Preventive effects of andrographolide on the development of diabetes in autoimmune diabetic NOD mice by inducing immune tolerance
Introduction
Type 1 diabetes (T1D) is caused by immunologically mediated selective destruction of insulin-producing β-cells in pancreatic islets with consequent insulin deficiency in humans and non-obese diabetic (NOD) mouse models [1]. Although pathogenesis and autoimmune processes of T1D have been determined, the clinical onset of T1D has not been intervened in, delayed, or prevented effectively [2]. In general, the progression of T1D is inhibited by two strategies: (1) suppressing or eliminating autoimmunity or (2) replacing β cells to replenish insulin [3]. Methods suppressing autoimmunity against β cells, such as the use of anti-CD3, anti-CD20 monoclonal antibody, or GAD65, alter Th1/Th2 balance and destroy autoreactive immune cells [4], [5]. Nevertheless, prophylactic or therapeutic drugs currently available for T1D are scarce.
Andrographolide (Fig. 1) is a diterpenoid lactone isolated from Andrographis paniculata, a traditional Chinese medicine that has been extensively used to treat infection, inflammation, cold, fever, and diarrhea in China [6], [7]. Andrographolide is also considered a pharmacologically immunological, antibacterial, antiviral, anti-inflammatory, antithrombotic, and hepatoprotective substance [8], [9], [10] and functions in glycemic control. Zhang et al. [11] demonstrated that andrographolide-lipoic acid conjugate is hypoglycemic and β-cell protective in alloxan-treated mice (a T1D model) because this conjugate has antioxidant and NF-κB inhibitory activities. In addition, oral treatment of andrographolide can lower plasma glucose concentrations dose dependently in streptozotocin-induced diabetic rats [12]. Moreover, andrographolide elicits immunomodulatory effects on the immune system. Iruretagoyena et al. [13] reported that andrographolide significantly alleviates experimental autoimmune encephalomyelitis by inhibiting T cell and antibody responses to myelin antigens. This study aimed to determine whether or not andrographolide controls the prevention of diabetes development in autoimmune NOD mice and whether or not such an effect originates from an immune regulatory activity.
Section snippets
Reagents
Andrographolide (purity > 98%; Hubei Jianyuan Chemical Co., Ltd., Wuhan, China) was used to prepare a 50 mM stock solution by dissolving in dimethyl sulfoxide. The resulting mixture was serially diluted in PBS immediately prior to experiments.
Experimental animals
Female NOD mice (NOD/LtJ) and female ICR mice (as age-matched control group) aged seven weeks were purchased from Beijing HFK Bio-Technology Co., Ltd. (Beijing, China). The experimental mice were maintained at the Experimental Animal Center of Tongji Medical
Delayed onset and decreased incidence of diabetes in NOD mice by andrographolide treatment
We initially examined the cumulative incidence of diabetes in NOD mice treated with or without andrographolide for 30 weeks. T1D spontaneously developed in approximately 70% of the non-treated female NOD mice, and this finding is consistent with that in a previous study [14]. By contrast, intragastrical (i.g.) injection of andrographolide prevented the development of diabetes in NOD mice aged 30 weeks (Fig. 2A). The incidences of diabetes were 1 of 12 (~ 8%), 2 of 12 (~ 17%), and 5 of 12 (~ 42%) for
Discussion
The loss of immune tolerance to β cells causes autoimmune-mediated destruction of insulin-producing β cells in T1D NOD mice and humans [15]. Few therapies have successfully restored euglycemia and self-tolerance to islets in overtly diabetic NOD mice [16], [17]. Agents inducing immune tolerance have been developed to combat T1D. For example, some agents inhibit pro-inflammatory responses that indirectly but powerfully influence the activity of Ag-activated T cells to various protective (Treg)
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2020, Biochemical PharmacologyCitation Excerpt :In addition, the effects of C421, C582, C713, C754 and C807 on PDX-1 protein were assessed, and results shown that C582, C713, C754, C807 significantly increased the expression of PDX-1 at protein level (Fig. 3D, E). Since it has been reported that Andrographis paniculata a traditional Chinese herb medicine has anti-diabetic effect [12,13], thus, C754, a extracted fraction of Andrographis paniculata was selected for further study. To screen out the active ingredients of C754, C754 was analyzed by HPLC-HR-MS. The total ion chromatogram (TIC) of C754 gave the characteristic pseudo-molecular ion peak at tR = 8.7, 701.4251 ([2 M+H]+) and 351.2161 ([M+H]+) in positive mode (Fig. 4A, B, D), which was in accordance with the retention time and molecular formula C20H30O5 of reference standard andrographolide (C1037) (Fig. 4C, E).
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These authors contributed equally to this work.