RESUMO
Dendrobium nobile Lindl. is registered in the Chinese Pharmacopoeia as a traditional medicine. Phytochemical investigation of the ethanol extract of D. nobile Lindl. stems yielded three alkaloid compounds, including two new compounds dendroxine B (2) and denrine B (3) as well as one known compound dendrobine (1). Here, we identified the structure of these compounds using spectroscopic analyses and compared them with those described in previous studies. Compounds 1-3 were found to show protective effect against amyloid-ß 1-42 (Aß1-42 )-induced neurotoxicity in rat pheochromocytoma (PC12) cells, among which dendrobine exhibited the most significant neuroprotective effect. Hoechst 33342/propidium iodide staining indicated that dendrobine ameliorated Aß1-42 -induced apoptosis. Moreover, quantitative real-time polymerase chain reaction and western blot analysis analysis demonstrated that dendrobine suppressed the activation of cyclin-dependent kinase 5 (CDK5), upregulated Bcl-2 expression, and downregulated Bax, cyto-c, and caspase-3 expression. Molecular docking analysis and surface plasmon resonance assay suggested that dendrobine directly bound to CDK5 protein with a KD value of 2.05 × 10-4 M. In summary, alkaloids are the neuroprotective constituents of D. nobile Lindl., and dendrobine protected PC12 cells against Aß1-42 -induced apoptosis by inhibiting CDK5 activation.
Assuntos
Alcaloides , Dendrobium , Animais , Ratos , Dendrobium/química , Quinase 5 Dependente de Ciclina/farmacologia , Células PC12 , Simulação de Acoplamento Molecular , Alcaloides/farmacologia , ApoptoseRESUMO
Anxiety disorders are a common mental illness that seriously endangered physical and mental health of human beings. The etiology of anxiety disorders is closely related to the abnormality of monoamines neurotransmitters, amino acids neurotransmitters and neuropeptides. The long-term use of anti-anxiety chemical drugs has some adverse effects, such as constipation, muscle relaxation, lethargy, tolerance and withdrawal symptoms. However, traditional Chinese medicines have advantages of multi-component, multi-target coordination, with less adverse reactions. Therefore, it is a promising prospect to develop novel anti-anxiety drugs from traditional Chinese medicines and formulas. This article reviewed some traditional Chinese medicines and formulas that can relieve anxiety symptoms. These include traditional Chinese medicines(Panax ginseng, Lycium ruthenium, Morus alba, Bupleurum plus dragon bone oyster soup, Chailong Jieyu Pills, and Naogongtai Formulas) with the effect on monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine; traditional Chinese medicines(Rehmannia glutinosa, Ziziphus jujuba Mill. var. spinosa, Jielv Anshen Decoction, Baixiangdan Capsules, Antianxietic Compound Prescription Capsules) with the effect on amino acid neurotransmitters, such as glutamic acid, γ-aminobutyrc acid; and traditional Chinese medicines(P. ginseng, Xiaoyao San, Shuyu Ningxin Decoction)with the effect on neuropeptide Y pathway, with the aim to provide theoretical basis for the further development of some novel and more effective anti-anxiety therapeutics from traditional Chinese medicine and formulas.
Assuntos
Ansiolíticos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Neurotransmissores , Humanos , Medicina Tradicional Chinesa , Norepinefrina , SerotoninaRESUMO
Hericium erinaceus is a culinary-medicinal mushroom used traditionally in Eastern Asia to improve memory. In this work, we investigated the neuroprotective and neuritogenic effects of the secondary metabolites isolated from the MeOH extract of cultured mycelium of H. erinaceus and the primary mechanisms involved. One new dihydropyridine compound (6) and one new natural product (2) together with five known compounds (1,3-5,7) were obtained and their structures were elucidated by spectroscopic analysis, including 2D NMR and HRMS. The cell-based screening for bioactivity showed that 4-chloro-3,5-dimethoxybenzoic methyl ester (1) and a cyathane diterpenoid, erincine A (3), not only potentiated NGF-induced neurite outgrowth but also protected neuronally-differentiated cells against deprivation of NGF in PC12 pheochromocytoma cells. Additionally, compound 3 induced neuritogenesis in primary rat cortex neurons. Furthermore, our results revealed that TrkA-mediated and Erk1/2-dependant pathways could be involved in 1 and 3-promoted NGF-induced neurite outgrowth in PC12 cells.
