Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Development of resistance to cytotoxic agents is a major limitation to their clinical use. Novel compounds are synthesized with a view to develop non-cross-resistant, less toxic and more potent activity. The detection of the anti-tumour properties of the inorganic compound cisplatin stimulated a broad search for other metal-containing complexes. Titanocene dichloride was synthesized on this basis and has shown potent anti-neoplastic activity in experimental animals. We have examined the in vitro activity of titanocene dichloride in two pairs of platinum-sensitive and resistant human ovarian carcinoma cell lines, A2780/2780CP and CH1/CH1cisR, and in mutated p53- and bcl-2-transfected clones of A2780 cells. A time- and concentration-dependent anti-proliferative effect was observed in all cell lines treated with titanocene dichloride. The drug was found to significantly overcome platinum resistance in the 2780CP and the CH1 cisR cell lines and in the bcl-2 and the mutant p53 transfectants of A2780 cells. Titanocene dichloride induced a block in late S/early G2 phase of the cell cycle; however apoptotic cell death occurred from any phase of cycle. Titanium-DNA adducts were detected in A2780 cells treated with titanocene dichloride using atomic absorption spectrometry, suggesting that DNA may be a target for this drug. In agreement with this finding, p53 accumulated rapidly in drug-treated A2780 cells, indicative of a role for titanocene dichloride as a DNA-damaging agent. We have also performed studies to determine whether titanocene dichloride could demonstrate synergy with other cytotoxic agents in vitro. Isobologram analysis of cytotoxicity data obtained suggests that the combination of titanocene dichloride and 5-fluorouracil (5-FU) is synergistic. The potent in vivo anti-tumour activity of this compound, supported by the encouraging results from two phase I clinical trials, suggests that titanocene dichloride could be a promising novel chemotherapeutic agent.
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PMID:Anti-proliferative activity and mechanism of action of titanocene dichloride. 964 19

Current biocompatibility testing involves the demonstration of cell proliferation, which is usually interpreted as a sign of positive biocompatibility when the materials sustain cell proliferation. As the field of biomaterials research is rapidly moving toward tissue-engineered devices and hybrid organs, control of cell function has become a main topic. Cell function, which involves specific differentiation pathways, cannot be separated from cell-cycle control. The study of cell-cycle control is an important extension of routine proliferation assays and has extensive roots in developmental and tumor biology. We studied the expression of the tumour suppressor gene p53 and the proliferation-associated antigen Ki67 of endothelial cells in response to biomaterial contact. Cells were seeded in six- or 24-well plates, in which one or three 12-mm-diameter biomaterial disks were laid down. After 48- and 72-h incubation periods, cells were processed for flow cytometry, immunofluorescence, or Western blotting. The following materials were used: titanium, NiCr alloy, and CoCr alloy. Cells were also exposed to 24-h (ISO-norm) extracts in 25-cm(2) culture flasks (600, 000 cells) for 24 and 48 h. For extract testing, serially diluted Ni-ion suspensions were also used. Human umbilical vein endothelial cells adhered to metal surfaces and started forming a monolayer within 3 days. Ki67 expression was positive in more than 60% after 2 days and decreased markedly after 3 days of adhesion. During this time cells developed focal contacts and produced a fibronectin matrix. p53 expression could be demonstrated with Western blotting and flow cytometry, but not with immunofluorescence. Differences due to both culturing time and material were found in expression patterns with both methods. Inverse correlations between Ki67 and p53 expression were detected, which are probably based on culture kinetics. The results indicate that expression of p53 and also Ki67 is clearly influenced by biomaterials in direct contact testing, despite the absence of obvious morphological differences. The p53 marker can be used for defining cell function in more detail, although the correlation with specific physiological function has still to be clarified.
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PMID:Cell-cycle control in cell-biomaterial interactions: expression of p53 and Ki67 in human umbilical vein endothelial cells in direct contact and extract testing of biomaterials. 1090 93

The most frequent complication of total joint arthroplasty is periprosthetic osteolysis initiated by an inflammatory response to orthopaedic wear debris, which if left untreated, can result in implant instability and failure, eventually requiring revision surgery. We have previously reported that osteogenic differentiation of human marrow stroma-derived mesenchymal stem cells (hMSCs) is suppressed upon exposure to titanium particles, accompanied by reduced bone sialoprotein (BSP) gene expression, diminished production of collagen type I and BSP, decreased cellular viability and proliferation, and inhibition of extracellular matrix mineralization. In this study, we have further investigated hMSC cytotoxicity upon exposure to submicron particles of commercially pure titanium (cpTi) and zirconium oxide (ZrO(2)). Our results showed that direct exposure to cpTi and ZrO(2) particles compromises cell viability through the induction of apoptosis, eliciting increased levels of the tumor suppressor proteins p53 and p73, in a manner dependent on material composition, particle dosage, and time. Additionally, conditioned medium collected from hMSCs exposed to cpTi particles, but not to ZrO(2) particles, is cytotoxic to hMSCs, inducing apoptosis in the absence of particles. These findings demonstrate that exposure to orthopaedically derived wear particles can compromise hMSC viability through the direct and indirect induction of apoptosis. Thus, prolonged in vivo exposure of marrow-derived hMSCs to implant-derived wear debris is likely to reduce the population of viable osteoprogenitor cells, and may contribute to poor periprosthetic bone quality and implant loosening.
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PMID:Direct and indirect induction of apoptosis in human mesenchymal stem cells in response to titanium particles. 1279 71

