FIG. 3.

Various inflammation-related microRNAs under circadian control suppress SIRT1, thereby removing the SIRT1-mediated blockade of NF-κB activation, whereas melatonin upregulates SIRT1 and downregulates several of these microRNAs. These relationships are valid for conditions of well-operating circadian oscillators, whereas strongly deviating findings are typically obtained in tumor cells, whose oscillators are often severely dysregulated (92, 95, 108). It should also be noted that many more microRNAs are under circadian control or modulated by melatonin (107). Various others have been shown to stimulate or suppress NF-κB activation or SIRT1 signaling, however, in the absence of information on circadian control (105). Moreover, NF-κB was typically negatively correlated with Nrf2, in many analyzed cases (105) (not incorporated here, for avoiding an overcomplicated scheme). The switching between NF-κB and Nrf2 reflects an important feature of proinflammatory versus anti-inflammatory and prooxidant versus antioxidant regulation. Before the discovery of the melatonin-SIRT1 relationship, it had been assumed that the influence of melatonin on the NF-κB/Nrf2 balance was independent of SIRT1. It may still be that melatonin and SIRT1 additionally act synergistically in parallel. NF-κB, nuclear factor κB; Nrf2, nuclear factor erythroid 2-related factor 2.