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PubMedDate not supplied

Molecular cloning and functional characterisation of VanX, a D-alanyl-D-alanine dipeptidase from Streptomyces coelicolor A3(2).

The vanX gene which encodes a D-alanyl-D-alanine dipeptidase is critical for vancomycin resistance in enterococci. A putative vanX gene from Streptomyces coelicolor A3(2), which is not known for vancomycin production, was identified by homology-based analysis and cloned by polymerase chain reaction. The S. coelicolor vanX gene was heterologously expressed in Escherichia coli BL21(DE3) and enzymatic assays of soluble protein fractions of VanX revealed a 93-fold increase in dipeptidase activity as compared to the nonrecombinant control, thus confirming its functionality. Interestingly, S. coelicolor was also found to be of intermediate resistance to vancomycin although it does not produce vancomycin, thus suggesting the role of VanX in defence or immunity. As such, the prevalence of vanX genes in the environment may be more common than previously thought.

Anti-Bacterial Agents↗
PubMed2004

Rational design of CH/pi interaction sites in a basic resolving agent.

A novel synthetic basic resolving agent, cis-1-aminobenz[f]indan-2-ol (ABI), was rationally designed by introducing effective CH/pi interaction sites to cis-1-aminoindan-2-ol (AI), whose chiral recognition ability has been reported from our laboratory. ABI was applicable to a wide variety of racemic arylalkanoic acids and showed moderate to excellent chiral recognition ability, which was obviously higher than that of AI. The fundamental and important role of CH/pi interactions, such as tunable CH(sp(2))/pi and CH(sp(3))/pi interactions, in the chiral recognition by ABI was revealed by X-ray crystallographic study.

Journal Article↗
PubMed2004

Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy?

Two-thirds of breast tumours are oestrogen-receptor positive and 60-70% of these tumours respond to interventions that reduce the effects of oestrogen. Until recently, tamoxifen was the drug of choice for the treatment of hormone-responsive early and advanced breast cancer. However, tamoxifen is associated with increased incidences of endometrial cancer and thromboembolic disease, and many tumours eventually become resistant to treatment with tamoxifen. Thus, there is a need for alternative therapies with different mechanisms of action. In postmenopausal women, aromatase inhibitors (AIs) suppress oestrogen levels by inhibiting oestrogen synthesis via the aromatase enzyme pathway. The third-generation AIs (anastrozole, letrozole and exemestane) are more potent than the earlier AIs (aminoglutethimide, formestane and fadrozole) with respect to both aromatase inhibition and oestrogen suppression. While the earlier AIs were unable to show any benefit over megestrol acetate or tamoxifen as second- and first-line therapy, respectively, in postmenopausal women with advanced breast cancer, third-generation AIs have shown significant benefits in both settings. Comparison of aromatase inhibition and oestrogen suppression between the third-generation AIs anastrozole and letrozole showed a small but significantly greater difference in the degree of suppression of oestrone and oestrone sulphate (but not oestradiol), with letrozole. In an open-label trial, there were no significant differences between letrozole and anastrozole for the clinical end points of time to progression (primary end point), time to treatment failure, overall survival, clinical benefit, duration of clinical benefit, time to response, duration of response or objective response rate in patients with confirmed hormone receptor-positive tumours. Together these data suggest that once a certain threshold of aromatase inhibition is reached, small differences in oestrogen suppression between the third-generation AIs do not lead to clinically significant differences in overall efficacy.

Anastrozole↗
PubMed2003

Increased H(2)O(2) counteracts the vasodilator and natriuretic effects of superoxide dismutation by tempol in renal medulla.

A membrane-permeable SOD mimetic, 4-hydroxytetramethyl-piperidine-1-oxyl (tempol), has been used as an antioxidant to prevent hypertension. We recently found that this SOD mimetic could not prevent development of hypertension induced by inhibition of renal medullary SOD with diethyldithiocarbamic acid. The present study tested a hypothesis that increased H2O2 counteracts the effects of tempol on renal medullary blood flow (MBF) and Na+ excretion (UNaV), thereby restraining the antihypertensive effect of this SOD mimetic. By in vivo microdialysis and Amplex red H2O2 microassay, it was found that interstitial H2O2 levels in the renal cortex and medulla in anesthetized rats averaged 55.91 +/- 3.66 and 102.18 +/- 5.16 nM, respectively. Renal medullary interstitial infusion of tempol (30 micromol x min-1x kg-1) significantly increased medullary H2O2 levels by 46%, and coinfusion of catalase (10 mg x min-1x kg-1) completely abolished this increase. Functionally, removal of H2O2 by catalase enhanced the tempol-induced increase in MBF, urine flow, and UNaV by 28, 41, and 30%, respectively. Direct delivery of H2O2 by renal medullary interstitial infusion (7.5-30 nmol x min-1x kg-1) significantly decreased renal MBF, urine flow, and UNaV, and catalase reversed the effects of H2O2. We conclude that tempol produces a renal medullary vasodilator effect and results in diuresis and natriuresis. However, this SOD mimetic increases the formation of H2O2, which constricts medullary vessels and, thereby, counteracts its vasodilator actions. This counteracting effect of H2O2 may limit the use of tempol as an antihypertensive agent under exaggerated oxidative stress in the kidney.

Animals↗
PubMed2004

Efficacy of multidrug therapy combined with mizoribine in children with diffuse IgA nephropathy in comparison with multidrug therapy without mizoribine and with methylprednisolone pulse therapy.

