Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The silicon phthalocyanine HOSiPcOSi(CH3)2(CH2)3 N(CH3)2 (Pc 4), is being studied as a photosensitizer for virus inactivation in red blood cell concentrates (RBCC). The RBCC spiked with cell-free human immunodeficiency virus (HIV) or with HIV actively replicating in the T-lymphocytic cell line CEM can be successfully inactivated (> or = 6 log10) when exposed to 2 microM Pc 4 and 90 J/cm2 red light (600-800 nm). Inactivation of > or = 6 log10 inducible HIV in the latently infected promonocytic cell line U1 occurred at 22.5 J/cm2 (H. Margolis-Nunno et al., Transfusion 36, 743-750, 1996). In order to understand the reason for the increased susceptibility of U1 to photosensitized inactivation we looked for induction of apoptosis by photodynamic treatment (PDT). Agarose gel electrophoresis was used to observe the appearance of a characteristic 180-200 base pair DNA ladder, which can indicate apoptosis. Using this assay it is shown that Pc 4 treatment induced apoptosis in U1 cells in a light dose-dependent manner, starting 30 min after light exposure. Using the ApopTag Plus kit (which attaches a fluorescent label to the 3'-OH ends of the degraded DNA) and flow cytometry, the percentage of cells undergoing apoptosis was quantitated. At 10.5 J/cm2, 3 h after light exposure, about 92.5% of the cells were apoptotic. Under these conditions 99% of the cells eventually die. The CEM cells similarly treated underwent apoptosis at slower kinetics and required higher light doses. Other cell lines latently infected with HIV (ACH-2 and OM 10.1) were as sensitive as U1 to HIV inactivation by Pc 4-PDT (H. Margolis-Nunno et al., Transfusion 36, 743-750, 1996) and underwent apoptosis at a similar kinetic. These results suggest that the enhanced inactivation of HIV in latently infected cells compared to CEM cells by Pc 4-PDT may be due, at least in part, to apoptosis in the former.
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PMID:Silicon phthalocyanine Pc 4 and red light causes apoptosis in HIV-infected cells. 907 31

Implantable biomaterials often trigger a variety of adverse responses. Because polydimethyl siloxane surfaces have good hemo- and bio-compatibility, it is generally believed that surface biocompatibility may be improved by modifying biomaterial surfaces with silicone-like properties. For this, we developed a series of polycaprolactone-polydimethylsiloxane-polycaprolactone (PDMS-PCL) copolymers. By mixing the substrate material--polyvinyl chloride--with low concentrations (1.2 and 2.4%) of the PDMS-PCL copolymer, we generated materials with silicone-like surface properties as reflected by increased surface silicon content and surface contact angles. We assessed the biocompatibility of these surfaces in vitro and found that the addition of PDMS-PCL significantly reduced the percentages of surface-'denatured' fibrinogen, a critical element of genesis of many adverse responses to implanted biomaterials. Indeed, using an animal implantation model, we find that PDMS-PCL-blended materials triggered significantly weaker inflammatory responses than did polyvinyl chloride, the substrate control. The results from these experiments suggest that the use of PDMS-PCL additives (2.4%) in polymer blends is a useful means of camouflaging the substrate surface properties and improving the biocompatibility of biomaterials.
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PMID:Anti-inflammatory properties of triblock siloxane copolymer-blended materials. 1045 7

Exposure to silica has been associated with progressive pulmonary inflammation and fibrosis. While the fibroblasts play an important role in the pathogenesis of silicosis, the direct interaction between silica and fibroblasts is poorly understood. We observed that silica particles stimulated intracellular ROS generation in Rat2 fibroblast, evidenced by DCFH oxidation. Silica-induced DCFH oxidation was inhibited by catalase and DPI, a flavoenzyme inhibitor. Additionally, the time course of elevation of the intracellular ROS was paralleled by the increases of MEK and ERK phosphorylation. Silica-induced ERK phosphorylation was also effectively attenuated by catalase and DPI. However, SOD enhanced the silica-induced ERK phosphorylation, indicating a role for H(2)O(2) in ERK activation. Furthermore, ERK and MEK phosphorylation are reproduced by H(2)O(2) treatment. Taken together, these results demonstrate that silica stimulates ROS production via flavoenzyme-dependent mechanism in Rat2 fibroblasts and the H(2)O(2), in turn, serves as a signal transduction element in activating MEK-ERK pathway.
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PMID:Silica-induced generation of reactive oxygen species in Rat2 fibroblast: role in activation of mitogen-activated protein kinase. 1047 90

