Abstract
Beta cell apoptosis induced by proinflammatory cytokines is one of the hallmarks of diabetes. Small molecules which can inhibit the cytokine-induced apoptosis could lead to new drug candidates that can be used in combination with existing therapeutic interventions against diabetes. The current study evaluated several effects of bergenin, an isocoumarin derivative, in beta cells in the presence of cytokines. These included (i) increase in beta cell viability (by measuring cellular ATP levels) (ii) suppression of beta cell apoptosis (by measuring caspase activity), (iii) improvement in beta cell function (by measuring glucose-stimulated insulin secretion), and (iv) improvement of beta cells mitochondrial physiological functions. The experiments were carried out using rat beta INS-1E cell line in the presence or absence of bergenin and a cocktail of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon- gamma) for 48 hr. Bergenin significantly inhibited beta cell apoptosis, as inferred from the reduction in the caspase-3 activity (IC50 = 7.29 ± 2.45 μM), and concurrently increased cellular ATP Levels (EC50 = 1.97 ± 0.47 μM). Bergenin also significantly enhanced insulin secretion (EC50 = 6.73 ± 2.15 μM) in INS-1E cells, presumably because of the decreased nitric oxide production (IC50 = 6.82 ± 2.83 μM). Bergenin restored mitochondrial membrane potential (EC50 = 2.27 ± 0.83 μM), decreased ROS production (IC50 = 14.63 ± 3.18 μM), and improved mitochondrial dehydrogenase activity (EC50 = 1.39 ± 0.62 μM). This study shows for the first time that bergenin protected beta cells from cytokine-induced apoptosis and restored insulin secretory function by virtue of its anti-inflammatory, antioxidant and anti-apoptotic properties. To sum up, the above mentioned data highlight bergenin as a promising anti-apoptotic agent in the context of diabetes.
Highlights
Medicinal plants contain a wide variety of pharmacologically important bioactive compounds, such as flavonoids, quinines, tannins, and ascorbic acid reported for their antioxidant, antiinflammatory, and hypoglycemic properties
We demonstrated that bergenin prevented cytokine-induced beta cell apoptosis, and at the same time, Bergenin protects beta cells against cytokine-induced apoptosis restored glucose-stimulated insulin secretion
INS-1E is a derivative of INS-1 cells originally established from an x-ray induced insulinoma in rat [24]
Summary
Medicinal plants contain a wide variety of pharmacologically important bioactive compounds, such as flavonoids, quinines, tannins, and ascorbic acid reported for their antioxidant, antiinflammatory, and hypoglycemic properties. The extracts of Bergenia rhizomes have been reported for their anti-inflammatory, analgesic, antibacterial, and diuretic properties. These extracts have been topically applied to the wounds, eyesores, and boils [3,4,5]. An isocoumarin derivative with five hydoxyl groups, is reported several important pharmacological activities, such as anti-inflammatory, hypolipidimic, antimalarial, hepatoprotective, antiarrhythmic, anti-HIV, and neuroprotective activities [6,7,8,9,10]. Our previous study had shown anti-inflammatory properties of bergenin, where it inhibited the production of inflammatory mediators, such as NO, and TNF-α [12]
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