RESUMO
Alzheimer's disease (AD) is a complex progressive neurodegenerative disorder affecting humans mainly through the deposition of Aß-amyloid (Aß) fibrils and accumulation of neurofibrillary tangles in the brain. Currently available AD treatments only exhibit symptomatic relief but do not generally intervene with the amyloid and tau pathologies. The extra-virgin olive oil (EVOO) monophenolic secoiridoid S-(-)-oleocanthal (OC) showed anti-inflammatory activity through COX system inhibition with potency comparable to the standard non-steroidal anti-inflammatory drug (NSAID) like ibuprofen. OC also showed positive in vitro, in vivo, and clinical therapeutic effects against cardiovascular diseases, many malignancies, and AD. Due to its pungent, astringent, and irritant taste, OC should be formulated in acceptable dosage form before its oral use as a potential nutraceutical. The objective of this study is to develop new OC oral formulations, assess whether they maintained OC activity on the attenuation of ß-amyloid pathology in a 5xFAD mouse model upon 4-month oral dosing use. Exploration of potential OC formulations underlying molecular mechanism is also within this study scope. OC powder formulation (OC-PF) and OC-solid dispersion formulation with erythritol (OC-SD) were prepared and characterized using FT-IR spectroscopy, powder X-ray diffraction, and scanning electron microscopy (ScEM) analyses. Both formulations showed an improved OC dissolution profile. OC-PF and OC-SD improved memory deficits of 5xFAD mice in behavioral studies. OC-PF and OC-SD exhibited significant attenuation of the accumulation of Aß plaques and tau phosphorylation in the brain of 5xFAD female mice. Both formulations markedly suppressed C3AR1 (complement component 3a receptor 1) activity by targeting the downstream marker STAT3. Collectively, these results demonstrate the potential for the application of OC-PF as a prospective nutraceutical or dietary supplement to control the progression of amyloid pathogenesis associated with AD.
Assuntos
Aldeídos/administração & dosagem , Doença de Alzheimer/tratamento farmacológico , Monoterpenos Ciclopentânicos/administração & dosagem , Suplementos Nutricionais , Azeite de Oliva/administração & dosagem , Fenóis/administração & dosagem , Placa Amiloide/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Formas de Dosagem , Feminino , Camundongos , Camundongos Transgênicos , Placa Amiloide/patologia , Pós , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Lung cancer (LC) represents the topmost mortality-causing cancer in the U.S. LC patients have overall poor survival rate with limited available treatment options. Dysregulation of the mesenchymal epithelial transition factor (c-MET) and cyclooxygenase 2 (COX2) initiates aggressive LC profile in a subset of patients. The Mediterranean extra-virgin olive oil (EVOO)-rich diet already documented to reduce multiple malignancies incidence. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid exclusively occurring in EVOO and showed documented anti-breast and other cancer activities via targeting c-MET. This study shows the novel ability of OC to suppress LC progression and metastasis through dual targeting of c-MET and COX-2. Western blot analysis and COX enzymatic assay showed significant reduction in the total and activated c-MET levels and inhibition of COX1/2 activity in the lung adenocarcinoma cells A549 and NCI-H322M, in vitro. In addition, OC treatment caused a dose-dependent inhibition of the HGF-induced LC cells migration. Daily oral treatment with 10 mg/kg OC for 8 weeks significantly suppressed the LC A549-Luc progression and prevented metastasis to brain and other organs in a nude mouse tail vein injection model. Further, microarray data of OC-treated lung tumors showed a distinct gene signature that confirmed the dual targeting of c-MET and COX2. Thus, the EVOO-based OC is an effective lead with translational potential for use as a prospective nutraceutical to control LC progression and metastasis.
Assuntos
Adenocarcinoma/patologia , Aldeídos/farmacologia , Aldeídos/uso terapêutico , Inibidores de Ciclo-Oxigenase 2 , Monoterpenos Ciclopentânicos/farmacologia , Monoterpenos Ciclopentânicos/uso terapêutico , Neoplasias Pulmonares/patologia , Azeite de Oliva/química , Fenóis/farmacologia , Fenóis/uso terapêutico , Fitoterapia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Adenocarcinoma/genética , Aldeídos/isolamento & purificação , Animais , Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/secundário , Linhagem Celular Tumoral , Monoterpenos Ciclopentânicos/isolamento & purificação , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Pulmonares/genética , Camundongos Nus , Fenóis/isolamento & purificaçãoRESUMO
In folk medicine, Polyalthia suberosa is used as abortifacient, laxative, febrifuge analgesic, filler of tooth cavities, and anti-HIV drug and for rheumatism and various skin infections. The present study was directed to evaluate the analgesic and anti-inflammatory activities of diethyl ether and n-hexane extracts of Polyalthia suberosa leaves (PSDE and PSNH). A variety of tests including formalin-induced paw licking test, acetic acid induced writhing test, and tail immersion test were used to assess the analgesic activity. In addition, xylene-induced ear edema test was used to evaluate anti-inflammatory activity of PSDE and PSNH. PSDE and PSNH at 200 and 400 mg/kg doses expressed analgesic as well as anti-inflammatory activities in mice. In formalin-induced paw licking test, acetic acid induced writhing test, and xylene-induced ear edema test, the extracts exhibited significant inhibition (âP < 0.05 versus control) of pain and inflammation. Alternatively, in tail immersion test, PSDE 400 mg/kg showed significant (âP < 0.05 versus control) latency at 30 min but another tested sample had no significant latency. From this study, it could be shown that Polyalthia suberosa leaves may contain analgesic and anti-inflammatory agents which support its use in traditional medicine.