br Materials and methods br Results br Discussion Importantl

Materials and methods
Results
Discussion Importantly, we observed that treatment with DA3-CH could reduce the pathophysiological processes in the hippocampal CA1 area after SE. At present, the unimolecular dual incretin receptor agonist has been developed as a treatment for type 2 diabetes, and exhibits enhanced insulinotropic and anti-hyperglycemic efficacy relative to mono-agonist in diabetic animals (Finan et al., 2013). As shown previously, the incretins do not affect blood BAF312 sale levels in non-diabetic animals or humans (Yuan et al., 2017; Faivre et al., 2012; George et al., 2014). In our experiment, we also demonstrated that DA3-CH has no effect on blood glucose levels of non-diabetic rats. Importantly, GLP-1/GIP dual agonists can cross the BBB and activate simultaneously the corresponding receptor in the CNS (Hölscher, 2018). Previous studies have indicated that the unimolecular dual incretin exert neuroprotective effect by inhibiting glial activation and neuroinflammation, suppressing oxidative stress and apoptosis, protecting the number and function of synapses, and regulating neurotransmitter release, more effectively than did selective GLP-1 mono-agonist in CNS diseases including stroke, PD and AD (Hölscher, 2018). In our study, we found that the DA3-CH -treated group showed lower levels of GFAP, Iba-1, IL-1β, TNF-α, demonstrating a much reduced chronic inflammation response, and lower Bax levels along with higher levels of Bcl-2 to demonstrate improved mitochondrial function. These means that treatment with DA3-CH significantly mitigated SE-induced glial activation, neuroinflammation, cell apoptosis and neuronal loss after SE. Importantly, neuronal cell loss in area CA1 of the hippocampus was much reduced by DA3-CH, underscoring the neuroprotective effect of DA3-CH.
Conflict of interest
Acknowledgements This study was financially supported UCB Foundation of China Association Against Epilepsy (Grant NO. 2017007), National Natural Science Foundation of China (Grant NO. 81601038), Shanxi Science and Technology Department (Grant NO. 2014021038-4) and Shanxi Medical University Innovation and Entrepreneurship Foundation of China (Grant NO. 057602).
Introduction Osteoporosis is a silent and progressive systemic skeletal disorder resulting in low bone mineral density (BMD) with fracture as its associated clinical consequence (Consensus Development Conference, 1993). The maintenance of skeletal strength through bone remodeling is regulated through complex interactions between bone cells and endocrine cells (Rosen and Klibanski, 2009). There is evidence for the role of gastro-intestinal hormones secreted in response to food intake in the maintenance of skeletal integrity and altered profiles of bone turnover-markers have been observed in the aftermath of meal ingestion (Elnenaei et al., 2010, Henriksen et al., 2003). Glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide (GIP)) is one such gastro-intestinal hormone. Secreted by K cells in the small intestine, GIP potentiates glucose-induced insulin secretion from pancreatic β-cells leading to reduced blood glucose levels (Saxena et al., 2010). In vitro studies have shown that GIP inhibits osteoclast differentiation and activity via a direct mechanism which may lead to a net effect of increased bone mass, although the effects of GIP could also be mediated, at least in part, by variation in insulin secretion (Fulzele and Clemens, 2012); in rats, administration of GIP reduces bone loss after ovariectomy (Bollag et al., 2001, Bollag et al., 2000, Zhong et al., 2007). GIP receptor (GIPR) is expressed in osteoblasts, osteocytes and osteoclasts as well as a wide range of tissues including adipocytes, pancreas, lungs, kidney and thyroid (Bollag et al., 2000, Zhong et al., 2007). Studies of transgenic mice overexpressing GIP show higher BMD and bone mineral content (BMC) than controls while in addition, they have elevated serum levels of GIP and total osteocalcin (Ding et al., 2008). Furthermore, in these mice, an age dependent decrease in GIPR expression has also been observed. Conversely, knockout mice deficient in GIPR have deranged cortical microarchitecture of bone leading to reduced bone ‘quality’ and strength and low fat mass (Mieczkowska et al., 2013). Taken together these observations represent one aspect of the complex shared molecular mechanisms between osteoporosis and diabetes. Type 1 diabetes (T1D) is associated with low BMD and increased fracture risk (Vestergaard et al., 2005) while type 2 diabetes (T2D), with its increased risk of fracture despite normal bone mass (Janghorbani et al., 2007, Nicodemus and Folsom, 2001), is complicated by the complex relationship between body weight, osteoporosis and T2D.