RESUMEN
7Methoxyheptaphylline (7MH) is a carbazole extracted from Clausena harmandiana, a medicinal plant that is used to treat headaches and stomachaches. The aim of the present study was to examine the neuroprotective effects and anticancer activity of 7MH. Cell death was assessed using an MTT assay and flow cytometry. The expression of apoptosisrelated proteins was determined by western blot analysis. An animal model was used to test antimetastasis. The interactions between 7MH and the molecular target were observed using molecular docking. The results revealed that 7MH provided protection against hydrogen peroxide (H2O2)induced neuronal cell death. In cancer cells, 7MH induced SHSY5Y, 4T1, HT29, HepG2, and LNCaP cell death. 7MH inhibited metastasis of HT29 cells in vitro and 4T1Luc cells in vitro and in vivo. 7MH inhibited proteins, including Pglycogen synthase kinase (GSK)3, and cleaved caspase3, but it activated antiapoptotic proteins in H2O2induced SHSY5Y cell death. By contrast, 7MH activated the cleaving of caspase3 and GSK3, but it suppressed antiapoptotic proteins in SHSY5Y cells. 7MH reduced the levels of NFκB and STAT3 in 4T1 cells; phosphop65, Erk, and MAPK13 in LNCaP cells; and phosphoErk and matrix metalloproteinase9 in HT29 cells. Molecular docking analysis showed that 7MH targets TAK1 kinase. The present study indicated that 7MH induced apoptosis of cancer cells and provided protection against H2O2induced neuron cell death via TAK1 kinase.
Asunto(s)
Peróxido de Hidrógeno , Neuroblastoma , Animales , Humanos , Caspasa 3/metabolismo , Peróxido de Hidrógeno/farmacología , Glucógeno Sintasa Quinasa 3 , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Neuroblastoma/metabolismo , Carbazoles/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Itching is the most frequent pathology in dermatology that has significant impacts on people's mental health and social life. Transient receptor potential vanilloid 3 (TRPV3) channel is a promising target for treating pruritus. However, few selecetive and potent antagonists have been reported. This study was designed to identify selective TRPV3 antagonist and elucidate its anti-pruritus pharmacology. EXPERIMENTAL APPROACH: FlexStation and calcium fluorescence imaging were conducted to track the functional compounds. Whole-cell patch clamp was used to record itch-related ion channel currents. Homologous recombination and site-directed mutagenesis were employed to construct TRPV3 channel chimeras and point mutations for exploring pharmacological mechanism. Mouse models were used for in vivo anti-pruritus assay. KEY RESULTS: An acridone alkaloid (citrusinine-II) was purified and characterized from Atalantia monophylla. It directly interacts with Y564 within S4 helix of TRPV3 to selectively inhibit the channel with a half maximal inhibitory concentration (IC50 ) of 12.43 µM. Citrusinine-II showed potential efficacy to attenuate both chronic and acute itch. Intradermal administration of citrusinine-II (143 ng/skin site) nearly completely inhibited itch behaviours. It also shows significant analgesic effects. Little side effects of the compound are observed. CONCLUSION AND IMPLICATIONS: By acting as a selective and potent inhibitor of TRPV3 channel, citrusinine-II shows valuable therapeutic effects in pruritus animal models and is a promising candidate drug and/or lead molecule for the development of anti-pruritus drugs.
Asunto(s)
Preparaciones de Plantas/uso terapéutico , Prurito , Canales Catiónicos TRPV , Animales , Modelos Animales de Enfermedad , Ratones , Dolor/tratamiento farmacológico , Prurito/tratamiento farmacológico , Rutaceae/química , Piel , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
A new flavonoid, atalantraflavone (1) as well as eight known compounds including atalantoflavone (2), racemoflavone (3), 5,4'-dihydroxy-(3â³,4â³-dihydro-3â³,4â³-dihydroxy)-2â³,2â³-dimethylpyrano-(5â³,6â³:7,8)-flavone (4), lupalbigenin (5), anabellamide (6), citrusinine I (7), p-hydroxybenzaldehyde (8), and frideline (9), were isolated from the leaves of Atalantia monophylla (L.) DC. Focusing on Alzheimer's disease, acetylcholine esterase (AChE) inhibition and antioxidant activity were evaluated using the modified Ellman's method and the ABTS scavenging assay, respectively. It was found that isoflavonoid 5, lupalbigenin, showed 79% inhibition to AChE and was 1.4-fold stronger than the tacrine standard. In addition, acridone 7, citrusinine I, displayed 90.68% antioxidant activity.