Research communications in molecular pathology and pharmacology最新文献

Telomerase, a ribonucleoprotein, stabilizing chromosomes by adding telomeric repeats to their ends, is highly expressed in most neoplastic cells and has a critical role in cellular immortalization. In this study, telomerase activity was measured in the peripheral blood mononuclear cells of patients with non-Hodgkin lymphoma (NHL). A total of 18 patients with B-cell NHL and 12 healthy volunteers were included in the study. Of the patients 7 (38.9%) were found to have telomerase activity, but no activity was detected in control subjects. No correlation was found between the telomerase activity and the grade of the disease. When the patients were divided into two subgroups as follicular and non-follicular NHL, telomerase activity was detected in 5 of 10 follicular NHL (50%) and 2 of 8 non-follicular NHL (25%) samples, but these results were not found statistically significant. In conclusion, there is detectable telomerase activity in peripheral blood of some patients with NHL, possibly suggesting the existence of neoplastic cells in the circulation or activation of lymphocytes.

Possible effects of muscle stretch on the spontaneous rhythmic contractile activity and the extent of contribution of voltage-dependent and Ca2+ -activated K+ (BK(Ca)) channels were examined mechanically in guinea-pig urinary bladder smooth muscle (UBSM). The amplitude of the spontaneous mechanical activity showed stretch-dependency. Iberiotoxin, a selective blocker of BK(Ca) channels, potently increased contraction amplitude, and this effect was more prominent when muscle length was more than twice of its initial length. BK(Ca) channels seem activated more strongly to counteract enhanced spontaneous mechanical activity with UBSM stretch.

The presence of nausea and vomiting is problematic for all selective serotonin re-uptake inhibitors (SSRIs), and their usefulness as anti-depressants is limited in this respect. In an attempt to examine the background of SSRI-induced emesis, the present study aims to describe the role of 5-hydroxytryptamine (serotonin:5-HT) from the viewpoint of 5-HT release in the mouse-isolated ileum. In this study, it was demonstrated that 5-HT release from the mouse-isolated ileum was significantly increased by fluvoxamine at a concentration of 10(-6) M. Also, it was demonstrated that granisetron, a 5-HT3 receptor antagonist, inhibited significantly the increase in fluvoxamine (10(-6) M) -induced 5-HT release. The effect of granisetron on fluvoxamine-induced 5-HT release was occurred in a concentration-dependent manner. The present study demonstrated for the first time that the SSRI-induced increase in 5-HT release from the isolated ileum was significantly inhibited by 5-HT3 receptor antagonist. These results suggest that 5-HT3 receptors might be involved in SSRI-induced 5-HT release from the mouse isolated ileal tissue. Fluvoxamine (10(-6) M)-induced 5-HT release was inhibited concentration -dependently by the concomitant perfusion of diltiazem. The results suggest that L-type calcium channel might be also involved in SSRI-induced 5-HT release from the isolated ileum. Furthermore, tetrodotoxin (10(-6) M) completely inhibited the increase in 5-HT release induced by fluvoxamine. This finding suggests that the increase of 5-HT induced by fluvoxamine involves enterochromaffin (EC) cell stimulation via an inter-neuron pathway in the gastrointestinal tract (GI). SSRI initiates an increase in the concentration of 5-HT in the GI tract. 5-HT released from the EC cells of the intestinal mucosa may stimulate the 5-HT3 receptors on vagal afferent nerve fibers. This depolarization of vagal afferents may result in a 5-HT increase in the brainstem and, thus, lead to emesis.

