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author:("Li, changhai")
1.  Periodic Heat Shock Accelerated the Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Pellet Culture 
PLoS ONE  2014;9(3):e91561.
Osteoarthritis (OA) is one of diseases that seriously affect elderly people's quality of life. Human mesenchymal stem cells (hMSCs) offer a potential promise for the joint repair in OA patients. However, chondrogenic differentiation from hMSCs in vitro takes a long time (∼6 weeks) and differentiated cells are still not as functionally mature as primary isolated chondrocytes, though chemical stimulations and mechanical loading have been intensively studied to enhance the hMSC differentiation. On the other hand, thermal stimulations of hMSC chondrogenesis have not been well explored. In this study, the direct effects of mild heat shock (HS) on the differentiation of hMSCs into chondrocytes in 3D pellet culture were investigated. Periodic HS at 41°C for 1 hr significantly increased sulfated glycosaminoglycan in 3D pellet culture at Day 10 of chondrogenesis. Immunohistochemical and Western Blot analyses revealed an increased expression of collagen type II and aggrecan in heat-shocked pellets than non heat-shocked pellets on Day 17 of chondrogenesis. In addition, HS also upregulated the expression of collagen type I and X as well as heat shock protein 70 on Day 17 and 24 of differentiation. These results demonstrate that HS accelerated the chondrogenic differentiation of hMSCs and induced an early maturation of chondrocytes differentiated from hMSCs. The results of this study will guide the design of future protocols using thermal treatments to facilitate cartilage regeneration with human mesenchymal stem cells.
doi:10.1371/journal.pone.0091561
PMCID: PMC3954764  PMID: 24632670
2.  Knockdown of VEGF receptor-1 (VEGFR-1) impairs macrophage infiltration, angiogenesis and growth of clear cell renal cell carcinoma (CRCC) 
Cancer Biology & Therapy  2011;12(10):872-880.
Angiogenesis is essential for tumor growth and metastasis. VEGF has been shown to be a central player in this process. The biological activity of VEGF is mainly mediated by two tyrosine kinase receptors, VEGFR-1 and VEGFR-2. While increasing evidence suggests that VEGF/VEGFR-1 signaling is crucial for tumor angiogenesis, its molecular mechanism is not well understood. Here we show that VEGFR-1 knockdown dramatically inhibits tumor growth. This inhibition is associated with significant decrease of tumor VEGF levels and tumor angiogenesis as well as an increased tumor necrosis. Moreover, we demonstrate that VEGF in CRCC tumors is mainly produced by tumor stromal cells instead of the tumor cells themselves. It has been shown that macrophages constitute a significant part of tumor stromal cells and produce a large amount of VEGF. We therefore examined the macrophage infiltration in the xenograft tumors. Remarkably, VEGFR-1 knockdown attenuates the tumor macrophages infiltration. To understand the mechanism, we investigated the impact of VEGFR-1 knockdown on the expression of monocyte chemoattractant protein-1 (MCP-1), one of the main chemoattractants for macrophages. Significantly, VEGFR-1 knockdown inhibits MCP-1 expression of CRCC cells. Taken together, these data indicate that VEGF/VEGFR-1 signaling plays an essential role in initiating tumor angiogenesis by regulating MCP-1 expression, which in turn, attracts macrophages infiltration and VEGF production. Thus, these studies suggest that blockade of VEGFR-1 function may provide a tumor-specific, VEGF-based therapeutic strategy for treatment of CRCC.
doi:10.4161/cbt.12.10.17672
PMCID: PMC3280902  PMID: 21989163
VEGF receptor 1; angiogenesis; tumor macrophage infiltration; monocyte chemoattractant protein-1 (MCP-1); tumor-specific therapy; angiogenic switch; and clear cell renal cell carcinoma (CRCC)
3.  Increasing extracellular matrix collagen level and MMP activity induces cyst development in polycystic kidney disease 
BMC Nephrology  2012;13:109.
Background
Polycystic Kidney Disease (PKD) kidneys exhibit increased extracellular matrix (ECM) collagen expression and metalloproteinases (MMPs) activity. We investigated the role of these increases on cystic disease progression in PKD kidneys.
Methods
We examined the role of type I collagen (collagen I) and membrane bound type 1 MMP (MT1-MMP) on cyst development using both in vitro 3 dimensional (3D) collagen gel culture and in vivo PCK rat model of PKD.
