Copper promotes the migration of bone marrow mesenchymal stem cells via Rnd3-dependent cytoskeleton remodeling.

The motility of mesenchymal stem cells (MSCs) is highly related to their homing in vivo, a critical issue in regenerative medicine. Our previous study indicated copper (Cu) might promote the recruitment of endogenous MSCs in canine esophagus defect model. In this study, we investigated the effect of Cu on the motility of bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanism in vitro. Cu supplementation could enhance the motility of BMSCs, and upregulate the expression of hypoxia-inducible factor 1α (Hif1α) at the protein level, and upregulate the expression of rho family GTPase 3 (Rnd3) at messenger RNA and protein level. When Hif1α was silenced by small interfering RNA (siRNA), Cu-induced Rnd3 upregulation was blocked. When Rnd3 was silenced by siRNA, the motility of BMSCs was decreased with or without Cu supplementation, and Cu-induced cytoskeleton remodeling was neutralized. Furthermore, overexpression of Rnd3 also increased the motility of BMSCs and induced cytoskeleton remodeling. Overall, our results demonstrated that Cu enhanced BMSCs migration through, at least in part, cytoskeleton remodeling via Hif1α-dependent upregulation of Rnd3. This study provided an insight into the mechanism of the effect of Cu on the motility of BMSCs, and a theoretical foundation of applying Cu to improve the recruitment of BMSCs in tissue engineering and cytotherapy.

Inhibition of paclitaxel resistance and apoptosis induction by cucurbitacin B in ovarian carcinoma cells.

Ovarian cancer is the leading cause of mortality among all gynecological malignancies. Drug resistance is a cause of ovarian cancer recurrence and low rate of overall survival. There is a requirement for more effective treatment approaches. Cucurbitacin B (CuB) is an antineoplastic agent derived from traditional Chinese medicinal herbs. Its activity against paclitaxel-resistant human ovarian cancer cells has, however, not yet been established. The purpose of the present study was to investigate the effect and mechanism of CuB on human paclitaxel-resistant ovarian cancer A2780/Taxol cells. Cell viability was evaluated by a cell counting assay, while cell cycle arrest and apoptosis were assessed by microscopy and flow cytometry, and proteins associated with apoptotic pathways and drug resistance were evaluated by western blotting. The present results demonstrated that CuB exerts dose- and time-dependent cytotoxicity against the ovarian cancer A2780 cell line, with half-maximal inhibitory concentration (IC50) values 0.48, 0.25 and 0.21 µM following 24, 48 and 72 h of incubation, respectively. Compared with its sensitive counterpart, A2780, paclitaxel-resistant A2780/Taxol cells had almost identical IC50 values. Cell cycle analysis demonstrated that treatment with CuB may induce cell cycle arrest at the G2/M phase of the cell cycle in the two cell lines. As revealed by Annexin V/propidium iodide-labeled flow cytometry and Hoechst 33258 staining, CuB-induced apoptosis was accompanied by activation of caspase-3 and downregulation of B-cell lymphoma-2. Western blotting demonstrated that CuB may enhance the expression of p53 and p21 in the two cell lines. CuB may also downregulate the expression of P-glycoprotein. These results indicate that CuB may exert a therapeutic effect on paclitaxel-resistant human ovarian cancer.

Cucurbitacin B inhibits 12-O-tetradecanoylphorbol 13-acetate-induced invasion and migration of human hepatoma cells through inactivating mitogen-activated protein kinase and PI3K/Akt signal transduction pathways.

AIM: Cucurbitacin B (CuB) is an active component isolated from various plants used as folk medicine in Asian countries and has shown diverse antitumor activities. There is, however, no documented effect of CuB on the migration and invasion of human hepatoma cells yet. The purpose of this study was to assess the effect of CuB on the migration and invasion of hepatoma cells and to explore the possible mechanism. METHODS: Human hepatoma cell lines HepG2 and BEL-7402 were used for the study. Effects of CuB on cancer cell migration and invasion were evaluated in vitro with wound healing and transwell assays. The effect of CuB on the expression of matrix metalloproteinase (MMP)-9, mitogen-activated protein kinases (MAPKs), Akt, nuclear factor-κB (NF-κB), c-Fos and c-Jun was investigated with gelatin zymography and/or western blotting. RESULTS: Cucurbitacin B has significantly suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cell invasion and migration in a concentration-dependent manner, which was accompanied with suppression of TPA-induced MMP-9 expression through inactivation of phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38 and Akt. In the nucleus, it has also strongly suppressed TPA-stimulated expression of NF-κB, c-Jun and c-Fos. CONCLUSION: Cucurbitacin B has a potential value for suppressing metastasis of human hepatoma cells through suppressing the expression of MMP-9.

