Qichen Shen

Bone regeneration is a complex and coordinated physiological process, and the different stages of this process have corresponding microenvironments to support cell development and physiological activities. However, biological scaffolds that provide different three-dimensional environments during different stages of bone regeneration are lacking. In this study, we report a novel composite scaffold (NPE@DCBM) inspired by the stages of bone regeneration; this scaffold was composed of a fibrin hydrogel loaded with nanoplatelet vesicles (NPVs), designated as NPE, and decellularized cancellous bone matrix (DCBM) microparticles. Initially, the NPE rapidly established a temporary microenvironment conducive to cell migration and angiogenesis. Subsequently, the DCBM simulated the molecular structure of bone and promoted new bone formation. In vitro, the NPVs regulated lipid metabolism in bone marrow mesenchymal stem cells (BMSCs), reprogramed the fate of BMSCs by activating the PI3K/AKT and MAPK/ERK positive feedback pathways, and increased BMSC functions, including proliferation, migration and proangiogenic potential. In vivo, NPV@DCBM accelerated bone tissue regeneration and repair. Initially, the NPE rapidly induced angiogenesis between DCBM microparticles, and subsequently, BMSCs differentiated into osteoblasts with DCBM microparticles at their core. In summary, the design of this composite scaffold that sequentially mimics different bone regeneration microenvironments may provide a promising strategy for bone regeneration, with clinical translational potential.

Our previous finding demonstrated that chronic corticosterone (CORT) may be involved in mediating the pathophysiology of premature aging in rats. Frequent jet lag increases the risk for many diseases, including obesity and type 2 diabetes, and is associated with the aging processes. However, the effect of jet lag on CORT-induced depression and its association with aging phenotypes remain unclear. In this study, the rats were exposed to both CORT and jet lag treatment, and the differences were analyzed and compared to rats with single CORT treatment. Our results showed that jet lag treatment aggravated CORT-induced depression-like behavior evidenced by sucrose intake test, forced swimming test, and open field test. Additionally, this treatment aggravated the shortening of telomeres, which possibly resulted in decreased telomerase activity, and downregulated the expression of telomere-binding factor 2 (TRF2) and telomerase reverse transcriptase compared to that in CORT rats, as revealed by quantitative real-time-polymerase chain reaction and western blot analysis, respectively. The shortening of telomeres may have been caused by increased oxidative stress, which was associated with the inhibition of sirtuin 3. Exposure to jet lag also aggravated the degeneration of mitochondrial functions, as shown by the decreases in the mRNA expression of COX1, ND1, and Tfam. Our findings provide physiological evidence that jet lag exposure may worsen stress-induced depression and age-related abnormalities.

Disrupted circadian rhythms are a recognized effect of depression, and our previous article demonstrated an association between depression and premature aging, but the underlying mechanisms are not well understood. In the present study, we used a mouse model of chronic corticosterone (CORT)-treated depression to elucidate a mechanism by which depression may be associated with the circadian clock and mediate age-related phenotypes. Mice received a daily injection of 20 mg/kg CORT for 21 consecutive days, and the depression-like behaviors of mice were identified by the sucrose intake test, tail suspension test and open field test. Our findings indicated that CORT injection may be correlated with the circadian clock by impairing circadian rhythms or shifting the phase values of clock genes. We also showed that CORT-treated mice exhibited a significant gradual reduction in body weight gain with increased oxidative stress, including reduced activity of antioxidant-related enzymes, reduced glutathione:glutathione disulfide ratio and cytochrome (Cyt)-C level, and elevated reactive oxygen species content. Moreover, chronic CORT injection affected inflammatory responses, the production of mitochondrial ATP and telomere shortening, which may be associated with the Sirtuin 3 (SIRT3) signaling pathway. Additionally, chronic CORT injection disrupted the circadian rhythms of some indexes of aging phenotypes and altered the phase values of these indexes. Our findings suggest that psychologically stressful conditions such as depression are linked to changes in circadian rhythms and age-related phenotypes.

Disruption of circadian clock timekeeping due to changes in the photoperiod enhances the risk of lipid metabolism disorders and metabolic syndrome. However, the effects of altered photoperiods on the circadian clock and lipid metabolism are not well understood. To explore the effects of altered photoperiods, we developed a rat model where rats were exposed to either short-day or long-day conditions. Our findings demonstrated that altered photoperiods mediated circadian clocks by partly disrupting rhythmicity and shifting phase values of clock genes. We also showed that compared to long-day conditions, rats under short-day conditions exhibited more photoperiodic changes in a variety of physiological outputs related to lipid metabolism, such as significant increases in serum triglyceride (TG), high-density lipoprotein, and leptin levels, as well as increased body weight, fat:weight ratio, and hepatic TG levels. These increments were gained possibly through upregulated expression of forkhead box O1 (FoxO1), which partly mediates the expression of peroxisome proliferator-activated receptorα (PPARα) to increase the expression of phosphoenolpyruvate carboxykinase (PEPCK), peroxisome proliferator-activated receptor-g coactivator-1β (PGC1β), and fatty acid synthase (Fasn). In addition, the oscillation rhythms of FoxO1, PEPCK, PGC1β, and Fasn expression levels in the livers of rats exposed to a short-day photoperiod were more robust than those exposed to a long-day photoperiod. These findings suggest that a change in photoperiod can partly disrupt the circadian rhythmcity of clock genes, impair lipid metabolism, and promote obesity.