Assuntos
Basidiomycota/química , Misturas Complexas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neuritos/metabolismo , Receptor trkA/metabolismo , Animais , Sobrevivência Celular , Misturas Complexas/química , Células PC12 , RatosRESUMO
Two picrotoxane sesquiterpene lactone glycosides, nepalactones A (1) and B (2), and one new coumarin, nepalarin (3), were isolated from the root barks of the poisonous plant Coriarianepalensis. Their structures were elucidated via HRESIMS and 1D and 2D NMR spectroscopic analyses, and further verified via transformation methods. In addition, compounds 1-3 and five semisynthetic congeners (1a-e) were assayed for the activity to induce neurite outgrowth in rat pheochromocytoma (PC12) cells. As a result, nepalactone A derivative 1c and nepalarin (3) significantly enhanced nerve growth factor (NGF)-mediated neurite outgrowth in PC12 cells.
Assuntos
Cumarínicos/farmacologia , Glicosídeos/farmacologia , Magnoliopsida/química , Neuritos/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Cumarínicos/química , Cumarínicos/isolamento & purificação , Sinergismo Farmacológico , Glicosídeos/química , Glicosídeos/isolamento & purificação , Estrutura Molecular , Fator de Crescimento Neural/farmacologia , Neuritos/metabolismo , Células PC12 , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Plantas Tóxicas/química , Ratos , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificaçãoRESUMO
One new meroterpenoid, named hericenone K (11), along with 10 known compounds (1-10), ergosterol peroxide (1), cerevisterol (2), 3ß,5α,9α-trihydroxy-ergosta-7,22-dien-6-one (3), inoterpene A (4), astradoric acid C (5), betulin (6), oleanolic acid (7), ursolic acid (8), hemisceramide (9), and 3,4-dihydro-5-methoxy-2-methyl-2-(4'-methyl-2'-oxo-3'-pentenyl)-9(7H)-oxo-2H-furo[3,4-h]benzopyran (10), was isolated from the fruiting bodies of the mushroom Hericium erinaceus. Their structures were characterized on the basis of spectroscopic methods, as well as through comparison with previously reported data. Compounds 3-6, 8, and 9 were isolated from Hericium species for the first time. Compounds 10 and 11 was suggested to be racemic by the CD spectrum data and specific rotations, which ware resolved by chiral HPLC into respective enantiomers. Compounds 1-3, (±)-10, (-)-10 and (+)-10 in the presence of NGF (20 ng/mL) exerted a significant increase in neurite-bearing cells.
Assuntos
Agaricales/química , Ergosterol/análogos & derivados , Fatores de Crescimento Neural/farmacologia , Neuritos/efeitos dos fármacos , Fitosteróis/farmacologia , Animais , Ceramidas/isolamento & purificação , Ceramidas/farmacologia , Ergosterol/isolamento & purificação , Ergosterol/farmacologia , Carpóforos/química , Monoterpenos/isolamento & purificação , Monoterpenos/farmacologia , Neuritos/fisiologia , Células PC12 , Fitosteróis/isolamento & purificação , Ratos , Estereoisomerismo , Triterpenos/isolamento & purificação , Triterpenos/farmacologiaRESUMO
Six new highly oxygenated polycyclic cyathane-xylosides, named striatoids A-F (1-6), were isolated from the cultures of the basidiomycete Cyathus striatus. Their structures were established by comprehensive spectroscopic analysis including 2D NMR (HMBC, HSQC, ROESY, (1)H-(1)H-COSY) and HRESIMS experiments. Compounds 2 and 3 possess an unusual 15,4'-ether ring system. The isolated compounds dose-dependently enhanced nerve growth factor (NGF)-mediated neurite outgrowth in rat pheochromocytoma (PC-12) cells.