PDT, a new therapeutic procedure for the management of many malignant conditions including skin cancer, involves the administration of a photosensitizing compound followed by illumination of the lesion with visible light. We earlier showed an involvement of: (i) WAF1/p21-cyclins (D1 and E)-cdk (2 and 6) network; and (ii) Rb/E2F-DP machinery during silicon phthalocyanine (Pc4)-PDT-mediated cell cycle dysregulation and apoptosis of human epidermoid carcinoma (A431) cells. Here, we investigated the involvement of EGFR-pathway during antiproliferative responses of Pc4-PDT in A431 cells and during ablation of murine skin papillomas. Pc4-PDT of A431 cells was found to result in a time-dependent down-modulation of the protein expression and phosphorylation of EGFR and Shc (an immediate downstream molecule in EGFR-pathway), during progressive increase in apoptotic response. To establish the relevance of these in vitro findings to in vivo situations, we subjected chemically- as well as ultraviolet B radiation-induced squamous papillomas in SENCAR and SKH-1 hairless mice, respectively, to Pc4-PDT, and assessed its effect on EGFR-pathway during ablation of these tumors. Pc4-PDT was found to result in a time-dependent: (i) inhibition of protein expressions of EGFR; and (ii) tyrosine phosphorylation of EGFR and Shc; and (iii) induction of apoptosis, during the regression of these tumors. These data suggest the involvement of EGFR-pathway during the antiproliferative effects of PDT. It is tempting to speculate that inhibitors of EGFR could enhance the therapeutic efficacy of PDT.
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PMID:In vitro and in vivo inhibition of epidermal growth factor receptor-tyrosine kinase pathway by photodynamic therapy. 1140 26

Mechanical stretch has been implicated in phenotypic changes as an adaptive response to stretch stress physically loaded in bladder smooth muscle cells (BSMCs). To investigate stretch-induced signaling, we examined the mitogen-activated protein kinase (MAPK) family using rat primary BSMCs. When BSMCs were subjected to sustained mechanical stretch using collagen-coated silicon membranes, activation of c-Jun NH(2)-terminal kinase (JNK) was most relevant among three subsets of MAPK family members: the activity was elevated from 5 min after stretch and peaked at 10 min with an 11-fold increase. Activation of p38 was weak compared with that of JNK, and ERK was not activated at all. JNK activation by mechanical stretch was totally dependent on extracellular Ca(2+) and inhibited by Gd(3+), a blocker of stretch-activated (SA) ion channels. Nifedipine and verapamil, inhibitors for voltage-dependent Ca(2+) channels, had no effect on this JNK activation. Moreover, none of the inhibitors pertussis toxin, genistein, wortmannin, or calphostin C affected stretch-induced JNK activation, indicating that G protein-coupled and tyrosine kinase receptors are unlikely to be involved in this JNK activation. On the other hand, W-7, a calmodulin inhibitor, and cyclosporin A, a calcineurin inhibitor, prevented JNK activation by stretch. These results suggest a novel pathway for stretch-induced activation of JNK in BSMCs: mechanical stretch evokes Ca(2+) influx via Gd(3+)-sensitive SA Ca(2+) channels, resulting in JNK activation under regulation in part by calmodulin and calcineurin.
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PMID:Essential role for extracellular Ca(2+) in JNK activation by mechanical stretch in bladder smooth muscle cells. 1154 52

The present study examined the effect of ambroxol on free radical production, granule enzyme release, and cell death in silica-activated rat alveolar macrophages. The action of ambroxol was assayed by measuring changes in the activities of protein kinase C (PKC) and tyrosine kinase (PTK) and in the intracellular calcium level. Ambroxol attenuated the production of superoxide, hydrogen peroxide, and nitric oxide and the release of acid phosphatase and lysozyme in macrophages activated by silica. Staurosporine, genistein, EGTA, and trifluoperazine inhibited the silica-induced free radical production and granule enzyme release. Silica induced the increase in PKC and PTK activities and the elevation of intracellular calcium level in macrophages, which was decreased by ambroxol. Silica induced a cell death and increased the caspase-3 activity in macrophages in a concentration-dependent manner. Ambroxol decreased the silica-induced cell viability loss in macrophages. The results show that ambroxol decreases the stimulated responses and cell death in rat alveolar macrophages exposed to silica, which may be accomplished by inhibition of activation processes, protein kinases, and calcium transport. The inhibitory effect of ambroxol on silica-induced cell death appears to provide the protective effect on pulmonary tissues against the toxic action of silica.
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PMID:Depressant effect of ambroxol on stimulated functional responses and cell death in rat alveolar macrophages exposed to silica in vitro. 1180 26

