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1.
Pharmaceutics ; 13(11)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34834209

RESUMO

The present study demonstrated that 2'-hydroxycinnamaldehyde (2'-HCA) induced apoptosis in human promyelocytic leukemia HL-60 cells through the activation of mitochondrial pathways including (1) translocation of Bim and Bax from the cytosol to mitochondria, (2) downregulation of Bcl-2 protein expression, (3) cytochrome c release into the cytosol, (4) loss of mitochondrial membrane potential (ΔΨm), and (5) caspase activation. 2'-HCA also induced the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase1/2 (ERK1/2) in HL-60 cells. The pharmacological and genetic inhibition of JNK effectively prevented 2'-HCA-induced apoptosis and activator protein-1 (AP-1)-DNA binding. In addition, 2'-HCA resulted in the accumulation of reactive oxygen species (ROS) and depletion of intracellular glutathione (GSH) and protein thiols (PSH) in HL-60 cells. NAC treatment abrogated 2'-HCA-induced JNK phosphorylation, AP-1-DNA binding, and Bim mitochondrial translocation, suggesting that oxidative stress may be required for 2'-HCA-induced intrinsic apoptosis. Xenograft mice inoculated with HL-60 leukemia cells demonstrated that the intraperitoneal administration of 2'-HCA inhibited tumor growth by increasing of TUNEL staining, the expression levels of nitrotyrosine and pro-apoptotic proteins, but reducing of PCNA protein expression. Taken together, our findings suggest that 2'-HCA induces apoptosis via the ROS-dependent JNK pathway and could be considered as a potential therapeutic agent for leukemia.

2.
Prog Neuropsychopharmacol Biol Psychiatry ; 31(7): 1363-9, 2007 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17698274

RESUMO

This experiment was performed to investigate whether obovatol isolated from the leaves of Magnolia obovata has anxiolytic-like effects through GABA-benzodiazepine-receptors Cl(-) channel activation. The anxiolytic-like effects of obovatol in mice were examined using the elevated plus-maze and the automatic hole-board apparatus. Oral administration of obovatol (0.2, 0.5 and 1.0 mg/kg) significantly increased the number of open arm entries and the spent time on open arm in the elevated plus-maze test, compared with those of saline. Obovatol (0.2, 0.5 and 1.0 mg/kg) also produced anxiolytic-like effects, as reflected by an increase in head-dipping behaviors. These effects were comparable to those of diazepam (1.0 mg/kg), a well known anxiolytic drug. On the other hand, the anxiolytic-like effects of obovatol and diazepam were reversed by flumazenil, a benzodiazepine receptor antagonist, suggesting that the anxiolytic-like effects of obovatol were involved in GABA-benzodiazepine receptors complex. Obovatol was muscle relaxant by rota-rod test, but its effect was weaker than diazepam. Spontaneous locomotor activity also was inhibited by obovatol. Obovatol selectively increased the GABA(A) receptors alpha(1) subunit expression in amygdala of mouse brain. Obovatol also showed to bind to benzodiazepine receptors competitively in experiments using [(3)H]flunitrazepam in the cerebral cortex of mouse brain. Moreover, obovatol (10, 20 and 50 microM) increased Cl(-) influx and the increased Cl(-) influx was inhibited by flumazenil, in primary cultured neuronal cells and IMR-32 human neuroblastoma cells. These results suggest that obovatol has anxiolytic-like effects, and these pharmacological effects may be mediated by GABA-benzodiazepine receptors-activated Cl(-) channel opening.


Assuntos
Ansiolíticos , Anti-Infecciosos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Magnolia/química , Éteres Fenílicos/uso terapêutico , Receptores de GABA-A/efeitos dos fármacos , Animais , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Cloretos/metabolismo , Flunitrazepam/metabolismo , Moduladores GABAérgicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos
3.
J Neuroimmune Pharmacol ; 7(1): 173-86, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21796424

RESUMO

Earlier studies indicate that obovatol (OBO), isolated from a medicinal herb Magnolia obovata, has anti-inflammatory and anti-oxidative properties. Depletion of glutathione (GSH) in glial cells with the γ-glutamylcysteine synthase inhibitor D,L-buthionine-S,R-sulfoximine (BSO) is known to produce oxidative stress which, in turn, induces these cells to secrete inflammatory cytokines and other neurotoxic substances. In the present study, we investigated the ability of OBO to protect SH-SY5Y neuroblastoma cells from this effect. Human microglia, astrocytes and their surrogate THP-1 and U373 cell lines were activated by treatment with BSO. Such treatment depleted their intracellular GSH and increased levels of damage to DNA, lipids and proteins (8-OHdG, lipid peroxide, protein carbonyls and 3-nitrotyrosine), and activated the inflammatory pathways P38 MAP kinase and NFκB. These are accompanied by release of proinflammatory factors such as TNFα, IL-6 and nitric oxide. Their conditioned media were toxic to SH-SY5Y cells. All these effects were attenuated by pre-treatment with OBO. Prior treatment of SH-SY5Y cells with OBO also attenuated THP-1 or U373 conditioned media neurotoxicity and also reduced oxidative damage produced by treatment with hydrogen peroxide or BSO. Prior treatment with OBO potentiated survival of SH-SY5Y cells exposed to conditioned medium from BSO-treated THP-1, U373 cells, microglia and astrocytes. The data indicate that OBO could be anti-inflammatory, anti-oxidative and neuroprotective, and be an effective agent for inhibiting pathogenesis in neurological diseases such as Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis in which glial-mediated neuroinflammation and oxidative stress are thought to contribute to disease progression.


Assuntos
Anti-Inflamatórios/farmacologia , Compostos de Bifenilo/farmacologia , Inflamação/prevenção & controle , Neuroglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Éteres Fenílicos/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Glutationa/metabolismo , Humanos , Fármacos Neuroprotetores/farmacologia
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