Assuntos
Cyathus/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Fatores de Crescimento Neural/agonistas , Animais , Diterpenos/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Células PC12 , RatosRESUMO
Malignant glioma, especially glioblastoma (GBM), has historically been associated with a low survival rate. The hyperactivation of STAT3 played a key role in GBM initiation and resistance to therapy; thus, there is an urgent requirement for novel STAT3 inhibitors. BP-1-102 was recently reported as a biochemical inhibitor of STAT3, but its roles and mechanism in biological behavior of glioma cells were still unclear. In this study, the effects of BP-1-102 on proliferation, apoptosis, invasion and neurosphere formation of glioma cell were investigated. Our results indicated that BP-1-102 inhibited the proliferation of U251 and A172 cells, and their IC50 values were 10.51 and 8.534 µM, respectively. Furthermore, BP-1-102 inhibited the invasion and migration abilities of U251 and A172 cells by decreasing the expression of matrix metallopeptidase 9, and induced glioma cell apoptosis by decreasing the expression of B-cell lymphoma-2. BP-1-102 also inhibited the formation of neurosphere. Mechanically, BP-1-102 reduced the phosphorylation of STAT3 and the p-STAT3's nuclear translocation in glioma cells. Thus, this study herein provided a potential drug for glioma therapy.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Ácidos Aminossalicílicos , Apoptose , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Glioma/metabolismo , Humanos , Metaloproteases/metabolismo , Metaloproteases/farmacologia , Invasividade Neoplásica/prevenção & controle , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT3/metabolismo , SulfonamidasRESUMO
Glioma stem cells (GSC) were important for Glioblastoma (GBM) initiation and chemotherapy resistance. Centrosomal protein of 55 kDa (CEP55) was a biomarker for multiple cancers. However, roles and mechanism of CEP55 in glioma tumorigenesis and stemness maintains of stem like cells was still unclear. U251 cells which stable overexpression or downregulation of CEP55 was obtained by lentivirus mediated transduction. Roles and mechanism of CEP55 in stemness maintains of stem like cells and tumorigenesis was investigated. Our results implied that knockdown the expression of CEP55 inhibited the invasion and migration of U251 cells, while overexpression of CEP55 displayed opposite results. Moreover, overexpression of CEP55 promoted neurosphere formation of glioma stem-like cells, while CEP55 knockdown decreased the number and size of neurosphere. Mechanistically, overexpression of CEP55 enhanced the expression of Forkhead box protein M1 (FOXM1), Matrix metalloproteinases (MMPs) and activated the NF-κB pathway, while knockdown CEP55 displayed opposite results. In conclusion, our results indicated that CEP55 played an important role in promoting the invasion and migration of U251 cell and self-renewal of glioma stem like cells which might be a new therapeutic target for glioma.
Assuntos
Agregação Celular/fisiologia , Proteínas de Ciclo Celular/fisiologia , Movimento Celular/fisiologia , Invasividade Neoplásica/fisiopatologia , Células-Tronco Neoplásicas/fisiologia , Carcinogênese , Proteínas de Ciclo Celular/biossíntese , Linhagem Celular Tumoral , Proteína Forkhead Box M1/biossíntese , Técnicas de Silenciamento de Genes , Glioma , Humanos , Lentivirus , Metaloproteinases da Matriz/biossíntese , Transdução de Sinais/fisiologia , Transdução GenéticaRESUMO
Sarcodonin G, one of the cyathane diterpenoids isolated from the mushroom Sarcodon scabrosus, possesses pronounced neurotrophic activity but ambiguous mechanical understanding. In this work, sarcodonin G was chosen as a lead compound to prepare a series of 19- O-benzoyl derivatives by semisynthesis and their neuritogenic activities were evaluated. 6 and 15 (10 µM) were investigated with opposite effects in PC12 cells. 6 exhibited a superior activity to sarcodonin G by promoting NGF-induced neurite outgrowth, while 15 showed an inhibitory effect. Supportingly, 6 and 15 (20 µM) significantly induced and suppressed neurite extension in primary cultured rat cortical neurons, respectively. In mechanism, the two derivatives were revealed to influence NGF-induced neurite outgrowth in PC12 cells through the regulation of PKC-dependent and -independent ERK/CREB signaling as well as the upstream TrkA receptor phosphorylation. Furthermore, a possible pattern of interaction among NGF, 6/15 and TrkA was presented using molecular simulations. It revealed that 6/15 may contribute to the stabilization of the NGF-TrkAd5 complex by establishing several hydrophobic and hydrogen-bond interactions with NGF and TrkA, respectively. Taken together, 6 and 15 modulate PKC-dependent and -independent ERK/CREB signaling pathways possibly by influencing the binding affinity of NGF to the receptor TrkA, and finally regulate neurite outgrowth in PC12 cells.
