RESUMO
Erinacine S, the new bioactive diterpenoid compound isolated from the ethanol extract of the mycelia of Hericium erinaceus, displays great health-promoting properties. However, the effects of erinacine S on inductive apoptosis in cancer cells such as gastric cancer and its molecular mechanisms remain unclear. Our results demonstrated that erinacine S treatment significantly induces cell apoptosis with increased ROS production in gastric cancer cells, but not in normal cells. Significantly, erinacine S also showed its inhibitory effects on tumor growth in an in vivo xenograft mouse model. Furthermore, immunohistochemical analyses revealed that erinacine S treatment significantly increases the FasL and TRAIL protein, whereas it decreases the levels of PCNA and cyclin D1 in the gastric cancer xenograft mice. Consistently, in AGS cells, erinacine S treatment not only triggers the activation of extrinsic apoptosis pathways (TRAIL, Fas-L and caspase-8, -9, -3), but it also suppresses the expression of the anti-apoptotic molecules Bcl-2 and Bcl-XL in a time-dependent manner. In addition, erinacine S also causes cell cycle G1 arrest by the inactivation of CDKs/cyclins. Moreover, our data revealed that activation of the ROS-derived and AKT/FAK/PAK1 pathways is involved in the erinacine S-mediated transcriptional activation of Fas-L and TRAIL through H3K4 trimethylation on their promoters. Together, this study sheds light on the anticancer effects of erinacine S on gastric cancer and its molecular mechanism in vitro and in vivo.
Assuntos
Antineoplásicos/farmacologia , Micélio , Sesterterpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Epigênese Genética , Humanos , Masculino , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Fitoterapia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Hericium erinaceus, a valuable pharmaceutical and edible mushroom, contains potent bioactive compounds such as H. erinaceus mycelium (HEM) and its derived ethanol extraction of erinacine A, which have been found to regulate physiological functions in our previous study. However, HEM or erinacine A with post-treatment regimens also shows effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, but its mechanisms remain unknown. By using annexin-V-fluorescein-isothiocyanate (FITC)/propidium iodide staining and a 2',7' -dichlorofluorescin diacetate (DCFDA) staining assay, the cell death, cell viability, and reactive oxygen species (ROS) of 1-methyl-4-phenylpyridinium (MMP+)-treated Neuro-2a (N2a) cells with or without erinacine A addition were measured, respectively. Furthermore, signaling molecules for regulating the p21/GADD45 cell death pathways and PAKalpha, p21 (RAC1) activated kinase 1 (PAK1) survival pathways were also detected in the cells treated with MPP+ and erinacine A by Western blots. In neurotoxic animal models of MPTP induction, the effects of HEM or erinacine A and its mechanism in vivo were determined by measuring the TH-positive cell numbers and the protein level of the substantia nigra through a brain histological examination. Our results demonstrated that post-treatment with erinacine A was capable of preventing the cytotoxicity of neuronal cells and the production of ROS in vitro and in vivo through the neuroprotective mechanism for erinacine A to rescue the neurotoxicity through the disruption of the IRE1α/TRAF2 interaction and the reduction of p21 and GADD45 expression. In addition, erinacine A treatment activated the conserved signaling pathways for neuronal survival via the phosphorylation of PAK1, AKT, LIM domain kinase 2 (LIMK2), extracellular signal-regulated kinases (ERK), and Cofilin. Similar changes in the signal molecules also were found in the substantia nigra of the MPTP, which caused TH+ neuron damage after being treated with erinacine A in the post-treatment regimens in a dose-dependent manner. Taken together, our data indicated a novel mechanism for post-treatment with erinacine A to protect from neurotoxicity through regulating neuronal survival and cell death pathways.