Results
We found that collagen concentration is critical in controlling the morphogenesis of MDCK cells cultured in 3D gels. MDCK cells did not form 3D structures at collagen I concentrations lower than 1 mg/ml but began forming tubules when the concentration reaches 1 mg/ml. Significantly, these cells began to form cyst when collagen I concentration reached to 1.2 mg/ml, and the ratios of cyst to tubule structures increased as the collagen I concentration increased. These cells exclusively formed cyst structures at a collagen I concentration of 1.8 mg/ml or higher. Overexpression of MT1-MMP in MDCK cells significantly induced cyst growth in 3D collagen gel culture. Conversely, inhibition of MMPs activity with doxycycline, a FDA approved pan-MMPs inhibitor, dramatically slowed cyst growth. More importantly, the treatment of PCK rats with doxycycline significantly decreased renal tubule cell proliferation and markedly inhibited the cystic disease progression.
Conclusions
Our data suggest that increased collagen expression and MMP activity in PKD kidneys may induce cyst formation and expansion. Our findings also suggest that MMPs may serve as a therapeutic target for the treatment of human PKD.
doi:10.1186/1471-2369-13-109
PMCID: PMC3487993  PMID: 22963260
Collagen I; 3 dimensional (3D) collagen gel culture; Doxycycline; Matrix metalloproteinase; PCK rats; Polycystic kidney disease
4.  Abl interactor 1 regulates Src-Id1-matrix metalloproteinase 9 axis and is required for invadopodia formation, extracellular matrix degradation and tumor growth of human breast cancer cells 
Carcinogenesis  2009;30(12):2109-2116.
Abl interactor 1 (Abi1) is a key regulator of actin polymerization/depolymerization. The involvement of Abi1 in the development of abnormal cytoskeletal functions of cancer cells has recently been reported. It remains unclear, however, how Abi1 exerts its effects in tumor cells and whether it contributes to tumor progression in vivo. We report here a novel function for Abi1 in the regulation of invadopodia formation and Src-inhibitor of differentiation protein 1 (Id1)-matrix metalloproteinase (MMP)-9 pathway in MDA-MB-231 human breast cancer cells. Abi1 is found in the invadopodia of MDA-MB-231 cells. Epigenetic silencing of the Abi1 gene by short hairpin RNA in MDA-MB-231 cells impaired the formation of invadopodia and resulted in downregulation of the Src activation and Id1/MMP-9 expression. The decreased invadopodia formation and MMP-9 expression correlate with a reduction in the ability of these cells to degrade extracellular matrix. Remarkably, the knockdown of Abi1 expression inhibited tumor cell proliferation and migration in vitro and slowed tumor growth in vivo. Taken together, these results indicate that the Abi1 signaling plays a critical role in breast cancer progression and suggest that this pathway may serve as a therapeutic target for the treatment of human breast cancer.
doi:10.1093/carcin/bgp251
PMCID: PMC2792316  PMID: 19843640
5.  Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor α by inhibiting NF-κB signaling pathway 
Molecular Cancer  2010;9:73.
Background
Tumor necrosis factor alpha (TNFα) has been used to treat certain tumors in clinic trials. However, the curative effect of TNFα has been undermined by the induced-NF-κB activation in many types of tumor. Maslinic acid (MA), a pharmacological safe natural product, has been known for its important effects as anti-oxidant, anti-inflammatory, and anti-viral activities. The aim of this study was to determine whether MA potentiates the anti-tumor activity of TNFα though the regulation of NF-κB activation.
Results
In this study, we demonstrate that MA significantly enhanced TNFα-induced inhibition of pancreatic cancer cell proliferation, invasion, and potentiated TNFα-induced cell apoptosis by suppressing TNFα-induced NF-κB activation in a dose- and time-dependent manner. Addition of MA inhibited TNFα-induced IκBα degradation, p65 phosphorylation, and nuclear translocation. Furthermore, MA decreased the expression levels of NF-κB-regulated genes, including genes involved in tumor cell proliferation (Cyclin D1, COX-2 and c-Myc), apoptosis (Survivin, Bcl-2, Bcl-xl, XIAP, IAP-1), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). In athymic nu/nu mouse model, we further demonstrated that MA significantly suppressed pancreatic tumor growth, induced tumor apoptosis, and inhibited NF-κB-regulated anti-apoptotic gene expression, such as Survivin and Bcl-xl.
Conclusions
Our data demonstrate that MA can potentiate the anti-tumor activities of TNFα and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-κB activation and its downstream gene expression. Therefore, MA together with TNFα could be new promising agents in the treatment of pancreatic cancer.
doi:10.1186/1476-4598-9-73
PMCID: PMC2907730  PMID: 20367887

Results 1-5 (5)