Wei Kuang

Decreased osteogenesis of adult mesenchymal stem cells by reactive oxygen species under cyclic stretch: a possible mechanism of age related osteoporosis

Age related defect of the osteogenic differentiation of mesenchymal stem cells (MSCs) plays a key role in osteoporosis. Mechanical loading is one of the most important physical stimuli for osteoblast differentiation. Here, we compared the osteogenic potential of MSCs from young and adult rats under three rounds of 2 h of cyclic stretch of 2.5% elongation at 1 Hz on 3 consecutive days. Cyclic stretch induced a significant osteogenic differentiation of MSCs from young rats, while a compromised osteogenesis in MSCs from the adult rats. Accordingly, there were much more reactive oxygen species (ROS) production in adult MSCs under cyclic stretch compared to young MSCs. Moreover, ROS scavenger N-acetylcysteine rescued the osteogenic differentiation of adult MSCs under cyclic stretch. Gene expression analysis revealed that superoxide dismutase 1 (SOD1) was significantly downregulated in those MSCs from adult rats. In summary, our data suggest that reduced SOD1 may result in excessive ROS production in adult MSCs under cyclic stretch, and thus manipulation of the MSCs from the adult donors with antioxidant would improve their osteogenic ability.

Inhibition of NFkappaB by activated c-Jun NH2 terminal kinase 1 acts as a switch for C2C12 cell death under excessive stretch.

Mechanical stimuli play an important role in adaptive response of skeletal muscles, while inappropriate stretches result in apoptosis. In this study, we investigated the contribution of cyclic stretches to apoptosis of myoblast C2C12 cells. A 24-h cyclic stretch at an extension level of over 15%/10 cycles/min produced abundant reactive oxygen species, leading to significant apoptosis. Under such stretches, JNK1 phosphorylation increased while NFkappaB activity decreased. Inhibition of JNK by a specific chemical inhibitor or RNAi increased cell survival, which was blocked by additional NFkappaB inhibition. Furthermore, inhibition of JNK rescued the transcriptional activity of NFkappaB and upregulated the expression of Bcl2 through NFkappaB nuclear localization, suggesting the existence of inhibition of NFkappaB by activated JNK pathway. Taken together, our study suggests that excessive ROS induced by undue stretch favor the activation of JNK1, which in turn inhibit the activity of NFkappaB, resulting in significant apoptosis.

Restoration of miR-34a in p53 deficient cells unexpectedly promotes the cell survival by increasing NFκB activity.

Upregulation of miR‐34a by p53 is recently believed to be a key mediator in the pro‐apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR‐34a levels in p53 deficient cells could rescue the response to DNA damage. Compared with the p53 wildtype U2OS cells, miR‐34a expression was much lower in p53 deficient Saos2 cells upon cisplatin treatment. Unexpectedly, delivery of miR‐34a in Saos2 cells does not increase the cell sensitivity to apoptosis. This effect was mediated by direct downregulation of SirT1 expression by miR‐34a, which in turn increased the NFκB activity. Inhibition of NFκB activity in Saos2 cells by Aspirin sensitized the miR‐34a overexpressing cells to cell death. Thus, in tumors with p53 deficiency, miR‐34a restoration alone confers drug resistance through Sirt1‐NFκB pathway and combination of miR‐34a and NFκB inhibitor could be considered as a promising therapeutic strategy. J. Cell. Biochem. 113: 2903–2908, 2012.

Dysregulation of the miR-146a-Smad4 axis impairs osteogenesis of bone mesenchymal stem cells under inflammation

Osteoporosis is a common disease that affects patient quality of life, especially among the elderly population. Although inflammation contributes significantly to osteoporosis, the underlying mechanism is unclear. In this study, we found that tumor necrosis factor (TNF)-α, an inflammatory environment mimic, inhibits osteogenesis of bone mesenchymal stem cells (BMSCs), induces miR-146a and decreases Smad4. Moreover, overexpression of miR-146a inhibited the osteogenic ability of BMSCs, whereas blocking miR-146a partially rescued the osteogenesis deficiency under TNF-α treatment. Molecularly, miR-146a decreased Smad4 expression at the protein level by binding to an element located in the Smad4 3′-untranslated region, and restoration of Smad4 reversed the inhibitory effects of miR-146a on osteogenesis. Together, our results showed that the inflammatory environment mimic TNF-α inhibits osteogenesis via upregulation of miR-146a and subsequent downregulation of Smad4, thus suggesting that therapeutic manipulation of miR-146a maybe a potential strategy to improve osteogenesis in the context of osteoporosis.

The Epigenetic Regulation in Tooth Development and Regeneration

BACKGROUND Tooth loss occurs with age and significantly impacts the quality of elderlys life both physically and psychologically. It has been well known that odontogenesis is a complicated process with sequential and reciprocal interactions between epithelial and mesenchymal tissues and different types of dental tissue-derived stem cells involve in it. However, only a small portion of the intricate mechanisms has been defined nowadays. Among them, epigenetics has become an increasingly important mechanism for tooth development and regeneration. OBJECTIVE This review aims at illustrating the function of epigenetic regulation in odontogenesis, which plays an important role in dental tissue-derived stem cell self-renewal and differentiation nowadays and would be a new strategy for tooth regeneration. RESULTS In this review, we introduced the natural process of tooth development and the functions of stem cells involved in. Furthermore, we summarized the current knowledge on epigenetic regulation including DNA methylation, histone modification, and non-coding RNAs during odontogenesis, providing the theoretical basis for tooth regeneration. CONCLUSION Along with a deeper understanding of odontogenesis, the epigenetic mechanism involved in has become increasingly important. Therefore, its necessary to further study the functions of epigenetic regulation in tooth development and regeneration, which may make tooth regeneration a reality in the future.

Plasma exchange therapy holds promise in the management of advanced cancer

Cancer is now emerging as the second most common cause of death worldwide. Currently the most widely used treatments for solid cancer are surgery, chemotherapy, radiotherapy and hormone therapy, all of which are of limited effects in improvement of the survival. It is well-established that circulating factors are involved in the development of cancer. And plasma exchange is a well-established therapeutic procedure commonly used in many autoimmune diseases through the elimination of pathologic mediators, including auto-antibodies, complement components, and cytokines. Thus, we hypothesize that plasma exchange therapy alone or in combination with the routine therapeutics should be considered as an alternative for the present treatments. Future clinical studies are needed to validate the hypothesis.