Autophagy-dependent mitochondrial function regulates osteoclast differentiation and maturation.

Bone homeostasis is maintained by bone remodeling, which involves continuous bone resorption by osteoclasts and bone formation by osteoblasts. Dysregulation of bone turnover, caused by osteoclast overactivation, causes destructive bone diseases. However, the mechanisms underlying the maintenance of osteoclast differentiation and activation are unclear. Herein, we examined the role of autophagy in the maintenance of osteoclast differentiation and maturation. We used in vitro and in vivo assays to evaluate relationships between mitochondrial activity and autophagy during osteoclast differentiation and maturation. Our results indicate that autophagy was enhanced during osteoclast differentiation and maturation, and autophagic activity was positively correlated with osteoclast activity and survival. Maintenance of mitochondrial function, which is critical during osteoclast differentiation and maturation, was controlled by autophagy. Continuous exposure of osteoclasts to glucocorticoids upregulated autophagic processes. Treatment with the autophagic inhibitor chloroquine suppressed prolonged survival of activated osteoclasts and attenuated excessive osteoclast activity. Our study shows that autophagy-dependent mitochondrial function plays an important role in osteoclast differentiation and maturation. Elucidating the mechanisms regulating autophagic activity in osteoclasts, and developing bone-tissue-specific inhibitors of autophagy, will lead to improved understanding of the pathologies involved in destructive bone diseases.

Highly Oxidized Ellagitannins of Carpinus japonica and Their Oxidation-Reduction Disproportionation.

In the research on ellagitannin metabolism, two unique dehydroellagitannins, carpinins E (1) and F (2), bearing dehydrohexahydroxydiphenoyl (DHHDP) and hydrated biscyclohexenetrione dicarboxyl ester (HBCHT) groups, were isolated from young leaves of Carpinus japonica. Upon heating in H2O or treatment with pH 6 buffer at room temperature, 1 and 2 afforded the reduction product 3, isocarpinin A, with an (R)-hexahydroxydiphenoyl (HHDP) group, suggesting the occurrence of redox disproportionation of the (S)-DHHDP group. This was supported by the increase in production of 3 in the pH 6 buffer solution by coexistence of epigallocatechin-3-O-gallate (15), accompanied by oxidation of 15. In contrast, treatment of 1 and 2 with ascorbic acid yielded 4, carpinin A, with an (S)-HHDP group. Upon heating with ascorbic acid, the HBCHT group was also reduced to an (S)-HHDP group, and 2 was converted to 2,3;4,6-bis(S)-HHDP glucose. In leaves of C. japonica, the tannins 1 and 2 are dominant in young spring leaves, but compounds 3 and 4 become the major components of tannins in mature leaves. These results suggest that, in ellagitannin biosynthesis, oxidative coupling of the two galloyl groups first generates a DHHDP group, and subsequent reduction of DHHDP esters produces HHDP esters.

Pupillary response reflects attentional modulation to sound after emotional arousal.

There have been various studies on the effects of emotional visual processing on subsequent non-emotional auditory stimuli. A previous study with EEG has shown that responses to deviant sounds presented after presenting negative pictures collected more attentional resources than those for neutral pictures. To investigate such a compelling between emotional and cognitive processing, this study aimed to examined pupillary responses to an auditory stimulus after a positive, negative, or neutral emotional state was elicited by an emotional image. An emotional image was followed by a beep sound that was either repetitive or unexpected, and the pupillary dilation was measured. As a result, we found that the early component of the pupillary response to the beep sound was larger for negative and positive emotional states than the neutral emotional state, whereas the late component was larger for the positive emotional state than the negative and neutral emotional states. In addition, the peak latency of the pupillary response was earlier for negative than neutral or positive images. Further, to compensate for the disadvantage of low-temporal resolution of the pupillary data, the pupillary responses were deconvoluted and used in the analysis. The deconvolution analysis of pupillary responses confirmed that the responses to beep sound were more likely to be modulated by the emotional state rather than being influenced by the short presentation interval between the images and sounds. These findings suggested that pupil size index modulations in the compelling situation between emotional and cognitive processing.