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1.
J Ethnopharmacol ; 329: 118133, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38580187

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Angelica roots are a significant source of traditional medicines for various cultures around the northern hemisphere, from indigenous communities in North America to Japan. Among its many applications, the roots are used to treat type 2 diabetes mellitus; however, this application is not mentioned often. Ethnopharmacological studies have reported the use of A. japonica var. hirsutiflora, A. furcijuga, A. shikokiana, and A. keiskei to treat diabetes symptoms, and further reports have demonstrated the three angelica roots, i.e., A. japonica var. hirsutiflora, A. reflexa, and A. dahurica, exhibit insulin secretagogue activity. AIM OF THE STUDY: This study aimed to phytochemically characterize and compare angelica roots monographed in the European Pharmacopeia 11th, isolate major plant metabolites, and assess extracts and isolates' capability to modulate pancreatic ß-cell function. MATERIALS AND METHODS: Root extracts of Angelica archangelica, Angelica dahurica, Angelica biserrata, and Angelica sinensis were phytochemically profiled using liquid chromatography method coupled with mass spectrometry. Based on this analysis, simple and furanocoumarins were isolated using chromatography techniques. Extracts (1.6-50 µg/mL) and isolated compounds (5-40 µmol/L) were studied for their ability to modulate insulin secretion in the rat insulinoma INS-1 pancreatic ß-cell model. Insulin was quantified by the homogeneous time-resolved fluorescence method. RESULTS: Forty-one secondary metabolites, mostly coumarins, were identified in angelica root extracts. A. archangelica, A. dahurica, and A. biserrata root extracts at concentration of 12.5-50 µg/mL potentiated glucose-induced insulin secretion, which correlated with their high coumarin content. Subsequently, 23 coumarins were isolated from these roots and screened using the same protocol. Coumarins substituted with the isoprenyl group were found to be responsible for the extracts' insulinotropic effect. CONCLUSIONS: Insulinotropic effects of three pharmacopeial angelica roots were found, the metabolite profiles and pharmacological activities of the roots were correlated, and key structures responsible for the modulation of pancreatic ß-cell function were identified. These findings may have implications for the traditional use of angelica roots in treating diabetes. Active plant metabolites may also become lead structures in the search for new antidiabetic treatments.


Asunto(s)
Angelica , Células Secretoras de Insulina , Fitoquímicos , Extractos Vegetales , Raíces de Plantas , Angelica/química , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Animales , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Fitoquímicos/análisis , Ratas , Insulina/metabolismo , Secreción de Insulina/efectos de los fármacos , Cumarinas/farmacología , Cumarinas/aislamiento & purificación , Hipoglucemiantes/farmacología , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/química
2.
Br J Pharmacol ; 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39327688

RESUMEN

BACKGROUND AND PURPOSE: The pharmacology of flavonoids on ß-cell function is largely undefined especially in the context of defective secretion of insulin. We sought to identify flavonoids that increased the insulin-secreting function of ß-cells and to explore the underlying mechanisms. EXPERIMENTAL APPROACH: INS-1 ß-cells in culture and islets of Langerhans isolated from control and diabetic male rats were used for insulin secretion experiments. Pharmacological and electrophysiological approaches were used for mechanistic studies. KEY RESULTS: Among a set of flavonoids, exposure of INS-1 ß-cells to resokaempferol (ResoK) enhanced glucose-stimulated insulin secretion and therefore we further characterised its activity and its pharmacological mechanism. ResoK glucose-dependently enhanced insulin secretion in INS-1 ß-cells and pancreatic islets isolated from rats. Mechanistically, whole cell patch clamp recordings in INS-1 cells showed that ResoK rapidly and dose-dependently enhanced the L-type Ca2+ current whereas it was inactive towards T-type Ca2+ current. Accordingly, pharmacological inhibition of L-type Ca2+ current but not T-type Ca2+ current blocked the effects of ResoK on glucose-stimulated insulin secretion. ResoK was still active on dysfunctional ß-cells as it ameliorated glucose-stimulated insulin secretion in glucotoxicity-induced dysfunctional INS-1 cells and in pancreatic islets isolated from diabetic rats. CONCLUSION AND IMPLICATIONS: ResoK is a glucose-dependent activator of insulin secretion. Our results indicated that the effects of ResoK on insulin secretion involved its capacity to stimulate L-type Ca2+ currents in cultured ß-cells. As ResoK was also effective on dysfunctional ß-cells, our work provides a new approach to stimulating insulin secretion, using compounds based on the structure of ResoK.

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