Here we report that K-Ras activated p38␥, a p38 MAPK family member, by inducing its expression without increasing its phosphorylation and that depletion of induced p38␥ suppressed Ras transformation in rat intestinal epithelial cells. This p38␥ activity contrasts with that of its family member, p38␣, which is activated by Ras through phosphorylation, leading to an inhibition of Ras transformation. Mechanistic analyses showed that unphosphorylated p38␥ may promote Ras transformation through an increased complex formation with ERK proteins. Significantly, functional p38␥ protein was expressed only in K-ras-mutated human colon cancer cells, and p38␥ transcripts were ubiquitously increased in a set of primary human colon cancer tissues. These studies thus demonstrate the essential role of p38␥ in K-Ras transformation independent of phosphorylation, and elevated p38␥ may serve as a novel diagnostic marker and therapeutic target for human colon cancer.
A dynamic cross-linked supramolecular network of poly(glycidyl methacrylate)s derivative chains was constructed on mesoporous silica nanoparticles via disulfide bond and ion-dipole interactions between cucurbit[7]urils and protonated diamines in the polymer chains. This kind of multifunctional organic-inorganic hybrid material with pH- and glutathione- (GSH-) stimuli responsiveness can be applied to anticancer drug delivery and controlled release. Good release performance toward doxorubicin hydrochloride (DOX) was achieved under the simulative tumor intracellular environment (pH = 5.0, CGSH = 2-10 mM). Significantly, the release amount of DOX increased upon lowering the solution pH value and increasing the concentration of GSH, as demonstrated by a series of controlled release experiments. Furthermore, the DOX-loaded hybrid nanomaterials displayed apparent cell-growth inhibition effects to cancer cell lines, as evidenced by MTT assay and confocal laser scanning microscopy.
Ras is believed to stimulate invasion and growth by different effector pathways, and yet, the existence of such effectors under physiologic conditions has not been shown. Estrogen receptor (ER), on the other hand, is both anti-invasive and proliferative in human breast cancer, with mechanisms for these paradoxical actions remaining largely unknown. Our previous work showed an essential role of p38; mitogenactivated protein kinase in Ras transformation in rat intestinal epithelial cells, and here, we show that p38; integrates invasive antagonism between Ras and ER to increase human breast cancer invasion without affecting their proliferative activity. Ras positively regulates p38; expression, and p38; in turn mediates Ras nonmitogenic signaling to increase invasion. Expression of the Ras/p38; axis, however, is trans-suppressed by ER that inhibits invasion and stimulates growth also by distinct mechanisms. Analysis of ER and its cytoplasmic localized mutant reveals that ER additionally binds to p38; protein, leading to its specific down-regulation in the nuclear compartment. A p38;-antagonistic activity of ER was further shown in a panel of breast cancer cell lines and was shown independent of estrogens by both ER depletion and ER expression. These results revealed that both Ras and ER use distinct pathways to regulate breast cancer growth and invasion, and that p38; specifically integrates their antagonistic activity to stimulate cell invasion. Selective targeting of p38;-dependent invasion pathways may be a novel strategy to control breast cancer progression. (Cancer Res 2006; 66(15): 7540-7)
Human chromosome ends are protected with kilobases repeats of TTAGGG. Telomere DNA shortens at replication. This shortening in most tumor cells is compensated by telomerase that adds telomere repeats to the 3′ end of the G-rich telomere strand. Four TTAGGG repeats can fold into G-quadruplex that is a poor substrate for telomerase. This property has been suggested to regulate telomerase activity in vivo and telomerase inhibition via G-quadruplex stabilization is considered a therapeutic strategy against cancer. Theoretically G-quadruplex can form anywhere along the long G-rich strand. Where G-quadruplex forms determines whether the 3′ telomere end is accessible to telomerase and may have implications in other functions telomere plays. We investigated G-quadruplex formation at different positions by DMS footprinting and exonuclease hydrolysis. We show that G-quadruplex preferentially forms at the very 3′ end than at internal positions. This property provides a molecular basis for telomerase inhibition by G-quadruplex formation. Moreover, it may also regulate those processes that depend on the structure of the very 3′ telomere end, for instance, the alternative lengthening of telomere mechanism, telomere T-loop formation, telomere end protection and the replication of bulky telomere DNA. Therefore, targeting telomere G-quadruplex may influence more telomere functions than simply inhibiting telomerase.
