[show abstract][hide abstract] ABSTRACT: We examined anti-tumor effects of zoledronic acid (ZOL), one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP), one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.
PLoS ONE 01/2013; 8(3):e60297. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Escherichia coli has three major K(+) uptake systems, Trk, Kup, and Kdp, which have been studied extensively at near neutral pH. However, the function of these transporters under acidic conditions is not well understood, although growth and survival under acidic conditions are important for bacterial pathogenesis. In this study, we examined the expression and activity of Kdp under acidic conditions and found that the transport activity of Kdp is decreased at low pH and that the expression of kdp is regulated by the internal K(+) concentration in a pH-independent manner. Consequently, the low activity of Kdp was compensated for by the induction of its elevated expression by low K(+) accumulation via Kdp at acidic pH.
[show abstract][hide abstract] ABSTRACT: The first enantioselective total synthesis of tangutorine has been achieved, wherein a Pd-catalyzed asymmetric allylic amination using a chiral diaminophosphine oxide (DIAPHOX) preligand was the key step.
[show abstract][hide abstract] ABSTRACT: In solid tumor and inflammation loci, low pH conditions have been observed as a consequence of either a lack of sufficient vascularization or excess activity of tumor cells, and T cells have been reported to infiltrate tumors and inflammation sites. However, it remains unclear how extracellular acidic environments affect immune cell function. A previous report proposed that a different signal transduction cascade might occur under low pH conditions in Jurkat T cells (Fukamachi T, Saito H, Kakegawa T, Kobayashi H. Different proteins are phosphorylated under acidic environments in Jurkat cells. Immunol Lett 2002;82:155-8). In this study, we investigated the protein phosphotyrosine level in Jurkat and Jurkat mutant cells under different pH conditions. The ZAP-70 phosphorylation level increased under acidic environments. P38 MAPK was more activated at acidic pH. The level of active p38 was low in mutant P116 deficient in ZAP-70, and interestingly the level remained consistently low at all pH values tested. The activation of ERK was not stimulated at low pH. These results suggest that extracellular low pH stimulates or enhances TCR signaling via ZAP-70 and p38.
[show abstract][hide abstract] ABSTRACT: The activity of the membrane-bound H+-ATPase of the beer spoilage bacterium Lactobacillus brevis ABBC45 increased upon adaptation to bacteriostatic hop compounds. The ATPase activity was optimal around pH 5.6 and increased up to fourfold when L. brevis was exposed to 666 microM hop compounds. The extent of activation depended on the concentration of hop compounds and was maximal at the highest concentration tested. The ATPase activity was strongly inhibited by N,N'-dicyclohexylcarbodiimide, a known inhibitor of FoF1-ATPase. Western blots of membrane proteins of L. brevis with antisera raised against the alpha- and beta-subunits of FoF1-ATPase from Enterococcus hirae showed that there was increased expression of the ATPase after hop adaptation. The expression levels, as well as the ATPase activity, decreased to the initial nonadapted levels when the hop-adapted cells were cultured further without hop compounds. These observations strongly indicate that proton pumping by the membrane-bound ATPase contributes considerably to the resistance of L. brevis to hop compounds.
Applied and Environmental Microbiology 12/2002; 68(11):5374-8. · 3.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: In order to test the ability of immune cells to grow under acidic conditions, Jurkat cells were cultured in medium at pH 6.3. At this acidic pH, the cells required approximately 2 days per generation, while the generation time was approximately 1 day for cells grown in near neutral medium. Western blot analysis using anti-phosphotyrosine antibody (4G10) showed that protein phosphorylation was affected by external pH. For example, the level of a 66-kDa phosphoprotein increased dramatically in acidic medium, whereas the amount of a 34-kDa phosphoprotein decreased. These results suggest that Jurkat cells use different signal pathways under acidic environments.
[show abstract][hide abstract] ABSTRACT: Bacteria can inhabit a wide range of environmental conditions, including extremes in pH ranging from 1 to 11. The primary strategy employed by bacteria in acidic environments is to maintain a constant cytoplasmic pH value. However, many data demonstrate that bacteria can grow under conditions in which pH values are out of the range in which cytoplasmic pH is kept constant. Based on these observations, a novel notion was proposed that bacteria have strategies to survive even if the cytoplasm is acidified by low external pH. Under these conditions, bacteria are obliged to use acid-resistant systems, implying that multiple systems having the same physiological role are operating at different cytoplasmic pH values. If this is true, it is quite likely that bacteria have genes that are induced by environmental stimuli under different pH conditions. In fact, acid-inducible genes often respond to another factor(s) besides pH. Furthermore, distinct genes might be required for growth or survival at acid pH under different environmental conditions because functions of many systems are dependent on external conditions. Systems operating at acid pH have been described to date, but numerous genes remain to be identified that function to protect bacteria from an acid challenge. Identification and analysis of these genes is critical, not only to elucidate bacterial physiology, but also to increase the understanding of bacterial pathogenesis.
The Journal of General and Applied Microbiology 11/2000; 46(5):235-243. · 0.74 Impact Factor