Introduction Glycogen synthase kinase GSK is an
Glycogen synthase kinase-3 (GSK-3) is an enzyme playing multiple roles in animal tissues and organs, and cb 839 is not an exception. Apart from involvement in regulation of apoptosis and survival GSK-3 influences neuronal morphology, synapse formation, memory reconsolidation in adult brains, and is a target for treatment of several neurological disorders, including Alzheimer's disease (AD), schizophrenia and bipolar disorder (for review see e.g. Cole, 2012; Guo et al., 2017; Hur and Zhou, 2010; Jope and Roh, 2006; McCubrey et al., 2017; Salcedo-Tello et al., 2011). GSK-3 senses growth factors and other extracellular stimuli (e.g. Wnt and Semaphorins) and modulates cellular abundance and activity of numerous transcription factors and other protein substrates influencing their phosphorylation status. Also, the activity of various signaling pathways of several neurotransmitters converge on GSK-3 (De Sarno et al., 2006). GSK-3 differs from other kinases in that it is a constitutively active enzyme and in response to stimuli, its activity is usually reduced.
There are two isoforms of GSK-3, α and β, which have 98% identity in their kinase domains. Nevertheless, it is suggested that the isoforms have distinct substrate preferences (Soutar et al., 2010). Deletion of one of the isoforms in mice results in distinct phenotypes, pointing to at least partially non-redundant functions of the proteins (Hoeflich et al., 2000; Kaidanovich-Beilin et al., 2009).
In a healthy adult brain, the level of GSK-3 is relatively constant and abundant (Woodgett, 1990; Yao et al., 2002). Its activity is regulated by phosphorylation, modulation of subcellular distribution, creation/disruption of specific protein complexes and also by the phosphorylation state of GSK-3 substrates, since in many cases, the substrates need to be “primed” by other kinases (Jope and Johnson, 2004). The relatively high activity of GSK-3 maintains morphology and function of mature neurons, while inactivation of the enzyme inhibits apoptosis and is implicated in mechanisms of neuronal survival under environmental stressors (e.g. amyloid peptides and hypoxia) (Bijur et al., 2000; Chiu and Chuang, 2010; Noble et al., 2005; Pap and Cooper, 1998). Thus, manipulation of GSK-3 activity in the brain appears to be a promising way of treatment of neurodegenerative diseases and mental disorders.
However, GSK-3 is a very hard-working kinase, and the list of its physiological substrates is long, as well as diverse (Sutherland, 2011). There is the potential danger that pharmacological inhibition of the enzyme standing at the crossroads of multiple metabolic pathways as a mean of treatment of a brain disorder could be a double-edged sword. Therefore, it is not surprising that the GSK-3 inhibitors rarely, if ever, reach Phase 2 clinical trials.
Materials and methods
Results and discussion
Funding The research work was partially supported by Polish Ministry of Science and Higher Education (Contract Grant Number: UMO-2015/19/B/NZ1/00332).
Conflicts of interest
Introduction The isoflavones are plant polyphenols which are accumulated in several legume species (Devi & Giridhar, 2014). They function biologically as plant defense compounds (Du, Huang, & Tang, 2010) and have health-related benefits when consumed in human diets (Masilamani, Wei, & Sampson, 2012). Determining mechanisms for increasing the accumulation of isoflavones in soybeans and other legumes has been of increasing research interest. For instance, isoflavones were found in several species, which were studied using diverse techniques such as HPLC-MS (Bórquez, Kennelly, & Simirgiotis, 2013), and several beneficial properties were reported including anticancer, antiinflammatory and antioxidant activities, among others (Ravindranath et al., 2004, Yu et al., 2016). The synthesis of secondary metabolites in plants can be constitutive and/or induced by environmental stresses. Secondary metabolites production stimulated by stress is often mediated by endogenous signaling molecules (Xu et al., 2012). Our previous research showed that nitric oxide-guanosine 3′, 5′-cyclic monophosphate (NO-cGMP) is an essential signal pathway that is involved in the regulation of isoflavone production in soybean sprouts under UV-B stress (Jiao, Wang, Yang, Tian, & Gu, 2016). The downstream signal transduction of NO involves many signaling compounds.