Adenosine receptors activate a number of signalling pathways

Adenosine receptors activate a number of signalling pathways involved in tissue survival including several mitogen-activated protein kinases (Fredholm et al., 2001). The common feature of all adenosine receptors is the positive coupling to ERK1/2, whilst A2B and A3 receptors can also activate the stress-activated protein kinases JNK and p38 (Fredholm et al., 2001, Hammarberg et al., 2004). ERK1/2 are prosurvival signals (Datta et al., 1999), whilst JNK is a proapoptotic signal (Lin and Dibling, 2002). A2A receptors are coupled with the activation of adenylyl cylase and generation of cAMP in a canonical way (Fredholm et al., 2001). Stimulation of the A2A receptors leads to activation of the cAMP-dependent protein kinase A (PKA) which in turn may phosphorylate a range of different proteins and transcription factors such as the cAMP response elastase inhibitor binding protein (CREB) (Lynge et al., 2003). Phosphorylated CREB in turn activates transcription of a number of prosurvival genes (Wilson et al., 1996, Riccio et al., 1999). In addition to the activation of anti-apoptotic signalling pathways, released adenosine may increase cochlear blood flow and oxygen supply via A2A receptors, and enhance anti-oxidant defences via A1 receptors (Vlajkovic et al., 2009). This implies that the balanced activation of A1 and A2A receptors resulting from pharmacological inhibition of ADK is likely required for the survival and proper functioning of critical tissues in the ageing cochlea.
Acknowledgements This study was supported by the NZ Lottery Grants Board, Royal National Institute for Deaf People (RNID, UK), Deafness Research Foundation (NZ), Lodge Discovery 501 (NZ) and grant NS061844 from the National Institutes of Health (NIH, USA).
Introduction Diabetes has become a major disease threatening human health around the world and the incidence has increased year by year. As Wild et al. estimated, the population of patients with diabetes is going to ascend from 171 million in 2000–366 million in 2030 [1]. T2DM is a complex, heterogeneous disease featuring peripheral insulin resistance and relatively inadequate insulin secretion [2]. The effect of insulin on inhibiting hepatic sugar output is weakened in T2DM patients, leading to excessive glucose production. Growing numbers of researches have proved that hepatic gluconeogenesis can maintain the glucose of cellular or whole-body in a steady state, so it plays a vital part in hepatic glucose metabolism. The excessive gluconeogenesis leading to elevated glucose release will result in hyperglycemia [3]. Therefore, one of the important objectives in the treatment of T2DM is to inhibit gluconeogenesis and reduce endogenous glucose production by improving hepatic insulin resistance, eventually controlling fasting blood glucose. Adenosine-5′ monophosphate kinase (AMPK) is an energy sensor, which acts as a metabolic master switch [4]. It plays a vital role in regulating whole-body energy homeostasis. AMPK can reduce peripheral insulin resistance by regulating glucose and lipid metabolism. Moreover, extensive researches have confirmed that the activation of AMPK also can inhibit hepatic glucose output and reduce fasting blood glucose [5,6]. It has been found that the activation of AMPK could phosphorylate TORC2 and reduce the expression of PEPCK and G6Pase, ultimately inhibiting hepatic gluconeogenesis [5,7]. Thus, the activation of AMPK can suppress hepatic glucose production and reduce the level of blood glucose. Phytotherapy has been playing a key role in the diseases treatment in resource-poor countries for decades. Also it is recommended by the World Health Organization to treat diabetes mellitus [8]. Vernonia amygdalina Delile(VA), which grows widely in Africa, is well-known for its medicinal value. In Nigeran and South Africa, VA is used for the management of diabetes. VA contains several active phytochemical compounds, including sesquiterpene lactone, flavonoids, phenol, saponins, tannins, steroid glucosides and glycosides [9,10]. These active phytochemical constituents endue VA with various pharmacological activities, including anti-cancer and anti-diabetes actions. Their therapeutic potentials for the treatment of diabetes in vivo [11,12] and in vitro [13] have been extensively investigated since 1992. It has been reported that VA affects glucose metabolism by promoting glycogen enzymes, stimulating glucose utilization in cells and potentiating glucose oxidation via the pentose phosphate pathway [14]. Additionally, it was found that VA can simultaneously suppress gluconeogenesis enzymes [15], but its gluconeogenesis mechanisms in liver and hepatocytes are still unknown. This work aims to observe the hypoglycemic actions of VA and its possible mechanism in STZ-induced mice and PA-induced HepG2 cells.