Cellular proliferation, poly

Figure 3. Proposed pleiotropic functions carried out by nuclear ADP-ribosylation reactions. Events such as cellular proliferation, differentiation, transformation, and DNA damage caused by external agents (e.g., ionizing radiation, drugs) involve changes in the integrity of DNA and/or chromatin architecture (a) which activate the poly(ADP-ribose) polymerase to catalyze the ADP-ribosylation of nuclear proteins predominantly at the expense of cytoplasmic NAD (b). The consequences of protein ADP-ribosylation are a decrease in cellular NAD content, alterations in chromatin structure, and possibly also the activity of various enzymes involved in chromatin function (c). This tripartite system operates, either wholly or partly, to ameliorate the activation of the polymerase by modulating the repair of DNA strand breaks, thereby affecting those processes which initially triggered the activation of the enzyme (d). Pr, protein NAm, nicotinamide (ADPR) , poly(ADP-ribose). (From Gaal and Pearson, 1986).

Since the discovery of poly(ADP-ribose) synthetase and its role in cellular NAD turnover there has been a great deal of speculation concerning the physiological function of this enzyme and the polymer it synthesizes. The observation that the poly(ADP-ribose) synthetase is responsible for modification of chromatin-associated proteins led to the suggestion of its involvement in regulation of nuclear metabolism. Correlations between synthesis of poly(ADP-ribose) and DNA repair, cellular differentiation, DNA synthesis, and cellular proliferation have been noted. In most of these instances, however, when one set of data... 

Poly(ADP-ribose) polymerase, a chromatin-bound enzyme, catalyzes postsynthetic modifications of various nuclear proteins through the covalent attachment of ADP-ribose units at the expense of the cellular NAD pool [1-3]. Poly(ADP-ribosylation) appears to be involved in DNA excision repair, cellular proliferation, and differentiation [1-3] and has been shown to induce architectural changes in chromatin [4-6]. 

The biocompatibility and cytotoxicity of alternating poly(ester amide)s (Fig. 5.2(a)) has been tested. Cellular proliferation is observed on the poly(ester amide)s material surface when seeded with mouse fibroblasts (Paredes et al, 1998a). No cytotoxic responses were detected, in either assay, after a 24 and 48 h incubation period with the cells, but the cytotoxic response increased after 72 h of incubation. 

Jeong and coworkers have reported peptide-based thermo-gelling systems using PEG-b-polyAla as an injectable cellular scaffold [315]. The polymer aqueous solution undergoes sol-gel transition as temperature increases. The fraction of the p-sheet structure of the poly Ala dictated the population and thickness of fibrous nanostructure in the hydrogel, which affected the proliferation and protein... 

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

To mimic the macromolecular-based ECM in biological tissue, the cell adhesion and proliferation properties of hydrogels are critical parameters. However, various hydrogels that originate from natural resources, such as alginate [87], chitosan [88, 89], and hyaluronic acid [90], and that are synthetically created, such as poly (7V-isopropylacrylamide) (PNIPAAm) [91], PEO [92], PVA [93], and poly(ethylene glycol) (PEG) [94], show a poor cellular viability without modification with cell adhesive proteins or peptides, such as collagen, laminin, fibronectin, and the RGD (Arg-Gly-Asp) sequence. 

Some researchers compared the behavior of stem cells on chitosan and other polymer substrates. It was found that the proliferation and differentiation of NSCs were inhibited on both chitosan and poly(vinylidenefluoride) (PVDF) membranes at a single-cell level [157]. However, in the form of neurospheres, the migration of NSCs was better promoted on the chitosan membranes in a serum-free environment. Similarly, in a study dealing with the effect of chitosan and collagen membranes on NSCs, the cellular responses were dependent on the presence or absence of serum in the culture medium [158]. Moreover, the chitosan/collagen hybrid membrane exhibited better ability to facilitate NSC migration from neurospheres and differentiation into neurons. 

An alternative explanation for the accumulation of DNA strand breaks with increasing time of incubation with MBA and the continued effects of MBA at times well after the minimum number of strand breaks was attained at 2 h of culture, would be a nonspecific effect of the inhibitor on DNA synthesis rather than that on ADP-ribosylation-mediated repair. One such possibiUty consistent with the data of Fig. 1, would be that MBA was itself directly or indirectly introducing breaks into the DNA. This hypothesis was excluded by experiments in which the effect of MBA was measured in cultures in which ADP-ribosylation had already been maximally inhibited by alternative inhibitors such as 3-aminobenzamide or high concentrations of nicotinamide, or heat shock [11] (data not shown). No additional breaks were introduced by MBA under these conditions. Furthermore, there was no effect of MBA on cellular levels of purine or pyrimidine nucleotides, and MBA treatment resulted in only 4% cell death. Table 2 shows that the inhibitory effects of MBA on ADP-ribosylation, and on cell proliferation were completely reversible. In addition, the data in Table 3 show a direct proportionality between concentration of MBA on the one hand and inhibition of ADP-ribosylation in permeabilized cells, increased number of DNA strand breaks and decreased cell proliferation at 48 h on the other hand. This, and the data cited above, permit us to conclude that MBA acts on this system by inhibiting the poly(ADP-ribosylation) reaction,... 

In a reported in vitro study of blood and cellular response to saturated AA-PEAs, the proliferation of endothelial cells adhered to SPEA substrates was much higher than on nonbiodegradable polymers like poly(n-butyl methacrylate) or polyethylene vinyl acetate copolymer (DeHfe et a/., 2005). 

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