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1.
Biochem Pharmacol ; 225: 116279, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38740221

RESUMO

Berberine, a natural isoquinoline alkaloid, exhibits a variety of pharmacological effects, but the pharmacological targets and mechanisms remain elusive. Here, we report a novel finding that berberine inhibits acetylcholine (ACh)-induced intracellular Ca2+ oscillations, mediated through an inhibition of the muscarinic subtype 3 (M3) receptor. Patch-clamp recordings and confocal Ca2+ imaging were applied to acute dissociated pancreatic acinar cells prepared from CD1 mice to examine the effects of berberine on ACh-induced Ca2+ oscillations. Whole-cell patch-clamp recordings showed that berberine (from 0.1 to 10 µM) reduced ACh-induced Ca2+ oscillations in a concentration-dependent manner, and this inhibition also depended on ACh concentrations. The inhibitory effect of berberine neither occurred in intracellular targets nor extracellular cholecystokinin (CCK) receptors, chloride (Cl-) channels, and store-operated Ca2+ channels. Together, the results demonstrate that berberine directly inhibits the muscarinic M3 receptors, further confirmed by evidence of the interaction between berberine and M3 receptors in pancreatic acinar cells.


Assuntos
Células Acinares , Berberina , Sinalização do Cálcio , Receptor Muscarínico M3 , Animais , Berberina/farmacologia , Receptor Muscarínico M3/metabolismo , Receptor Muscarínico M3/antagonistas & inibidores , Camundongos , Células Acinares/efeitos dos fármacos , Células Acinares/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Masculino , Acetilcolina/metabolismo , Cálcio/metabolismo , Relação Dose-Resposta a Droga
2.
Acta Pharmacol Sin ; 42(9): 1507-1515, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33311599

RESUMO

Astroglioma is the most common primary tumor in the central nervous system without effective treatment strategies. Temozolomide (TMZ) is a chemotherapeutic drug to treat astroglioma but exhibits low potency and has side effects. Therefore, there is an urgent need to develop new compounds to treat astroglioma. Dalbergia sissoo Roxb was the source of Dalbergia odorifera in traditional Chinese medicine (TCM) and has been clinically used as an anti-tumor medicine. 4-Methoxydalbergione (4MOD) is purified from Dalbergia sissoo Roxb., and shows an inhibitory effect on osteosarcoma, but its effects on astroglioma have not been reported. Here, we evaluate its anti-astroglioma effects on both in vitro and in vivo models. In cultured astroglioma U87 cells, 4MOD inhibited cell proliferation and induced cell apoptosis in a time- and concentration-dependent manner. Compared with TMZ, 4MOD exhibited a tenfold greater potency of anti-astroglioma effects. 4MOD effectively stalled the cell cycle in G2 phase. Transcriptome sequencing (RNA-seq) showed that 4MOD upregulated 158 genes and downregulated 204 genes that are mainly enriched in cell membrane, cell division, cell cycle, p53, TNF, and MAPK signaling pathways, which may underlie its anti-tumor mechanisms. In a nude mouse xenograft model transplanted with U87 cells, 10 mg/kg 4MOD slowed down tumor growth rate, while at 30 mg/kg dose, it reduced tumor size. Collectively, this study demonstrates that 4MOD is a potent native compound that remarkably inhibits U87 astroglioma growth in both in vitro and in vivo models.


Assuntos
Astrocitoma/tratamento farmacológico , Astrocitoma/metabolismo , Benzoquinonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Astrocitoma/genética , Astrocitoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dalbergia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Expressão Gênica , Xenoenxertos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus
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