, and also as traditional medicines. Phytochemicals isolated from different pepper species have been found to modulate the pharmacokinetics of orally administered drugs. This study investigated the possibility to apply capsaicin and piperine (extracted alkaloids) as modulators for drug delivery across the nasal epithelium. Both a nasal epithelial cell line (RPMI 2650) and excised sheep nasal tissue were used as models to investigate the effects of the selected pepper compounds on drug permeation. FITC-dextran 4400 (MW 4400 Da) was used as a large molecular weight marker compound for paracellular transport, while rhodamine 123 was used as a marker compound that is a substrate for P-glycoprotein-mediated efflux. From the permeation results, it was clear that capsaicin inhibited P-glycoprotein efflux to a larger extent, while piperine showed drug permeation enhancement via other mechanisms. The cell cytotoxicity studies indicated that capsaicin was noncytotoxic up to a concentration of 200 µM and piperine up to a concentration of 500 µM as indicated by cell viability above 80%. The histological analysis of the excised nasal tissue and cultured RPMI 2650 cell layers indicated that some damage occurred after treatment with 200 µM capsaicin, but no changes were observed for piperine up to a concentration of 50 µM.


Assuntos
Alcaloides/uso terapêutico , Benzodioxóis/uso terapêutico , Capsaicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Mucosa Nasal/metabolismo , Veículos Farmacêuticos/uso terapêutico , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Alcaloides/farmacologia , Animais , Benzodioxóis/farmacologia , Capsaicina/farmacologia , Mucosa Nasal/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Ovinos
9.
Fitoterapia ; 137: 104268, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306720

RESUMO

Solanum nigrum L. (also called as European black nightshade) has been traditionally used as folk medicine and food in some regions. Phytochemical investigations of the immature fruits of S. nigrum yielded five steroidal alkaloid glycosides (1-5), including an unprecedented nor-spirosolane type steroidal alkaloid with a five-membered ring A (1) and two novel spirosolane type steroidal alkaloid glycosides (2, 3), together with eight known phenolic compounds (6-13). Their structures were elucidated on the basis of spectroscopic and chemical methods, including IR, NMR, HR-ESI-MS, and GC analyses. Five steroidal alkaloid glycosides were tested for their potential antiproliferative effects against HL-60, U-937, Jurkat, K562, and HepG2 cell lines and inhibitory activities on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in a macrophage cell line RAW 264.7. Compound 1 exhibited significant inhibition on NO production with an IC50 value of 23.4 ±â€¯2.0 µM, compared to positive control indomethacin (IC50, 47.40 ±â€¯4.50 µM). Compound 4 exhibited significant cytotoxicity against all tested cell lines.


Assuntos
Alcaloides/farmacologia , Glicosídeos/farmacologia , Solanum nigrum/química , Esteroides/farmacologia , Alcaloides/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , China , Frutas/química , Glicosídeos/isolamento & purificação , Humanos , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Células RAW 264.7 , Esteroides/isolamento & purificação
10.
Fitoterapia ; 137: 104277, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31351127

RESUMO

Five new Lycopodium alkaloids, huperzine Y1 (1), huperzine Y2 (2), huperzine Y3 (3), (+)-huperzine Z (4a) and (-)-huperzine Z (4b) as well as ten known alkaloids (5-14) were isolated from Huperzia serrata. The structures of the new compounds were established using extensive spectroscopic (1D and 2D NMR, IR, and HRESIMS) and calculated electronic circular dichroism (ECD) methods. Compounds 4a and 4b were a pair of enantiomers successfully separated by chiral HPLC resolution. Compounds 2 and 3 indicated inhibitory activities against acetylcholinesterase with IC50 value of 57.1 ±â€¯1.6 and 32.7 ±â€¯1.0 µΜ, respectively. However, no compound showed inhibitory effect on butyrocholinesterase at the concentration of 100 µΜ.


Assuntos
Alcaloides/farmacologia , Huperzia/química , Acetilcolinesterase , Alcaloides/isolamento & purificação , Butirilcolinesterase , China , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
11.
Chem Biodivers ; 16(8): e1900299, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31287220

RESUMO

The biotransformation of huperzine B (hupB), one of the characteristic bioactive constituents of the medicinal plant Huperzia serrata, by a fungal endophyte of the host plant was studied. One new compound, 8α,15α-epoxyhuperzine B (1), along with two known oxygenated hupB analogs, 16-hydroxyhuperzine B (2) and carinatumin B (3), was isolated and identified. The structures of all the isolates were deduced by spectroscopic methods including NMR, MS, IR, and UV spectra. The known compounds 2 and 3 were obtained from a microbial source for the first time. To the best of our knowledge, it is the first report on the microbial transformation of hupB and would facilitate further structural modification of hupB by chemo-enzymatic method. In the LPS-induced neuro-inflammation injury assay, 8α,15α-epoxyhuperzine B (1) exhibited moderate neuroprotective activity by increasing the viability of U251 cell lines with an EC50 of 40.1 nm.


