Pathophysiological roles of aldo-keto reductases (AKR1C1 and AKR1C3) in development of cisplatin resistance in human colon cancers.

Cisplatin (cis-diamminedichloroplatinum, CDDP) is widely used for treatment of patients with solid tumors formed in various organs including the lung, prostate and cervix, but is much less sensitive in colon and breast cancers. One major factor implicated in the ineffectiveness has been suggested to be acquisition of the CDDP resistance. Here, we established the CDDP-resistant phenotypes of human colon HCT15 cells by continuously exposing them to incremental concentrations of the drug, and monitored expressions of aldo-keto reductases (AKRs) 1A1, 1B1, 1B10, 1C1, 1C2 and 1C3. Among the six AKRs, AKR1C1 and AKR1C3 are highly induced with the CDDP resistance. The resistance lowered the sensitivity toward cellular damages evoked by oxidative stress-derived aldehydes, 4-hydroxy-2-nonenal and 4-oxo-2-nonenal that are detoxified by AKR1C1 and AKR1C3. Overexpression of AKR1C1 or AKR1C3 in the parental HCT15 cells mitigated the cytotoxicity of the aldehydes and CDDP. Knockdown of both AKR1C1 and AKR1C3 in the resistant cells or treatment of the cells with specific inhibitors of the AKRs increased the sensitivity to CDDP toxicity. Thus, the two AKRs participate in the mechanism underlying the CDDP resistance probably via detoxification of the aldehydes resulting from enhanced oxidative stress. The resistant cells also showed an enhancement in proteolytic activity of proteasome accompanied by overexpression of its catalytic subunits (PSMß9 and PSMß10). Pretreatment of the resistant cells with a potent proteasome inhibitor Z-Leu-Leu-Leu-al augmented the CDDP sensitization elicited by the AKR inhibitors. Additionally, the treatment of the cells with Z-Leu-Leu-Leu-al and the AKR inhibitors induced the expressions of the two AKRs and proteasome subunits. Collectively, these results suggest the involvement of up-regulated AKR1C1, AKR1C3 and proteasome in CDDP resistance of colon cancers and support a chemotherapeutic role for their inhibitors.

Involvement of the aldo-keto reductase, AKR1B10, in mitomycin-c resistance through reactive oxygen species-dependent mechanisms.

The human aldo-keto reductase (AKR) 1B10 is suggested as a tumor marker in various solid tumors. Using colon cancer cells, we found that AKR1B10 was induced with acquisition of resistance to the anticancer drug mitomycin-c (MMC). In the resistant cells, treatment with an AKR1B10 inhibitor decreased their MMC tolerance. In the nonresistant cells, overexpression and silencing of AKR1B10 decreased and increased, respectively, susceptibility to cytotoxic effects of MMC and 4-hydroxy-2-nonenal, which was formed as a product of lipid peroxidation by MMC treatment. These results suggest a role of AKR1B10 in the development of MMC resistance, which may be mediated by its ability to detoxify cytotoxic aldehydes including 4-hydroxy-2-nonenal.

Plaque removal with an experimental chewable toothbrush and a control manual toothbrush in a care-dependent elderly population: a pilot study.

OBJECTIVE: Oral hygiene and oral health are major concerns for care-dependent elderly persons. The objective of this study was to examine the plaque removal efficacy of a novel experimental chewable toothbrush used by the subjects themselves. METHODOLOGY: Fourteen subjects whose oral care was usually provided by caregivers in nursing facilities were enrolled in a two-phase, crossover study. The study was designed to evaluate plaque removal following a single brushing with either an experimental chewable toothbrush used by the subjects themselves, or a control manual toothbrush used by caregivers on the subjects. Plaque removal was assessed according to the plaque index of Silness and Löe. RESULTS: The overall plaque scores were significantly reduced from 2.14 +/- 0.53 to 1.23 +/- 0.39 using the experimental brush, and from 2.08 +/- 0.43 to 1.22 +/- 0.17 using the control brush (p < 0.05). Relative plaque reduction was 41.0 +/- 17.6% for the experimental brush group and 38.8 +/- 16.6% for the control brush group, with no significant difference between the two brushes (p = 0.84). On lingual tooth surfaces, the experimental brush showed a plaque reduction of 68.8 +/- 13.7% compared to 38.4 +/- 22.9% with the control brush, and the difference was statistically significant (p = 0.011). The chewable toothbrushes were harmless and acceptable to the subjects. CONCLUSION: The experimental brush was able to remove a significant amount of plaque, particularly on the lingual surfaces, demonstrating its effectiveness for plaque removal when used by care-dependent elderly.

[Beta-lactamase activity and susceptibilities to antibiotics among some species of bacteria isolated from medical institution between December 1999 and February 2000].

We studied the beta-lactamase activity and susceptibilities to antibiotics in 604 strains among 10 species of bacteria isolated from 10 medical institutions in Tottori and Shimane Prefectures between December 1999 and February 2000. beta-Lactamase activity was measured by the nitrocefin test and penicillinase/cephalosporinase activities were measured by acidometry. beta-Lactamase activity was detected in 72.1% of S. aureus, 18.8% of H. influenzae, and 96.3% of M. catarrhalis. Penicillinase/cephalosporinase activities were detected in 17.8%/22.2% of E. coli, 9.7%/0.0% of K. pneumoniae, 18.6%/95.3% of E. cloacae, 12.7%/79.4% of S. marcescens, and 7.1%/31.8% of P. aeruginosa. Three of 72 strains (4.2%) of K. pneumoniae and 5 of 90 strains (5.6%) of E. coli were assessed as ESBL-producing bacteria using the NCCLS proposed screening method based on routine susceptibility testing results. BLNAR were detected in 13 of 69 strains (18.8%) of H. influenzae.