New injectable and implantable contraceptives that provide a slow, steady dose of hormone over long periods of time promise convenient, trouble-free contraception not related to intercourse. Like oral progestagen-only contraceptives, they prevent fertilization by impeding sperm penetration through the cervical mucus, and, also like oral progestagens, their major side effects are menstrual disorders. Injectable contraceptives have the advantage that they can be administered by trained health workers and the disadvantage that they cannot be removed. New 90-day injectables that do not release initial high levels of progestagens are being developed. Family Health International is conducting Phase III clinical trials of the NET 90-day injectable, which releases .66 mg progestagen a day. Other 90-day injectables include a levonorgestrel and a progesterone injectable being developed by Stolle, a norgestimate injectable being tested by Ortho Pharmaceutical, and steroid ester injectables being developed by the World Health Organization and the US National Institute of Child Health and Human Development. Combined estrogen-progesterone monthly injectables are used by millions of women in Mexico, Latin America, and China; and 2 monthly combined injectables, HRP112 and HRP102, are being tested by the World Health Organization. 2 injectables, Upjohn's Depo-Provera and Schering's Noristerat, have been available for over a decade. Both are extremely effective, with pregnancy rates of less than 2/100 woman-years of use. Depo-Provera has been approved for use in the UK and West Germany but not in the US, due to the development of breast and endometrial tumors in experimental animals. The longest acting steroid contraceptives are the implantables. Family Health International is conducting Phase III clinical trials of the biodegradable NET pellets, containing 85% norethindrone and 15% cholesterol, developed by Endocon, Inc. Capronor, a biodegradable capsule containing levonorgestrel, developed by the Research Triangle Institute, is currently being tested in animals. The Population Council's Norplant consists of 36 mg levonorgestrel in 6 silicon elastomer capsules, which are not biodegradable. Norplant is effective for 5 years, after which the capsules must be removed. Norplant is highly effective, with a pregnancy rate of less than 1/100 woman-years of use. Its advantages are the lack of estrogen-related side effects and a swift return to fertility. Disadvantages are a higher initial cost and the need for insertion and removal by trained personnel.
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PMID:Long-acting steroids provide new options. 1231 56

Macrophages play a fundamental role in silicosis in part by removing silica particles and producing inflammatory mediators in response to silica. Tumor necrosis factor alpha (TNFalpha) is a prominent mediator in silicosis. Silica induction of apoptosis in macrophages might be mediated by TNFalpha. However, TNFalpha also activates signal transduction pathways (NF-kappaB and AP-1) that rescue cells from apoptosis. Therefore, we studied the TNFalpha-mediated mechanisms that confer macrophage protection against the pro-apoptotic effects of silica. We will show that exposure to silica induced TNFalpha production by RAW 264.7 cells, but not by IC-21. Silica-induced activation of NF-kappaB and AP-1 was only observed in RAW 264.7 macrophages. ERK activation in response to silica exposure was only observed in RAW 264.7 macrophages, whereas activation of p38 phosphorylation was predominantly observed in IC-21 macrophages. No changes in JNK activity were observed in either cell line in response to silica exposure. Silica induced apoptosis in both macrophage cell lines, but the induction of apoptosis was significantly larger in IC-21 cells. Protection against apoptosis in RAW 264.7 cells in response to silica was mediated by enhanced NF-kappaB activation and ERK-mediated phosphorylation of the p55 TNFalpha receptor. Inhibition of these two protective mechanisms by specific pharmacological inhibitors or transfection of dominant negative mutants that inhibit IkappaBalpha or ERK phosphorylation significantly increased silica-induced apoptosis in RAW 264.7 macrophages. These data suggest that NF-kappaB activation and ERK-mediated phosphorylation of the p55 TNF receptor are important cell survival mechanisms in the macrophage response to silica exposure.
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PMID:Phosphorylation of tumor necrosis factor receptor 1 (p55) protects macrophages from silica-induced apoptosis. 1457 Aug 68

A series of sorbitol-containing polyesters were synthesized via a one-pot lipase-catalyzed condensation polymerization. Thin films were prepared by spin coating on silicon wafers and surfaces were analyzed by tapping mode atomic force microscopy and contact angle measurements. Surface morphologies and surface energies across the series of polyester films, including a poly(epsilon-caprolactone) (PCL) control were nearly indistinguishable. Biocompatibility of the sorbitol-containing polyester series was evaluated against a PCL control by measuring cell spreading and proliferation of a mouse fibroblast 3T3 cell line in vitro. Results confirmed that the sorbitol-containing polyester surfaces elicited cell behavior similar to the PCL control. These results establish the sorbitol-containing polyester series as a promising material for tissue engineering research and development.
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PMID:Biocompatibility of sorbitol-containing polyesters. Part I: Synthesis, surface analysis and cell response in vitro. 1504 9

Static secondary ion mass spectrometry (S-SIMS) emerges as one of the most adequate methods for the surface characterisation of polymers with an information depth of essentially one monolayer. The continuing search for increased analytical sensitivity and specificity has led to exploring the use of polyatomic primary ions as an alternative to the traditionally applied monoatomic projectiles. As part of a systematic investigation on polyatomic bombardment of organic and inorganic solids, this paper focuses on selected polyesters. Mass spectra and ion yields are compared for layers deposited on silicon wafers by spincoating solutions with different concentrations of poly(epsilon-caprolactone) (PCL), poly(butylene adipate) (PBA) and poly(ethylene adipate) (PEA). Accurate mass measurements have been used to support the assignment of the ions and link the composition of the detected ions to the analyte structure. Use of polyatomic projectiles increases the yield of structural ions with a factor of +/-15, +/-30 and +/-10 for PCL, PBA and PEA, respectively, in comparison to bombardment with Ga+ primary ions, while the molecular specificity is improved by the detection of additional high m/z ions.
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PMID:Comparison of primary monoatomic with primary polyatomic ions for the characterisation of polyesters with static secondary ion mass spectrometry. 1566 15


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