ABSTRACT:Clivorine, a naturally occurring pyrrolizidine alkaloid, causes liver toxicity via its metabolic activation to generate toxic metabolite (pyrrolic ester). Female Sprague-Dawley (SD) rats are reported to be less susceptible to clivorine intoxication than male SD rats. However, the biochemical mechanism causing such gender difference is largely unknown. The present study investigated hepatic microsomal metabolism of clivorine in female rats to delineate the mechanism of the gender difference. Two pathways, which directly metabolize clivorine, were observed. First, the metabolic activation to produce the toxic pyrrolic ester followed by formations of bound pyrroles, dehydroretronecine, 7-glutathionyldehydroretronecine, and clivoric acid were found in female rats, and CYP3A1/2 isozymes were identified to catalyze the metabolic activation. Compared with male rats (ϳ21%), the metabolic activation in female rats was significantly lower (ϳ4%) possibly because of significantly lower CYP3A1/2 levels expressed in female rats. Second, a direct hydrolysis to generate the novel female rat-specific metabolite deacetylclivorine was shown as the predominant pathway (ϳ16% clivorine metabolism) in female rat liver microsomes and was determined to be mediated by microsomal hydrolase A. Furthermore, when the metabolic activation was completely inhibited by ketoconazole, the amount of deacetylclivorine formed in a 1-h incubation significantly increased from 19.44 ؎ 3.00 to 54.87 ؎ 9.30 nmol/mg protein, suggesting that the two pathways compete with each other. Therefore, the lower susceptibility of female SD rats to clivorine intoxication is suggested to be caused by the significantly higher extent of the direct hydrolysis and a lower degree of the metabolic activation.Pyrrolizidine alkaloid (PA) poisoning has drawn worldwide attention because of a wide distribution of PA-containing plants and their induced serious and diversified toxicities, especially hepatotoxicity and carcinogenicity (Mattocks, 1968;Mori et al., 1985;Huxtable, 1989;Buhler et al., 1990;Fu et al., 2002Fu et al., , 2004, as well as pneumotoxicity (Huxtable, 1990;Taylor et al., 1997), neurotoxicity (Roeder, 2000), and embryotoxicity (Tu et al., 1988). Two types of PA, namely, retronecine and otonecine, are mainly responsible for the PA-induced hepatotoxicity (Mori et al., 1985;Huxtable, 1989;Buhler et al., 1990;Fu et al., 2004). Clivorine, a representative toxic otonecine-type PA, is present in many Ligularia species and especially exists as a predominant PA in the traditional Chinese medicinal herb Ligularia hodgsonii Hook (Lin et al., 2000b;Xia et al., 2004). Clivorine has been reported to cause hepatotoxicity and carcinogenicity in rodents and a positive mutagenic response in the Ames test in the presence of rat liver homogenates, suggesting the importance of hepatic metabolic activation in its intoxication (Yamanaka et al., 1979;Kuhara et al., 1980;Xia et al., 2004). In our previous studies, hepatic microsomal metabolism of clivorine in male Sprague-Dawle...
luminogens with aggregation-induced emission (AIE) properties, referred to as AIEgens, first discovered by Tang and coworkers in 2001, exhibit enhanced emission in the aggregated state, [1] leading to the rapid development of AIE materials with diverse applications in ion detection, [2] explosive sensors, [3] cell imaging, [4] photodynamic therapy, [5] optoelectronic systems, [6] and light-harvesting systems. [7] A seminal approach to fabricate smart luminescent materials is the manipulation of AIEgens with supramolecular macrocycle-based host-guest chemistry, which could induce remarkable enhancement of fluorescence intensity of materials due to the host-guest interactions between macrocycles and AIEgens that restrict the intramolecular rotation of luminophores.[8] Pillar[n]arenes, as a new generation of synthetic macrocyclic hosts first reported by Ogoshi et al. in 2008, have proved captivating advantages including symmetrical and rigid structure, versatile functionality, [9] and good solubility. [10] Among the members of the pillar[n]arene family, pillar[5]arene and its derivatives, in which 1,4-disubstituted hydroquinones are connected by five methylene units in the 2,5-positions, exhibit the advantages of: 1) desirable host candidate to bind neutral molecules in organic solvents due to the electron-rich cavity; [11] 2) high yielding in the preparation process for further functionalization; [12] and 3) rigid structure donated stiff component in the fabrication of functional materials, and have showed great potential in sensors, [13] biomedical field, [14] catalysts, [15] separation and storage, [16] supramolecular gels, [17] and light-harvesting systems. [18] For instance, Huang and co-workers constructed an elegant host-guest inclusion complex from water-soluble pillar[6]arene and a tetraphenylethene (TPE) derivative that exhibited strong fluorescence in dilute solution. [19] Interestingly, fluorescent supramolecular assemblies that possess stimuli-responsive properties and dynamic features have been fabricated from AIEgen-containing building blocks, in particular with the aid of supramolecular macrocycles, such as crown ethers, [20] calix[n]arenes, [21] cyclodextrins, [22] cucurbit[n] urils, [23] and pillar[n]arenes, [21,24] instead of simple addition of poor solvents to induce the formation of disorganized aggregates. However, research on the cooperative manipulation of AIE by a polymer host material that contains many synthetic macrocycles installed on one single polymer chain has rarely Linear copolymer hosts bearing a number of pillar[5]arene dangling side chains are synthesized for the facile construction of highly emissive supramolecular polymer networks (SPNs) upon noncovalently cross-linking with a series of tetraphenyethylene (TPE)-based tetratopic guests terminated with different functional groups through supramolecular host-guest interactions. An extremely high fluorescence quantum yield (98.22%) of the SPNs materials is obtained in tetrahydrofuran (THF) by fine-tuning the parameters...
Activated hepatic stellate cells (HSC) are the primary source of excessive production of extracellular matrix during liver fibrogenesis. Although the underlying mechanisms remain incompletely understood, it is widely accepted that oxidative stress plays a critical role in liver fibrogenesis. Suppression of HSC growth and activation, as well as induction of apoptosis, have been proposed as therapeutic strategies for treatment and prevention of this disease. In the present report, we elucidated, for the first time, effects of the antioxidant (-)-epigallocatechin-3-gallate (EGCG), a major (and the most active) component of green tea extracts, on cultured HSC growth and activation. Our results revealed that EGCG significantly inhibited cultured HSC growth by inducing cell cycle arrest and apoptosis in a dose- and time-dependent manner. In addition, EGCG markedly suppressed the activation of cultured HSC as demonstrated by blocking transforming growth factor-beta signal transduction and by inhibiting the expression of alpha1(I) collagen, fibronectin and alpha-smooth muscle actin genes induced by acetaldehyde, the most active metabolite of ethanol. Furthermore, EGCG reacted differently in the inhibition of nuclear factor-kappaB activity between cultured HSC with or without acetaldehyde stimulation. Taken together, our results indicated that EGCG was a novel and effective inhibitor for activated HSC growth and activation in vitro. Further studies are necessary to evaluate the effect of this polyphenol in prevention of quiescent HSC activation in vivo, and to further elucidate the underlying mechanisms.
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