RESUMO
BACKGROUND/AIMS: Inflammation is one of the main contributors to chronic diseases such as cancer. It is of great value to identify the potential activity of various medicinal plants for regulating or blocking uncontrolled chronic inflammation. We investigated whether the root extract of Morus australis possesses antiinflammatory and antioxidative stress potential and hepatic protective activity. METHODS: The microwave-assisted extractionwere was used to prepare the ethanol extract from the dried root of Morus australis (MRE), including polyphenolic and flavonoid contents. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells was examined the anti-inflammatory and anti-oxidative potential of MRE. CCl4-induced mouse hepatic damage were performed to detect the hepatic protective potential in vivo. Immunohistochemistry (IHC) and western blot assays were used to detect target proteins. RESULTS: MRE contained approximately 23% phenolic compounds and 3% flavonoids. The major flavonoid component of MRE was morusin. MRE and morusin inhibited lipopolysaccharide-induced production of nitrite and prostaglandin E2 in RAW264.7 cells. MRE and morusin also suppressed the formation of intracellular reactive oxygen species and the expression of iNOS and COX-2. In an in vivo study, a thiobarbituric acid reactive substances assay showed that MRE inhibited CCl4-induced oxidative stress and expression of nitrotyrosine. MRE also decreased CCl4-induced hepatic iNOS and COX-2 expression, as well as CCl4-induced hepatic inflammation and necrosis in mice. CONCLUSION: MRE exhibited antiinflammatory and hepatic protective activity.
Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Flavonoides/uso terapêutico , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Flavonoides/química , Flavonoides/farmacologia , Mediadores da Inflamação/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morus/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células RAW 264.7RESUMO
BACKGROUND: Hericium erinaceus is an edible mushroom; its various pharmacological effects which have been investigated. This study aimed to demonstrate whether efficacy of oral administration of H. erinaceus mycelium (HEM) and its isolated diterpenoid derivative, erinacine A, can act as an anti-neuroinflammatory agent to bring about neuroprotection using an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease, which results in motor disturbances, in addition to elucidating the mechanisms involved. METHODS: Mice were treated with and without HEM or erinacine A, after MPTP injection for brain injuries by the degeneration of dopaminergic nigrostriatal neurons. The efficacy of oral administration of HEM improved MPTP-induced loss of tyrosine hydroxylase positive neurons and brain impairment in the substantia nigra pars compacta as measured by brain histological examination. RESULTS: Treatment with HEM reduced MPTP-induced dopaminergic cell loss, apoptotic cell death induced by oxidative stress, as well as the level of glutathione, nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE). Furthermore, HEM reversed MPTP-associated motor deficits, as revealed by the analysis of rotarod assessment. Our results demonstrated that erinacine A decreases the impairment of MPP-induced neuronal cell cytotoxicity and apoptosis, which were accompanied by ER stress-sustained activation of the IRE1α/TRAF2, JNK1/2 and p38 MAPK pathways, the expression of C/EBP homologous protein (CHOP), IKB-ß and NF-κB, as well as Fas and Bax. CONCLUSION: These physiological and brain histological changes provide HEM neuron-protective insights into the progression of Parkinson's disease, and this protective effect seems to exist both in vivo and in vitro.
Assuntos
Agaricales/química , Apoptose/efeitos dos fármacos , Diterpenos/isolamento & purificação , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Intoxicação por MPTP/tratamento farmacológico , Micélio/química , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Animais , Comportamento Animal , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Diterpenos/química , Endorribonucleases/metabolismo , Intoxicação por MPTP/fisiopatologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: After endoscopic treatment of bleeding peptic ulcer, a high-dose infusion of omeprazole substantially reduces the risk of recurrent bleeding. The role of oral proton pump inhibitors for these patients is uncertain. The purpose of the present study was to assess whether the use of oral esomeprazole would reduce the frequency of recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. METHODS: Patients with actively bleeding ulcers or ulcers with non-bleeding visible vessels were treated with an epinephrine injection followed by thermocoagulation. After hemostasis had been achieved, they were randomly assigned in a double-blind fashion to receive esomeprazole (40 mg p.o. twice daily for 3 days) or placebo. The outcome measures studied were recurrent bleeding, blood transfusion requirement, surgery and death. RESULTS: A total of 70 patients were enrolled, 35 in each group. Bleeding recurred within 30 days in two patients (5.7%) in the esomeprazole group, as compared with three (8.6%) in the placebo group (P = 0.999). Blood transfusion requirement was 2.8 +/- 1.4 units in the esomeprazole group and 2.7 +/- 1.3 units in the placebo group (P = 0.761). Duration of hospitalization was 4.82 +/- 1.8 days in the esomeprazole group and 4.58 +/- 2.7 days in the placebo group (P = 0.792). No patients needed surgery for control of bleeding and no patients died in both groups. CONCLUSIONS: After successful endoscopic treatment of bleeding peptic ulcer, oral use of esomeprazole might offer no additional benefit on the risk of recurrent bleeding.