摘要: Objective Hepatic sinusoidal angiogenesis owing to dysfunctional liver sinusoidal endothelial cells (LSECs) accompanied by an abnormal angioarchitecture is a symbol related to liver fibrogenesis, which indicates a potential target for therapeutic interventions. However, there are few researches connecting angiogenesis with liver fibrosis, and the deeper mechanism remains to be explored. Materials and Methods Cell angiogenesis and angiogenic protein were examined in primary LSECs of rats, and multifarious cellular and molecular assays revealed the efficiency of curcumol intervention in fibrotic mice. Results We found that curcumol inhibited angiogenic properties through regulating their upstream mediator hypoxia-inducible factor-1 alpha (HIF-1 alpha). The transcription activation of HIF-1 alpha was regulated by hedgehog signalling on the one hand, and the protein stabilization of HIF-1 alpha was under the control of Prospero-related homeobox 1 (PROX1) on the other. A deubiquitinase called USP19 could be recruited by PROX1 and involved in ubiquitin-dependent degradation of HIF-1 alpha. Furthermore, our researches revealed that hedgehog signalling participated in the activation of PROX1 transcription probably in vitro. Besides, curcumol was found to ameliorate liver fibrosis and sinusoid angiogenesis via hedgehog pathway in carbon tetrachloride (CCl4) induced liver fibrotic mice. The protein expression of key regulatory factors, PROX1 and HIF-1 alpha, was consistent with the Smo, the marker protein of Hh signalling pathway. Conclusions In this article, we evidenced that curcumol controlling LSEC-mediated angiogenesis could be a promising therapeutic approach for liver fibrosis.

摘要: Cartilage is a connective tissue in the skeletal system and has limited regeneration ability and unique biomechanical reactivity. The growth and development of cartilage can be affected by different physical, chemical and biological factors, such as mechanical stress, inflammation, osmotic pressure, hypoxia and signalling transduction. Primary cilia are multifunctional sensory organelles that regulate diverse signalling transduction and cell activities. They are crucial for the regulation of cartilage development and act in a variety of ways, such as react to mechanical stress, mediate signalling transduction, regulate cartilage-related diseases progression and affect cartilage tumorigenesis. Therefore, research on primary cilia-mediated cartilage growth and development is currently extremely popular. This review outlines the role of primary cilia in cartilage development in recent years and elaborates on the potential regulatory mechanisms from different aspects.

摘要: Human high-temperature requirement protein 1 (HTRA1) is a member of serine proteases and consists of four well-defined domains-an IGFBP domain, a Kazal domain, a protease domain and a PDZ domain. HTRA1 is a secretory protein and also present intracellularly and associated with microtubules. HTRA1 regulates a broad range of physiological processes via its proteolytic activity. This review examines the role of HTRA1 in bone biology, osteoarthritis, intervertebral disc (IVD) degeneration and tumorigenesis. HTRA1 mediates diverse pathological processes via a variety of signalling pathways, such as TGF-beta and NF-kappa B. The expression of HTRA1 is increased in arthritis and IVD degeneration, suggesting that HTRA1 protein is attributed to cartilage degeneration and disease progression. Emerging evidence also suggests that HTRA1 has a role in tumorigenesis. Further understanding the mechanisms by which HTRA1 displays as an extrinsic and intrinsic regulator in a cell type-specific manner will be important for the development of HTRA1 as a therapeutic target.

摘要: Objective We aimed to investigate the roles and underlying mechanisms of YAP in the proliferation of neuroblastoma cells. Methods The expression level of YAP was evaluated by Western blotting and immunocytochemistry. Cell viability, cell proliferation and growth were detected by CCK-8, PH3 and Ki67 immunostaining, and the real-time cell analyser system. The nuclear and cytoplasmic proteins of p27(Kip1) were dissociated by the nuclear-cytosol extraction kit and were detected by Western blotting and immunocytochemistry. mRNA levels of Akt, CDK5 and CRM1 were determined by qRT-PCR. Results YAP was enriched in SH-SY5Y cells (a human neuroblastoma cell line). Knock-down of YAP in SH-SY5Y cells or SK-N-SH cell line (another human neuroblastoma cell line) significantly decreased cell viability, inhibited cell proliferation and growth. Mechanistically, knock-down of YAP increased the nuclear location of p27(Kip1), whereas serum-induced YAP activation decreased the nuclear location of p27(Kip1) and was required for cell proliferation. Meanwhile, overexpression of YAP in these serum-starved SH-SY5Y cells decreased the nuclear location of p27(Kip1), promoted cell proliferation and overexpression of p27(Kip1) in YAP-activated cells inhibited cell proliferation. Furthermore, knock-down of YAP reduced Akt mRNA and protein levels. Overexpression of Akt in YAP-downregulated cells decreased the nuclear location of p27(Kip1) and accelerated the proliferation of SH-SY5Y cells. Conclusions Our studies suggest that YAP promotes the proliferation of neuroblastoma cells through negatively controlling the nuclear location of p27(Kip1) mediated by Akt.

摘要: ObjectivesThe successional dental lamina is the distinctive structure on the lingual side of the vertebrate tooth germ. The aim of this study was to investigate the relationship among Sox2, Claudin10 and laminin5 and the role of Sox2 in successional dental lamina proliferation during vertebrate tooth development. Materials and MethodsTo understand the successional dental lamina, two types of successional tooth formation, that in geckos (with multiple rounds of tooth generation) and that in mice (with only one round of tooth generation), were analysed. ResultsUnique coexpression patterns of Sox2 and Claudin10 expression were compared in the successional dental lamina from the cap stage to the late bell stage in the mouse tooth germ and in juvenile gecko teeth to support continuous tooth replacement. Furthermore, Laminin5 expression was shown in the cap stage and decreased after the bell stage. Upon comparing the epithelial cell cycles and cell proliferation in successional dental lamina regions between mouse and gecko molars using BrdU and IdU staining and pulse-chase methods, distinctive patterns of continuous expression were revealed. Moreover, Sox2 overexpression with a lentiviral system resulted in hyperplastic dental epithelium in mouse molars. ConclusionsOur findings indicate that the regulation of Sox2 in dental lamina proliferation is fundamental to the successional dental lamina in both species.