Congenital syndromes involving the lungs: pathogenetic models based on chinese medicine theories.

BACKGROUND: Striking similarity seems to exist between the Jing-Luo and Zang-Fu theories of Chinese Medicine (CM) and clinical features of many so-called multiple congenital anomaly/mental retardation syndromes (MCA/MRs), as both may involve multiple organs and/or body systems. MATERIALS, METHODS, AND RESULTS: Comparison of MCA/MRs involving the lungs and paths of 5 Jing-Mai traversing the organ has suggested that development of lung and radial ray (embryonic structure that gives rise to radial-side structures of the upper limb, in particular thumb and radius) are closely connected. The Lung Jing-Mai and those traversing the Kidneys may well explain combined malformations involving the lungs, radial ray, and the body's developmental midline. Furthermore, Zang-Fu theories such as "The Lungs rule the skin and body hair," and "The Lungs as a Zang pair with the Large Intestine" also seem to be in keeping with syndromes simultaneously affecting the lungs, colon, and skin. It may be deducible that the Jing-Mai, as described by CM, probably exists, and that the Jing-Mai and Zang-Fu theories have correctly summarized the connections between particular parts of the human body during embryonic development. CONCLUSIONS: The CM theories therefore may provide important insights into the pathogenesis of relevant diseases as well as clues for development of new treatment for lung-related diseases.

The Jing-Mai connections of the heart.

BACKGROUND: The Jing-Mai (variously translated as the Channel, Vessel or Meridians), as described by traditional Chinese medicine, probably exists and has represented the connections between various parts of human body during embryonic development. According to the Chinese theories, there are 14 major Jing-Mai within the human body, of which four are directly connected with the Heart. METHODS: The described paths of the four Jing-Mai were compared with features of congenital syndromes involving particular types of congenital heart defects. RESULTS: Specific correlation seem to exist between such four Jing-Mai and known developmental mechanisms underlying various congenital heart defects: the Kidney Jing-Mai-ectomesenchymal tissue migration abnormalities; the Spleen Jing-Mai-situs and looping defects; the Heart Jing-Mai-abnormal cell death; the Small Intestine Jing-Mai (and the Heart Jing-Mai)-extracellular matrix anomalies. CONCLUSIONS: The Chinese theories seem to provide some intriguing insights into the pathogeneses of congenital heart defects. The Jing-Mai seems to distinguish from, but nevertheless have a close relationship with the blood vessels. Utilization of the Jing-Mai will probably enable a better understanding and development of new treatments for cardiovascular diseases.

Human Phenome based on traditional Chinese medicine--a solution to congenital syndromology.

The occurrence of many congenital syndromes has long been an enigma. Clinically, the phenotype of any given genetic defect usually varies to some extent, whilst, pathogenetically, features within each syndrome are probably interconnected, albeit by largely unknown mechanisms. Through its unique theories such as the Jing-Mai (variously translated as the Channels, Vessels or Meridians), Zang-Fu (the Yin and Yang internal organs) and Wu-Xing (translated as the Five-Phase Correspondence or Five-Element theory), traditional Chinese medicine (TCM) seems to have comprehensively summarized the makeup of the human phenotypes. By combining the above TCM theories with modem medical knowledge, the intrinsic mechanisms between various aspects of the phenotypic makeup of the human individual, i.e. the Human Phenome, may be deduced. Analysis of congenital syndromes in light of the Human Phenome seems to suggest that various genetic defects may cause diseases in a similar fashion; i.e. primarily with structural abnormalities distributed along the four Jing-Mai connected with the Kidneys (midline defects) as well as "Marrow" aberrations (anomalies of hematology/immunology, endocrine, central nervous system and the bones). The derived Human Phenome may thereby enable a better understanding of such conditions and provide a model for the study of multigenic traits. On the other hand, blind spots of clinical observation and unknown aspects of human nature, e.g. circuits formed by the JingMai, symmetries of the Jing-Mai and Zang-Fu, and correspondences between body physiques, spiritual factors and the external world may also be deduced. The TCM-based Human Phenome may thereby offer a fresh view for genotype-phenotype correlations, insights into genedevelopment mechanisms, as well as potential directions for the development of new treatments.