Assuntos
Derivados de Benzeno/farmacologia , Fármacos do Sistema Nervoso Central/farmacologia , Diterpenos/farmacologia , Fator de Crescimento Neural/metabolismo , Crescimento Neuronal/efeitos dos fármacos , Animais , Derivados de Benzeno/síntese química , Fármacos do Sistema Nervoso Central/síntese química , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Crescimento Neuronal/fisiologia , Células PC12 , Cultura Primária de Células , Ratos , Receptor trkA/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Cyathane diterpenoids, occurring exclusively in higher basidiomycete (mushrooms), represent a structurally diverse class of natural products based on a characteristic 5-6-7 tricyclic carbon scaffold, including 105 members reported to date. These compounds show a diverse range of biological activities, such as antimicrobial, anti-MRSA, agonistic toward the kappa-opioid receptor, antiinflammatory, anti-proliferative and nerve growth factor (NGF)-like properties. The present review focuses on the structure diversity, structure elucidation and biological studies of these compounds, including mechanisms of actions and structure-activity relationships (SARs). In addition, new progress in chemical synthesis of cyathane diterpenoids is discussed.
Assuntos
Basidiomycota/química , Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Diterpenos/síntese química , Diterpenos/química , Diterpenos/isolamento & purificação , Estrutura Molecular , Fator de Crescimento Neural/antagonistas & inibidores , Fator de Crescimento Neural/biossíntese , Relação Estrutura-AtividadeRESUMO
Semisynthetic analogues of the natural product 1-O-acetylbritannilactone (ABL), a sesquiterpene isolated from the medicinal plant Inula britannica, have been prepared and exhibited significant in vitro cytotoxic activities against four cell lines including three human cancer cell lines (HCT116, HEp-2 and HeLa) and one normal hamster cell line (CHO). Structure-activity relationships indicate that esterification of 6-OH (enhanced lipophilicity) and α-methylene-γ-lactone functionalities play important roles in conferring cytotoxicity. Among the tested compounds, 14 bearing a lauroyl group (12C) at the 6-OH position displayed most potent in vitro cytotoxic activity, with IC50 values between 2.91 and 6.78 µM, comparable to the positive control etoposide (VP-16, IC50 values between 2.13 and 4.79 µM). Moreover, the compound 14 triggered remarkable apoptosis at a low concentration, and induced cell cycle arrest in G2/M phase in HCT116 cells. The biological assays conducted with normal cells (CHO) revealed that all the synthetic compounds are no selective against cancer cell lines tested.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inula/química , Lactonas/síntese química , Lactonas/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Células CHO , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Cricetinae , Cricetulus , Humanos , Concentração Inibidora 50 , Lactonas/química , Relação Estrutura-AtividadeRESUMO
Five new sesquiterpene polyol esters with a dihydro-ß-agarofuran skeleton, designated as wightianines A-E (1-5), besides two known compounds, were isolated from the methanolic extract of the whole plant of the traditional herbal medicine Parnassia wightiana Wall. The structures of the isolated compounds were elucidated on the basis of spectroscopic analyses, including two-dimensional nuclear magnetic resonance techniques (correlation spectroscopy, heteronuclear multiple-quantum coherence, nuclear Overhauser effect spectrometry, and heteronuclear multiple-bond correlation) and electronic circular dichroism studies. The antifungal and insecticidal activities of five compounds were evaluated against several plant pathogenic fungi and armyworm larvae (Mythimna separata Walker). Among the test metabolites, compounds 2 and 7 both exhibited potent antifungal activity against the phytopathogenic fungus Cytospora sp. with minimum inhibitory concentration values of 0.78 µg/mL, which are equal to the two positive controls, hymexazol and carbendazim. However, no insecticidal activity of the test compounds was observed in the present study. Compounds 2 and 7 could be promising leads for developing new fungicides against agriculturally important fungus Cytospora sp.