Assuntos
Alcaloides/química , Huperzia/química , Alcaloides/metabolismo , Alcaloides/farmacologia , Biotransformação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Huperzia/metabolismo , Lipopolissacarídeos/toxicidade , Conformação Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia
12.
Phytochemistry ; 166: 112060, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302343

RESUMO

Continued interest in bioactive alkaloids led to the isolation of four undescribed alkaloids along with 74 known ones from the aerial parts of Tabernaemontana bufalina Lour. The structures of the yet undescribed alkaloids were elucidated based on NMR, IR, UV, MS and CD spectroscopic data and X-ray crystal diffraction and, according to the plant source, named as taberhaines A-D (1-4). The known compounds comprised of 66 monoterpenoid indole, three carboline and five isoquinoline alkaloids. Among them, the known apparicine inhibited significantly the activity of xanthine oxidase, which plays an important role for gout, with an IC50 value of 0.65 µM, compared to the standard drug allopurinol (IC50 = 0.60 µM).


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Tabernaemontana/química , Xantina Oxidase/antagonistas & inibidores , Alcaloides/isolamento & purificação , Domínio Catalítico , Inibidores Enzimáticos/isolamento & purificação , Concentração Inibidora 50 , Modelos Moleculares , Xantina Oxidase/química
13.
Chem Pharm Bull (Tokyo) ; 67(7): 666-674, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257322

RESUMO

Dimeric sesquiterpene thioalkaloids from the rhizomes of Nuphar pumilum exhibited immunosuppressive effects using a sheep erythrocyte plaque forming cell (PFC) assay, as well as an anti-metastasis effect, and rapid apoptosis-inducing effects in tumor cell lines. In particular, dimeric sesquiterpene thioalkaloids with a hydroxy group (6-hydroxythiobinupharidine, 6,6'-dihydroxythiobinupharidine, 6-hydroxythionuphlutine B) showed substantial effects, whereas dimeric sesquiterpene thioalkaloids lacking the hydroxy group (thiobinupharidine, thionuphlutine B, 6'-hydroxythionuphlutine B, neothiobinupharidine, thionuphlutine B ß-sulfoxide, neothiobinupharidine ß-sulfoxide) and monomeric sesquiterpene alkaloids (nupharidine, 7-epideoxynupharidine, nupharolutine) showed weak activity. In this review, we summarize our studies of the biofunctional effects of these alkaloids.


Assuntos
Alcaloides/química , Nuphar/química , Sesquiterpenos/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Imunossupressores/química , Imunossupressores/isolamento & purificação , Imunossupressores/farmacologia , Nuphar/metabolismo
14.
Fitoterapia ; 136: 104186, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31150769

RESUMO

Five new amide alkaloids, named delamide A-E (1-5), along with five known ones, methyl-N-(3-carboxy-2-methylpropanoyl) anthranilate (6), benzoic acid, 2-[(1-oxodecyl) amino]-methylester (7), puberline (8), benzoic acid, 2-[(4-methoxy-2-methyl-1, 4-dioxobutyl) amino]-methylester (9) and benzoic acid, 2-[(4-methoxy-3-methyl-1, 4-dioxobutyl) amino]-methylester (10) were isolated from the extract of Delphinium brunonianum. Their structures were elucidated by extensive spectroscopic analyses (including 1D-, 2D-NMR, and HR-ESI-MS). 1-10 were also evaluated for their acetylcholinesterase (AChE) inhibiting activity by the Ellman's method. Delamide A (1) showed highly selective AChE inhibition activity. The kinetic analysis revealed that 1 was a mixed-type reversible inhibitor of AChE.


Assuntos
Alcaloides/farmacologia , Inibidores da Colinesterase/farmacologia , Delphinium/química , Componentes Aéreos da Planta/química , Alcaloides/isolamento & purificação , Inibidores da Colinesterase/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Tibet
15.
Planta Med ; 85(9-10): 738-744, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31185502