American society favors life style habits that lead to a plethora of physical disabilities, i.e., poor nutrition and a lack of exercise contribute to chronic disabilities and disease. Even though our life expectancies have increased, chronic disorders such as sarcopenia, diabetes, stroke and cardiovascular disease have become more prevalent. Nevertheless, Americans are slowly becoming more educated in health practices. A variety of therapies and nutritional supplements are being investigated to prevent and/or counteract chronic health disorders and aging. Muscle wasting referred to as "sarcopenia" commonly occurs in the elderly. This is very unfortunate, because the aging human body has the intrinsic ability to maintain itself in a healthy state, e.g., maintain muscle. Proper physical activity and a healthful diet in the elderly are the best ways to counteract the sarcopenia and other aspects of the aging phenomenon. In addition, potential replacement therapy and supplements are fervently being researched in hope of finding the next "Fountain of Youth." With important discoveries made everyday, progress is being made towards a future where both the young and old will have an improved quality of life based on improved knowledge of fitness, nutrition, replacement and supplemental therapy.

Steroid hormones, especially androgens, are believed to play a key role in the etiology of prostate cancer. Therefore, polymorphisms in genes involved in the androgen metabolism may affect the risk of prostate cancer. One such gene is CYP17, which encodes the cytochrome P450c17alpha enzyme that mediates both 17alpha-hydroxylase and 17,20-lyase in the steroid biosynthesis pathway. A polymorphism in the 5'-promoter region of the CYP17 gene has been associated with increased risk for prostate cancer. The T to C transition in the risk allele creates a new recognition site for the restriction enzyme MspA1. In this study we investigated the distribution of this polymorphism in the Turkish population and its association with prostate cancer and benign prostatic hyperplasia. Genotype frequencies in the patients with prostate cancer or prostatic hyperplasia and the control group were not significantly different. Our data provide no evidence for an association between prostate cancer risk and the CYP17 gene polymorphism.

Thimerosal (TH) (ethylmercurithiosalicylate) is a mercurial compound with the ability to exert cytoprotective effect against several ulcerogens. This investigation was undertaken to study the mechanism by which TH exerts its gastro-protective effect in rats. Acid secretion studies were undertaken in pylorus-ligated shay rats with and without TH treatment. The level of nonprotein sulfhydryls (NP-SH), myeloperoxidase (MPO) and gastric wall mucus were also measured in the glandular stomach of rats following ethanol-induced gastric lesions. The results of this study showed that TH (0.3, 1.0 and 3.0 mg/kg) significantly and dose-dependently reduced gastric secretion and acidity in pylorus-ligated shay rats and protected animals against ethanol-induced gastric injury. Pretreatment of animals with TH significantly attenuated ethanol-induced depletion of NP-SH and increase in MPO in glandular mucosa. Thus, gastro-protective effect of TH may be attributed to its ability to reduce acid secretion, oxidative stress, and neutrophil activity besides it well reported effect on gastro-protective PG and NO.

This study examined gene polymorphisms in dihydropteroate synthase (DHPS), dihydrofolate reductase (DHFR) and cytochrome b of Pneumocystis carinii isolated from 34 patients with P. carinii pneumonia (PCP) in Japan. Four amino acid substitutions (Thr55Ala, Pro57Ser, His60Gln and Glu169Gly) in DHPS, 2 mutations (Ala67Val and Cys166Tyr) in DHFR and 1 mutation (Leu280Phe) in cytochrome b were found in 9 (26.5%), 2 (5.9%) and 1 (2.9%) patient, respectively. No linkage of mutations in DHPS to those in DHFR or cytochrome b was observed. The patients whose isolates showed mutations in DHPS, DHFR and cytochrome b were not exposed to sulfonamides, DHFR inhibitors and atovaquone before they developed PCP, except for 2 patients. Co-trimoxazole treatment failed more frequently in patients whose isolates had DHPS mutations than in those whose isolates showed wild-type DHPS (n=6 [85.7%] versus n=3 [12.5%]; P=0.001). Our results suggest that DHPS mutations may contribute to failure of co-trimoxazole treatment for PCP.

