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Journal of Translational Medicine

, 7:62

First Online: 16 July 2009Received: 06 April 2009Accepted: 16 July 2009DOI: 10.1186-1479-5876-7-62

Cite this article as: Zhang, Z., Jiang, J., Yu, P. et al. J Transl Med 2009 7: 62. doi:10.1186-1479-5876-7-62

Abstract

BackgroundWhile all anti-diabetic agents can decrease blood glucose level directly or indirectly, few are able to protect and preserve both pancreatic beta cell mass and their insulin-secreting functions. Thus, there is an urgent need to find an agent or combination of agents that can lower blood glucose and preserve pancreatic beta cells at the same time. Herein, we report a dual-functional andrographolide-lipoic acid conjugate AL-1. The anti-diabetic and beta cell protective activities of this novel andrographolide-lipoic acid conjugate were investigated.

MethodsIn alloxan-treated mice a model of type 1 diabetes, drugs were administered orally once daily for 6 days post-alloxan treatment. Fasting blood glucose and serum insulin were determined. Pathologic and immunohistochemical analysis of pancreatic islets were performed. Translocation of glucose transporter subtype 4 in soleus muscle was detected by western blot. In RIN-m cells in vitro, the effect of AL-1 on H2O2-induced damage and reactive oxidative species production stimulated by high glucose and glibenclamide were measured. Inhibition of nuclear factor kappa B NF-κB activation induced by IL-1β and IFN-γ was investigated.

ResultsIn alloxan-induced diabetic mouse model, AL-1 lowered blood glucose, increased insulin and prevented loss of beta cells and their dysfunction, stimulated glucose transport protein subtype 4 GLUT4 membrane translocation in soleus muscles. Pretreatment of RIN-m cells with AL-1 prevented H2O2-induced cellular damage, quenched glucose and glibenclamide-stimulated reactive oxidative species production, and inhibited cytokine-stimulated NF-κB activation.

ConclusionWe have demonstrated that AL-1 had both hypoglycemic and beta cell protective effects which translated into antioxidant and NF-κB inhibitory activity. AL-1 is a potential new anti-diabetic agent.

AbbreviationsA. paniculataAndrographis paniculata

Androandrographolide

AL-1andrographolide-lipoic acid conjugate

DAB3, 3-diaminobenzidine

DLRdual luciferase reporter

DMSOdimethyl sulfoxide

GLUT4glucose transporter subtype 4

HRPhorseradish peroxidase

IFN-γinterferon gamma

IL-1βinterleukin-1beta

LAalpha-lipoic acid

NF-κBnuclear factor kappa B

PMSFphenylmethylsulfonyl fluoride

ROSreactive oxidative species

STZstreptozotocin.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-7-62 contains supplementary material, which is available to authorized users.

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Autor: Zaijun Zhang - Jie Jiang - Pei Yu - Xiangping Zeng - James W Larrick - Yuqiang Wang

Fuente: https://link.springer.com/







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