Oral gavage delivery of Cornus officinalis extract delays type 1 diabetes onset and hyperglycemia in non-obese diabetic (NOD) mice.

Type 1 diabetes (T1D) is an autoimmune disease initiated by genetic predisposition and environmental influences, which result in the specific destruction of insulin-producing pancreatic ß-cells. Currently, there are over 1.6 million cases of T1D in the United States with a worldwide incidence rate that has been increasing since 1990. Here, we examined the effect of Cornus officinalis (CO), a well-known ethnopharmacological agent, on a T1D model of the non-obese diabetic (NOD) mouse. A measured dose of CO extract was delivered into 10-week-old NOD mice by oral gavage for 15 weeks. T1D incidence and hyperglycemia were significantly lower in the CO-treated group as compared to the water gavage (WT) and a no handling or treatment control group (NHT) following treatment. T1D onset per group was 30%, 60% and 86% for the CO, WT and NHT groups, respectively. Circulating C-peptide was higher, and pancreatic insulitis was decreased in non-T1D CO-treated mice. Our findings suggest that CO may have therapeutic potential as both a safe and effective interventional agent to slow early stage T1D progression.

Proteomic examination of Cornus officinalis stimulated 1.1B4 human pancreatic cells reveals activation of autophagy and Keap1/Nrf2 pathway.

Type 1 diabetes (T1D) is an autoimmune disease initiated by genetic predisposition and environmental influences culminating in the immunologically mediated destruction of pancreatic ß-cells with eventual loss of insulin production. Although T1D can be accurately predicted via autoantibodies, therapies are lacking that can intercede autoimmunity and protect pancreatic ß-cells. There are no approved interventional modalities established for this purpose. One such potential source for clinical agents of this use is from the frequently utilized Cornus officinalis (CO) in the field of ethnopharmacology. Studies by our lab and others have demonstrated that CO has robust proliferative, metabolic, and cytokine protective effects on pancreatic ß-cells. To identify the molecular mechanism of the biological effects of CO, we performed a proteomic and phosphoproteomic analysis examining the cellular networks impacted by CO application on the 1.1B4 pancreatic ß-cell line. Our label-free mass spectrometry approach has demonstrated significant increased phosphorylation of the selective autophagy receptor of p62 (Sequestosome-1/SQSTM1/p62) and predicted activation of the antioxidant Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) pathway. Further validation by immunoblotting and immunofluorescence revealed markers of autophagy such as increased LC3-II and decreased total p62 along with nuclear localization of Nrf2. Both autophagy and the Keap1/Nrf2 pathways have been shown to be impaired in human and animal models of T1D and may serve as an excellent potential therapeutic target stimulated by CO.