There are several reports providing evidences that

There are several reports providing evidences that functional and mechanistic connection between Sirt1 and LKB1/AMPK in metabolic regulation [26], [32], [33]. It has been reported that the deacetylation of LKB1 by Sirt1 is one of the determining factors of the subcellular localization of LKB1. In agreement with this, our recent study has shown that IgE/Ag stimulation of mast akt inhibitor increased Ac-Lys of LKB1 and nuclear sequestration of LKB1 which blunted the inhibitory role of LKB1/AMPK in mast cell activation [11], [23]. The activation of Sirt1 with resveratrol induced deacetylation of LKB1 leading to activation of LKB1/AMPK pathway, showing positive regulation of LKB1/AMPK by Sirt1 [11], [23]. The present study showed that Tan IIA increased Sirt1-depdenent lysine-deacetylation of LKB1, resulting in sequential activation of LKB1/AMPK pathway. Although the underlying mechanism for LKB1 activation following deacetylation in mast cells is not completely understood, it has been suggested that cytosolic translocation of LKB1 binds to its activator STRAD and/or MO25 with concurrent increase in LKB1 activity [26], [34]. Therefore, the further study on the regulation of LKB1 by Sirt1 in mast cells is warranted. In addition to the reciprocal regulation between Sirt1 and AMPK, we have shown that Sirt1 is negatively regulated by protein-tyrosine phosphatase 1B (PTP1B) which plays a positive role in IgE/Ag-stimulated mast cell activation [11], [23]. The regulation of Sirt1 by PTP1B has been shown to be mediated by physical interaction. Very recently, tanshinones isolated from S. miltiorrhiza has been reported to inhibit PTP1B activity in cell free system [35]. Therefore, it would be interesting to study the effects of Tan IIA on PTP1B to determine the mechanisms of Sirt1 activation by Tan IIA in mast cells. Indeed, the anti-allergic activity of Tan IIA is reminiscent of that of resveratrol and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), which activate Sirt1 and AMPK, respectively [11], [23]. Importantly, the anti-allergic effect of Tan IIA is abrogated when either Sirt1, LKB1, or AMPKα2 is absent, lending strong support to our conclusion that Tan IIA exerts its anti-allergic effect by activating this pathway. Although we cannot not rule out the possibility that Tan IIA acts on certain target(s) that modulate the activity of Sirt1 or on additional target(s) unrelated to the Sirt1-LKB1-AMPK axis, our present study nonetheless provides a clear molecular explanation for why this natural product possesses both anti-metabolic and anti-allergic effects. Overall, possible inhibitory mechanism of Tan II on mast cell activation is summarized in Fig. 9. Tan IIA attenuates FcεRI-mediated phosphorylation of PLCγ1, ERK1/2, JNK, IKK, but not Akt and p38. Consistently, Tan IIA inhibits degranulation, generation of eicosanoids (LTC4 and PGD2), secretion of pro-inflammatory cytokines (TNF-α, IL-6), and increase of intracellular Ca2+ through the activation of Sirt/LKB1/AMPK a trimeric complex without affecting FcεRI-proximal tyrosine kinases. Allergic diseases have reached pandemic levels in developed countries and represent a major source of morbidity, mortality, and healthcare expenses. Clinically, cromoglicate, steroids, and receptor antagonists for histamine or cysteinyl leukotrienes have been used as anti-allergic drugs for many years [36], although they have strong side effects and are often ineffective. Although Syk inhibitors have been proposed as potential candidates for the development of anti-allergic agents [37], a clinical trial of a Syk inhibitor was unsuccessful [38], likely because Syk is expressed in numerous types of leukocytes, and mice die perinatally [39]. Omalizumab, a monoclonal antibody against IgE [40], and dupilumab, a monoclonal antibody against IL-4 receptor α [41], were recently approved for the treatment of patients with allergic diseases, but they are aggressively priced, costing $10,000–12,000 US dollars annually. Therefore, identification of an alternative anti-allergic drug target is desirable. Considering the beneficial biological functions of Sirt1-LKB1-AMPK in general plus the fact that S. miltiorrhiza has been used safely in China for more than 2,000 years for the treatment of cardiovascular diseases [27], Tan IIA or its derivatives may be promising novel agents for the treatment of mast cell-mediated allergic disorders.