ABSTRACT
Non-coding RNA (ncRNA), expressed widely in organisms and comprised of a complex, regulatory and controlling biologically network, is an emerging theme in the biomedicine field at present. Regulatory sncRNAs, for example, microRNA (miRNA), endogenous small interfering RNA (siRNA) and PIWI-interacting RNA (piRNA), are the key members of the gene regulatory network and play important roles in the regulation of multiple pathophysiological activities in cells. Male infertility, a serious social problem all over the world, is mainly related the malfunctions of the spermatogenesis caused by known or unknown factors; and finally result in azoospermia, oligozoospermia or asthenospermia. Recent research indicated that regulatory sncRNAs play important roles in the development, differentiation and mature of the germ cells and their functions at different stages by silencing the transposable elements and regulating the expression of coding gene; and their abnormal expression in germ cells at different stage is closely related to male infertility. In this review, the roles and recent progresses of regulatory sncRNA focusing on piRNA to provide insight for future research in this field and for the diagnoses, interventions and treatments of male infertility are briefly summarized.
ABSTRACT
OBJECTIVE: To discuss early exploratory bridging studies between early screening phase and pivotal general toxicology studies and their application during new drug development. METHODS: The opinions on acute toxicity study from international counterparts and current application in domestic and overseas were briefly reviewed. At the same time, the study design and the strengths of an alternative maximum tolerated dose /dose range finding (MTD/DRF) study widely used abroad were fully discussed. Furthermore, considerations were also highlighted based on the authors' experience, which may aid in the design and the conduct of such bridging studies. RESULTS AND CONCLUSION: MTD/DRF study could provide more valuable information for subsequent non-clinical regulatory toxicity studies. It is a rational and practical general toxicological study with bridging character.
ABSTRACT
The development of human endometrial carcinoma (HEC) is a complex pathologic process involves several oncogenes and tumor suppressor genes. The full-length paired-box gene 2 (pax2), a recently discovered oncogene, promotes cell proliferation and growth and inhibits apoptosis of HEC cells. Here, we examined the effect of pax2 small interfering RNA (siRNA) on the growth of transplanted HEC cells in nude mice. The expression of Pax2 in 21 cases of normal endometrium and 38 cases of HEC was examined by immohistochemistry (IHC). HEC models were developed by subcutaneously transferring HEC cells into nude mice, followed by treatment with empty lentivirus vector, lentivirus vector-based pax2 siRNA, and phosphate buffered saline, respectively. Four weeks later, tumor size was measured, tumor inhibition rate was calculated, and histological analyses were conducted after staining with hematoxylin and eosin. The expression of Pax2 and Bcl-2 was detected by Western blot; proliferating cell nuclear antigen (PCNA) was detected by IHC. Significant differences were observed in the positive rate of Pax2 between normal endometrium and HEC (14.2% vs. 60.5%, P < 0.01). The expression index of Pax2 in well differentiated tumors was 1.88 ± 1.68, much lower than that in tumors of moderate (3.07 ± 1.96, P < 0.05) or poor differentiation (5.45 ± 2.76, P <0.01). Tumor necrosis increased, nuclear basophilia stain decreased, tumor growth was inhibited, and PCNA, Pax2, and Bcl-2 expression was reduced in HEC models treated with pax2 siRNA. These results indicate that Pax2 expression is related to HEC tumor biology with the increased expression of Pax2 correlated to malignancy. pax2 siRNA down-regulates Pax2 expression and inhibits tumorigenesis of HEC in nude mice, possibly due to cell apoptosis and the inhibition of tumor proliferation induced by down-regulation of Bcl-2.