RESUMO

Chronic heart failure is the terminal stage of various cardiovascular diseases. Despite the availability of several classes of drugs, there is still an unmet need for effective treatment. Based on bench work during the past two decades, we have proposed that enhancement of ß 2-adrenergic receptor signaling in combination with the presently preferred ß 1-adrenergic receptor blockade would be a promising strategy. Chinese herbal medicines have been shown to be effective in the treatment of heart failure, although the mechanisms largely remain unknown. In the present study, we screened an herbal medicine compound/extract library for ß-adrenergic receptor ligands to determine the target of certain effective botanical remedies and seek a leading compound(s) for chronic heart failure treatment. Using a high-throughput screening assay, we identified higenamine, which has a long history in chronic heart failure treatment in traditional Chinese medicine, to be a potent ß-adrenergic receptor agonist. Further experiments using specific inhibitors showed that higenamine activated both ß 1-adrenergic receptor and ß 2-adrenergic receptor. Inhibition of its action by pertussis toxin (a Gi inhibitor) indicated that it is a ß 2-adrenergic receptor Gs/Gi dual agonist. Contractility experiments demonstrated a positive inotropic effect of higenamine. In conclusion, we found an herbal compound, higenamine, to be a dual agonist for ß 1/ß 2-adrenergic receptors with no preference in stimulating the Gs and Gi pathways in ß 2-adrenergic receptor signaling. Our results elucidated not only the target of higenamine to explain its pharmacological effect in treating chronic heart failure, but also the mechanisms of its cardiac toxicity.


Assuntos
Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Alcaloides/farmacologia , Medicamentos de Ervas Chinesas/química , Ensaios de Triagem em Larga Escala/métodos , Tetra-Hidroisoquinolinas/farmacologia , Alcaloides/química , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Simulação de Acoplamento Molecular , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Tetra-Hidroisoquinolinas/química
16.
Mar Drugs ; 17(6)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151240

RESUMO

So far, the Futuna Islands located in the Central Indo-Pacific Ocean have not been inventoried for their diversity in marine sponges and associated chemical diversity. As part of the Tara Pacific expedition, the first chemical investigation of the sponge Narrabeena nigra collected around the Futuna Islands yielded 18 brominated alkaloids: seven new bromotryptamine derivatives 1-7 and one new bromotyramine derivative 8 together with 10 known metabolites of both families 9-18. Their structures were deduced from extensive analyses of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) data. In silico metabolite anticipation using the online tool MetWork revealed the presence of a key and minor biosynthetic intermediates. These 18 compounds showed almost no cytotoxic effect up to 10 µM on human neuroblastoma SH-SY5Y and microglia BV2 cells, and some of them exhibited an interesting neuroprotective activity by reducing oxidative damage.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Poríferos/química , Alcaloides/isolamento & purificação , Alcaloides/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Humanos , Internet , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Oceano Pacífico , Clima Tropical
17.
Fitoterapia ; 137: 104196, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31175948

RESUMO

Depressive disorders remain a current public health problem whose prevalence has increased in the past decades. In the constant search for new therapeutic alternatives, ß-carboline alkaloids have been identified as good candidates for new antidepressant drugs. In this systematic review, we summarized all pre-clinical investigations involving the use of natural or semisynthetic ß-carboline in depression models. A literature search was conducted in August 2018, using PubMed, Scopus and Science Direct databases. All reports were carefully analyzed, and data extraction was conducted through standardized forms. Methodological quality assessment of in vivo studies was also performed. The entire systematic review was performed according to PRISMA statement. From a total of 373 articles, 26 met all inclusion criteria. In vitro and in vivo studies have evaluated a wide variety of ß-carbolines through enzymatic and binding assays, and acute or chronic animal models. Most of the in vivo and in vitro studies is concentrated on two molecules: harman and harmine. They have been investigated in several animal models and some mechanisms of action have been proposed for their antidepressant activity. In general, ß-carbolines modulate 5-HT and GABA systems, promote neurogenesis, induce neuroendocrine response and restore astrocytic function, being effective when administrated acutely or chronically in different animal models, including chronic mild stress protocols. In short, ß-carbolines are multi-target antidepressant compounds and may be useful in the treatment of depressive disorders.


Assuntos
Alcaloides/farmacologia , Antidepressivos/farmacologia , Carbolinas/farmacologia , Depressão/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos , Harmina/análogos & derivados , Harmina/farmacologia
18.
BMC Complement Altern Med ; 19(1): 138, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221141