UV irradiation can cause cutaneous damage that may be specific according to the wavelength of UV rays. For example, damage from UVB irradiation manifests itself in the form of sunburn cells and enhancement of the expression of p53, while damage from UVA exposure results in an increase in the expression of vimentin. These reactions to UV irradiation were used in this work to evaluate the photoprotective capacities of two sunblock preparations that were applied to the surface of the skin. One sunblock preparation is a UVB absorber containing zinc oxide (ZnO) and titanium oxide (TiO2) exclusively. The other sunblock preparation is a new organo-mineral sunblock containing Tinosorb M, OCM, ZnO and TiO2. Evaluation of the photoprotective capacities of both preparations on hairless rat skin and on in vitro reconstructed human epidermis revealed that they were effective in preventing UVB-induced damage. In contrast, only the organo-mineral sunblock was effective in the prevention of UVA-specific damage such as dermal alterations characterized by the expression of vimentin. Furthermore, our data support the fact that hairless rat skin and in vitro reconstructed human epidermis are a reliable basis for the evaluation of the photoprotective capacities of various sunscreens against UVB and UVA damage.
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PMID:Assessment of the skin photoprotective capacities of an organo-mineral broad-spectrum sunblock on two ex vivo skin models. 1453 95

Living-cell microarrays are powerful tools for functional genomics and drug discovery. However, despite several attempts to improve this technology, it is still a challenge to obtain microarrays of cells efficiently overexpressing or downregulating specific genes to address complex phenotypes. Here, we present a cell-based microarray for phenotype screening on primary and cancer cells based on the localized reverse infection by retroviruses. Viral vectors are immobilized on a nanostructured titanium dioxide (ns-TiO2) film obtained by depositing a supersonic beam of titania clusters on a glass substrate. We validated the retroviral cell array by overexpression of GFP reporter genes in primary and cancer cells, and by RNA interference of p53 in primary cells by analyzing effects in cell growth. We demonstrate that ns-TiO2 retroviral arrays are an enabling tool for the study of gene function of families of genes for complex phenotypes and for the identification of novel drug targets.
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PMID:Retroviral microarray-based platform on nanostructured TiO2 for functional genomics and drug discovery. 1727 6

In arthroplasty prostheses and dental implant, titanium is an excellent biocompatible material for its advanced physical qualities and better biocompatibility. However, it was reported that high ratios of titanium particles can be liberated due to the continual loading or articulation cycles of the implant. Because bone marrow stem cells (BMSCs) located adjacent to the implant are critical contributors to osseous tissue integrity, this study researched the influence of titanium particles on BMSCs' viability, proliferation, and cell skeleton. In addition, the phagocytosis of titanium particles by BMSCs and expression of tumor suppressor protein p53 were also examined. It was found that exposure of BMSCs to titanium particles disrupted their viability and proliferation in vitro, which may due to the phagocytosis of titanium particles by BMSCs. Moreover, cell skeleton was destroyed and the p53 protein level increased as the titanium particles were added. For these results, it was concluded that titanium particles had a cytotoxic effect on BMSCs in vitro and would inhibit the bone formation around the implant.
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PMID:The effect of titanium particles on rat bone marrow stem cells in vitro. 1987 81

To understand the underlying mechanism for apoptosis induced by titanium dioxide nanoparticles (TNP), human airway epithelial cell line was cultured to investigate the relevant apoptosis pathways. Our results showed that the levels of reactive oxygen species and morphological apoptosis increased in a dose-dependent manner whereas cell viability decreased in a similar manner in response to TNP exposure in the BEAS-2B cells. The activities of caspase 3 and PARP were also increased in parallel to the morphological apoptosis. Levels of caspase 9 increased significantly whereas there were no detectable changes in caspase 8 and t-Bid in the TNP treated cells. Caspase 9 inhibition blocked the TNP-induced activation of caspase 3 significantly. The levels of bax, cytochrome C, p53 and bcl-2 also changed reflecting the activation of intrinsic apoptosis pathway. Our results provide solid evidence that apoptosis in BEAS-2B cells exposed to TNP occurred via a mitochondrial apoptosis pathway independent of caspase 8/t-Bid pathway.
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PMID:Titanium dioxide nanoparticles cause apoptosis in BEAS-2B cells through the caspase 8/t-Bid-independent mitochondrial pathway. 2036 50