The novel antitumor compound NC-190 strongly inhibited the growth of FM3A cells with an IC50 of 0.019 microg/ml (0.042 microM) when cultured with NC-190 for 48 h. NC-190 potently suppressed DNA synthesis, with 90% inhibition observed at 0.1 microg/ml of NC-190. RNA and protein syntheses were also suppressed under the same conditions, but to a lesser extent. We then measured the cellular enzymatic activities of DNA polymerase alpha, RNA polymerase, thymidine kinase, thymidylate synthase and Leu-tRNA synthetase of FM3A cells cultured with or without NC-190. Of these 5 enzymes, the activity of thymidine kinase was most strongly suppressed by NC-190, by 77%. Although NC-190 did not directly inhibit the activitiy of thymidine kinase in a cell-free system, expression of mRNA of thymidine kinase was suppressed by 75% in NC-190-treated cells. These results indicate that NC-190 can suppress the expression of the gene for thymidine kinase and the inhibition of thymidine kinase contributes to the inhibition of cell growth by NC-190 together with the inhibition of topoisomerase II.

Co-oxidation of phenacetin, acetaminophen (APAP) and p-aminophenol (p-AP) by prostaglandin H synthase (PHS) was investigated in human and rat renal microsomes. The formation of prostaglandin E2 (PGE2) was assessed in cortex, outer and inner medulla following phenacetin, APAP and p-AP (0-5 mM) incubations. For all compounds and concentrations tested, a significantly higher PGE2 production was observed in inner medulla compared to cortex. Rat inner medulla incubated with phenacetin resulted in an increased formation of PGE2 at all concentrations compared to control (1 mM phenacetin increased production by 243%). Human inner medulla demonstrated an increased PGE2 production at 1, 3 and 5 mM phenacetin versus control (136% increase at 1 mM). An increase in PGE2 formation in rat and human inner medulla was observed at low APAP concentrations (0.1, 0.3, 0.5 and 1 mM) compared to control (216% and 396% in human and rat respectively following 1 mM APAP). 5 mM APAP inhibited PGE2 formation in the rat inner medulla but not in human inner medulla. An inhibition of PGE2 production by 5 mM p-AP was observed in both the rat and human inner medulla. In the rat PGE2 production was inhibited 69% by 5 mM, whereas in the human the inhibition was 76% at 5 mM. These studies demonstrate a species-specific PHS-mediated renal metabolism of APAP, with the human kidney demonstrating a continous formation of reactive metabolites at high concentrations of APAP. However, phenacetin and p-AP are metabolized in a similar manner in these 2 species.

The molecular mechanisms mediating the cellular adaptations to exercise training in human skeletal muscle are very poorly understood. To investigate the effect of endurance training on the expression of various genes at the mRNA levels in human skeletal muscle, focusing on angiogeneic factors, antioxidant enzymes, and uncoupling proteins (UCPs), seven untrained male students underwent an intensive swimming training five times a week for 3 months and two male students an intensive running training, respectively. Muscle biopsies were taken before training and about 48 h after the last session. All the subjects markedly increased their maximal oxygen uptake levels due to training (P < 0.001), indicating an improvement in aerobic capacity. After training, there were significant (P < 0.04) decreases in the expression of mRNAs for heat shock protein 70, Cu,Zn-superoxide dismutase (Cu,Zn-SOD), and Mn-SOD but a significant (P < 0.02) increase in UCP2 mRNA expression, whereas no definite changes were observed in the levels of mRNAs for vascular endothelial growth factor (VEGF), basic fibroblast growth factor, hypoxia-inducible factor-1alpha (HIF1alpha), myoglobin, or UCP3. The changes in HIF1alpha mRNA expression correlated well with those in VEGF mRNA expression after training (r=0.875, P < 0.01), suggesting that HIF1alpha influences the training-induced VEGF gene expression or alternatively that VEGF and HIF1alpha expressions are coregulated at the transcriptional level in human skeletal muscle. Taken together, it is envisioned that cumulative effects of transient changes in transcription during recovery from successive bouts of exercise may represent the underlying kinetic basis for the cellular adaptations associated with endurance training.