RESUMO

BACKGROUND: Oxymatrine (OM), a quinolizidine alkaloid extracted from a herb Sophorae Flavescentis Radix, has been used to treat liver fibrotic diseases. However, the mechanism of its anti-fibrosis effects is still unclear. TGF-ß/Smad signaling and miR-195 have been proved to paly an important role in hepatic stellate cells (HSCs) activation and liver fibrosis. In this study, we investigated whether OM could inhibit HSCs activation through TGF-ß1/miR-195/Smads signaling or not. METHODS: First, the effects of OM on HSC-T6 in different concentrations and time points were tested by MTT assay. We choose three appropriate concentrations of OM as treatment concentrations in following experiment. By Quantitative Real-time PCR and Western Blot, then we investigated the effect of OM on miR-195, Smad7 and α-SMA's expressions to prove the correlation between OM and the TGF-ß1/miR-195/Smads signaling. Last, miR-195 mimic and INF-γ were used to investigate the relation between miR-195 and OM in HSC activation. RESULTS: Our results showed that the proliferation of HSC was significantly inhibited when OM concentration was higher than 200 µg/mL after 24 h, 100 µg/mL after 48 h and 10 µg/mL after 72 h. The IC50 of OM after 24, 48 and 72 h were 539, 454, 387 µg/mL respectively. OM could down-regulate miR-195 and α-SMA (P < 0.01), while up-regulate Smad7 (P < 0.05). In HSC-T6 cells transfected with miR-195 mimic and pretreated with OM, miR-195 and α-SMA were up-regulated (P < 0.05), and Smad7 was down-regulated (P < 0.05) . CONCLUSIONS: Given these results, OM could inhibit TGF-ß1 induced activation of HSC-T6 proliferation in a dose-dependent and time-dependent manner to some extent. We proved that OM inhibited HSC activation through down-regulating the expression of miR-195 and up-regulating Smad7.


Assuntos
Alcaloides/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , MicroRNAs/metabolismo , Extratos Vegetais/farmacologia , Quinolizinas/farmacologia , Proteína Smad7/metabolismo , Sophora/química , Fator de Crescimento Transformador beta1/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Interferon gama/genética , Interferon gama/metabolismo , MicroRNAs/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad7/genética , Fator de Crescimento Transformador beta1/genética
19.
Zhongguo Zhong Yao Za Zhi ; 44(8): 1623-1634, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090327

RESUMO

Antithrombus is one of the effective methods to prevent and treat cardiovascular diseases. Based on the theory of traditional Chinese medicine,the author's previous research and relevant literature,it was found that the alkaloids in Houttuynia cordata has potential antithrombotic effect. However,the pharmacological substance basis and antithrombotic mechanism of H. cordata have not been clarified. In this study,molecular docking was used for virtual screening of antithrombotic alkaloids from H. cordata. Seventy alkaloids selected from H. cordata were screened in the docking ligand data-base with teen thrombosis targets with known crystal structures as the receptors. In addition,the small-molecule approved or to be approved drugs of targets from Drug Bank database were set as a positive reference with minimum score(S value) of each target's approved or to be approved drugs as threshold. The Dock module in Molecular Operating Environment(Version 2016) software was applied to screen the potential active compounds which their scores(S value) were lower than the minimum score of reference. At last the mechanism of antithrombotic effect was preliminarily revealed by compared the main active sites of the test alkaloids with original ligands and references. This study provided some useful information to development of antithrombus drugs.


Assuntos
Alcaloides/farmacologia , Fibrinolíticos/farmacologia , Houttuynia/química , Simulação de Acoplamento Molecular , Compostos Fitoquímicos/farmacologia
20.
Zhongguo Zhong Yao Za Zhi ; 44(8): 1635-1641, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090328

RESUMO

Breast cancer is one of the leading causes for cancer-related death among women worldwide. Coptidis Rhizoma has antibacterial,anti-inflammatory,anti-tumor and other pharmacological activities,but whether exercise could synergistically promote the role of RC in the treatment of breast cancer has not been reported. In this experiment,the effects and mechanism of total alkaloids of Coptidis Rhizoma combined with exercise on the tumor growth of orthotopically transplanted 4 T1 breast cancer were systemically studied in mice. Balb/C mice transplanted with 4 T1 cells in situ were used as models. The total alkaloids of RC(145 mg·kg-1·d-1) alone or in combination with exercise(10 m·min-1,30 min/time,5 times/week) were given for 28 days,and then the changes in body weight and tumor volume,tumor weight,interleukin-1ß(IL-1ß),serum estradiol(E2) content,and expression levels of estrogen receptor α(ERα),cell cycle related proteins CDK4,CDK6,cyclin D1,CDK2,and cyclin E in tumor tissues. The results showed that total alkaloids of Coptidis Rhizoma could significantly inhibit the growth of 4 T1 breast cancer in mice(P< 0. 01),and exercise significantly promoted the anti-tumor activity of total alkaloids of Coptidis Rhizoma(P<0. 01),and reduced E2 and IL-1ß levels in mice. Western blot and flow cytometry showed that the total alkaloids of Coptidis Rhizoma combined with exercise could down-regulate the protein expression levels of ERα,CDK4,CDK6,cyclin D1,CDK2 and cyclin E in cancer cells,block the transformation of G1/S in 4 T1 cell cycle,and inhibit DNA synthesis in breast cancer cells. The total alkaloids of Coptidis Rhizoma combined with exercise showed synergistic effect in inhibition of tumor growth in mice with orthotopically transplanted 4 T1 breast cancer.


Assuntos
Alcaloides/farmacologia , Neoplasias da Mama/terapia , Ciclo Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Condicionamento Físico Animal , Animais , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Rizoma
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