Despite that applications of titanium dioxide nanoparticles (TiO(2)-NPs) have been developed in the fields of paints, waste water treatment, sterilization, cosmetics, food additive, bio-medical ceramic and implant biomaterials and so on, relatively few studies have been conducted to determine the neurotoxicity of TiO(2)-NPs exposure. In the present study, we investigated the cytotoxicity of TiO(2)-NPs using PC12 cells and intended to clarify the molecular mechanisms underlying the biological effects of TiO(2)-NPs. PC12 cell is a type of cells, which have been used as an in vitro model of dopaminergic neurons for neurodegenerative diseases research. In addition, the roles of the particle size and crystal structure of TiO(2)-NPs to the neurotoxicity were also investigated. The anatase TiO(2)-NPs displayed a dose-dependent behavior on decreasing cell viability, increasing levels of lactate dehydrogenase (LDH), activating oxidative stress, inducing apoptosis, disturbing cell cycle, triggering JNK- and p53-mediated signaling pathway. In comparison to anatase TiO(2)-NPs, the rutile TiO(2)-NPs showed moderately toxic effect on neuron cells. The micron-sized TiO(2) did not exhibit any toxic response. It is suggested from our results that reactive oxygen species (ROS) have a mediation effect to oxidative stress and up-regulation of JNK and P53 phosphorylation involved in mechanistic pathways of TiO(2)-NPs can induce apoptosis and cell cycle arrest in PC12 cells. In addition, both the size and crystal structure of TiO(2)-NPs exposure contributed to the neurotoxicity. Nanoparticles were more toxic than micrometer-sized particles and the anatase form were more toxic than the rutile.
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PMID:Involvement of JNK and P53 activation in G2/M cell cycle arrest and apoptosis induced by titanium dioxide nanoparticles in neuron cells. 2169 33

A new sunscreen ingredient, methoxycinnamidopropyl polysilsesquioxane (MCP-PSQ), which contains an UV-absorbing p-methoxycinnamoyl group, has been developed synthetically and evaluated using in vitro and in vivo approaches. Previous studies revealed that MCP-PSQ has a raising or boosting effect on the sun protection factor (SPF) of other sunscreen agents. In this study, we demonstrated that MCP-PSQ, an organic/inorganic hybrid compound, has photoprotective effects for human fibroblasts, and for hairless mouse and human skin. MCP-PSQ increases cell viability and suppresses the expression of p53 protein in fibroblasts after UV exposure. In addition, the numbers of sunburn cells and mast cells are reduced by topical application of MCP-PSQ on hairless mouse skin after UV irradiation. A 10% MCP-PSQ cream has higher and similar effects on SPF values for human skin compared to 5% titanium dioxide (TiO(2)) and 5% ethylhexyl methoxycinnamate (EHMC), respectively. The SPF value obtained using the MCP-PSQ cream did not drop after UV irradiation of the cream itself. However, higher dose of UV irradiation is required to guarantee the stability or photostability of the formulation. Further, there were no side effects such as erythema, edema, itch or tingling, suggesting that MCP-PSQ is a good sunscreen agent.
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PMID:Photoprotective effects of methoxycinnamidopropyl polysilsesquioxane. 2153 75

We report on a 47-year-old woman in whom an anaplastic astrocytoma was resected in 2006. Postoperative radiation had to be interrupted because of a wound infection necessitating explantation of the infected bone flap and implantation of a titanium mesh. Subsequently, radiation therapy was completed and temozolomide was administered for 45 cycles. In the beginning of 2010 a new contrast enhancing mass was seen in the former tumor region. The mass was subtotally excised and showed no histomorphological similarity to the first lesion but represented a highly pleomorphic and mainly sarcomatoid differentiated malignant tumor. The lack of expression of GFAP or MAP-2 raised the question of a secondary malignancy, however, molecular genetic analysis of IDH1 and p53 revealed the same mutations in the anaplastic astrocytoma from 2006 as in the sarcomatoid tumor operated in 2010. Furthermore, accumulation of mutated IDH1 and TP53 protein could be demonstrated immunohistochemically. Thus, the second tumor represented the rare instance of recurrence of an anaplastic astrocytoma as a secondary gliosarcoma and a second malignant neoplasm was ruled out. The postoperative therapy and the inflammation might have contributed to the severe change in morphological phenotype of the glioma.
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PMID:Diagnostic utility of IDH1- and p53-mutation analysis in secondary gliosarcoma. 2195 26


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