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Many metabolic and physiological processes display daily rhythms oscillated by the internal circadian clock system. This rhythm is generated by interlocked transcription-(post) translation feedback loops of clock genes: the core oscillatory loop, being composed of CLOCK/BMAL1 heterodimer activating the expressions of PER and CRY that directly repress CLOCK/BMAL1, is accompanied by accessory loops consisted with REV-ERB nuclear receptor repressing Bmal1 or with DBP competing with E4BP4 on D-box site. These clock proteins are regulated by phosphorylation and ubiquitination (PER/CRY), and acetylation (CLOCK/BMAL1). Recently, a deacetylating protein SIRT1 mediated metabolic pathway is discovered to be interlocked with core oscillatory loop via Nampt expression, a late-limiting enzyme in NAD+ salvage pathway. Since many key-step enzymes of metabolisms are regulated by the circadian clock, circadian clock system may intimately link to cellular metabolism.

The suprachiasmatic nucleus (SCN) is considered the master circadian pacemaker that controls most of the physical circadian rhythms of mammals including behavior. Studies of clock genes have implied that oscillatory mechanisms function in peripheral organs and isolated cells, and that they are entrained to the SCN. The circadian clock is an intracellular, transcriptional-translational mechanism that shares the same molecular components in the SCN and in peripheral cells. Hundreds of tissue-specific circadian genes that regulate an impressive diversity of biological processes have been identified using DNA microarray technology. This review summarized the recent information of clock and clock-controlled genes in mammals.

Polychlorinated biphenyls (PCB) causes the release of superoxide during the metabolic process. Therefore, Yusho victims are thought to be exposed to oxidative stress caused by PCB, because high concentrations of PCB are still detected in the serum of Yusho victims. Recently, total antioxidant power (TAP) has been proposed as one of excellent markers of defense capacity against oxidative stresses. In order to estimate the antioxidant capacity in Yusho victims, we measured serum TAP in certified Yusho victims and age-matched noncertified subjects. The mean values of serum TAP were 0.479 +/- 0.017 in certified Yusho victims and 0.397 +/- 0.013 microM in non-certified subjects, respectively. There was a significant difference in the serum values of TAP between certified Yusho victims and uncertified subjects. TAP was reported to increase in the case of severe oxidative stress and PCB can give rise to an oxidative stress in Yusho victims. Therefore, it was supposed that TAP could increase in the oxidative stress of Yusho probably by some negative feedback mechanisms. The exact mechanism is still unclear, and further examinations should be conducted in the future.

Recently, large body of evidences that Wnt plays an important role in regulation of tissue patterning and skeletogenesis including membranous and enchondral ossification is accumulating. Several genetic studies also indicate that low density lipoprotein receptor related protein (LRP) 5, LRP6, beta-catenin and lymphoid enhancer-binding factor/T-cell factor (LEF/TCF) participate in osteogenic action induced by Wnt family members. In contrast, secreted Frizzled-related proteins and dickkopf (Dkk) proteins, natural Wnt inhibitory factors, inhibit Wnt-dependent osteogenesis, presumably functioning as a negative feedback loop. In addition, Wnt signaling interacts with BMP signaling, thereby modulating its osteogenic action. Thus, the network systems of Wnt signaling temporally and spatially controls osteogenic action of Wnt family members.

Cyclic ADP-ribose (cADPR) is suggested to be a novel messenger of ryanodine receptors (RyR) in various cellular systems. However, the regulation of its synthesis in response to cell stimulation and its functional roles are still unclear. We examined the physiological relevance of cADPR to the messenger role in stimulation-secretion coupling in bovine adrenal chromaffin cells. In digitonin-permeabilized cells, cADPR-induced Ca2+ release but not caffeine-, ryanodine-, and IP3-induced Ca2+ release was inhibited by FK506 which bind to FKBP and dissociate it from the RyR. These evidence suggesting that cADPR may be the ligand for FKBP-RyR complex, resulting in a dynamic regulation of RyR-mediated Ca2+ release. ACh causes biphasic [Ca2+]i rise, an initial transient rise followed by sustained rise, in intact cells. 8Br-cADPR, an antagonist of cADPR and FK506 specifically reduced the sustained phases of ACh-induced [Ca2+]i rise. Imperatoxin inhibitor (IpTxi) blocked the inhibitory effect of 8Br-cADPR and FK506, suggesting that cADPR contributes to sustained [Ca2+]i rise. 8Br-cADPR, FK506, and IpTxi reduced CA release in response to ACh in chromaffin cells. These results provide evidence that the synthesis of cADPR is regulated by cell stimulation, and the cADPR/Ca(2+)-induced Ca2+ release pathway forms a positive feedback to stimulation-induced secretory response in the chromaffin cells.