AIM: To evaluate the efficacy of prednisolone, warfarin, and dipyridamole therapy combined with mizoribine (PWDM) in the treatment of diffuse immunoglobulin A (IgA) nephropathy in comparison with prednisolone, warfarin, and dipyridamole therapy without mizoribine (PWD) and with methylprednisolone pulse therapy (PWD pulse). METHODS: We collected data on 61 patients diagnosed with diffuse IgA nephropathy, and these patients were retrospectively divided into three groups without randomization. Group A included 21 patients before 1987 who were treated with PWD for 24 months, group B included 20 patients from 1987 to 1989 who were treated with PWD pulse therapy for 24 months, and group C included 20 patients after 1990 who were treated with PWDM for 24 months. Clinical features and pathological findings in each group were analyzed retrospectively. RESULTS: The time from initiation of therapy in group A, group B, and group C was 8.9 +/- 5.2, 8.1 +/- 3.9, and 7.7 +/- 3.8 years, respectively. At the latest follow-up examination, the mean urinary protein excretion (mg/m2/h) was 17 +/- 10 in group A, 22 +/- 20 in group B, and 6 +/- 6 in group C and had decreased significantly in group C as compared with the other groups. The activity index in all three groups was lower at the second biopsy than that at the first biopsy (5.1 +/- 0.8 vs. 6.5 +/- 2.1 in group A, p < 0.05; 5.6 +/- 0.9 vs. 6.6 +/- 1.7 in group B, p < 0.01, and 4.5 +/- 1.0 vs. 6.8 +/- 1.9 in group C, p < 0.01). The chronicity index in groups A and B at second biopsy was higher than at first biopsy (7.3 +/- 1.4 vs. 4.8 +/- 1.0 in group A, p < 0.01, and 8.1 +/- 2.0 vs. 5.3 +/- 0.9 in group B, p < 0.01), but was unchanged in group C. At the latest follow-up examination, 1 patient (4.8%) in group A, 3 patients (15%) in group B, and none (0%) in group C had renal insufficiency. CONCLUSION: These results suggest that PWDM appears to be more effective than PWD or PWD pulse in ameliorating proteinuria and histological severity of patients with IgA nephropathy.

Adolescent↗
PubMed2002

Atorvastatin lowers C-reactive protein and improves endothelium-dependent vasodilation in type 2 diabetes mellitus.

Endothelial dysfunction is frequently found in diabetic subjects. This study was performed to investigate whether atorvastatin therapy was able to reverse endothelial dysfunction in type 2 diabetes and, if so, whether the effect was due to its antiinflammatory action. Eighty patients (baseline low density lipoprotein, 4.37 +/- 0.71 mmol/liter) were randomized to atorvastatin (10 mg daily for 3 months, followed by 20 mg daily for 3 months) or placebo in a double blind study. Endothelial function was assessed by high resolution vascular ultrasound, and high sensitivity C-reactive protein (CRP) was assessed by immunoturbidimetric assay. Diabetic patients had higher CRP (P < 0.01) than matched nondiabetic controls, and both endothelium-dependent and independent vasodilation were impaired (P < 0.01). Atorvastatin (10 and 20 mg) lowered plasma cholesterol by 32.9% and 38.0%, triglyceride by 15.4% and 23.1%, and low density lipoprotein by 43.4% and 50.1%, respectively. At 6 months, plasma CRP decreased in the atorvastatin group compared with baseline (P < 0.05). Endothelium-dependent vasodilation improved in the atorvastatin group compared with the placebo group (P < 0.05). The percent change in endothelium-dependent vasodilation at 6 months correlated with the percent change in CRP (r = -0.44; P < 0.05), but not with changes in plasma lipids. In conclusion, treatment with atorvastatin in type 2 diabetes led to a significant improvement in endothelium-dependent vasodilation, which might be partly related to its anti-inflammatory effect.

Anti-Inflammatory Agents↗
PubMed2005

Inhibitory effects of naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice.

We have investigated the effect of naringenin (NGEN) on tumor growth in various human cancer cell lines and sarcoma S-180-implanted mice. NGEN showed cytotoxicity in cell lines derived from cancer of the breast (MCF-7, MDA-MB-231), stomach (KATOIII, MKN-7), liver (HepG2, Hep3B, Huh7), cervix (Hela, Hela-TG), pancreas (PK-1), and colon (Caco-2) as well as leukemia (HL-60, NALM-6, Jurkat, U937). NGEN-induced cytotoxicity was low in Caco-2 and high in leukemia cells compared to other cell lines. NGEN dose-dependently induced apoptosis, with hypodiploid cells detected in both Caco-2 and HL-60 by flow cytometric analysis. In vivo, NGEN inhibited tumor growth in sarcoma S-180-implanted mice, following intraperitoneal or peroral injection once a day for 5 d. Naringin (NG) also inhibited tumor growth by peroral injection but not intraperitoneal injection. NGEN, one of the most abundant flavonoids in citrus fruits, may have a potentially useful inhibitory effect on tumor growth.

Animals↗
PubMed2005

SARS transmission pattern in Singapore reassessed by viral sequence variation analysis.

BACKGROUND: Epidemiological investigations of infectious disease are mainly dependent on indirect contact information and only occasionally assisted by characterization of pathogen sequence variation from clinical isolates. Direct sequence analysis of the pathogen, particularly at a population level, is generally thought to be too cumbersome, technically difficult, and expensive. We present here a novel application of mass spectrometry (MS)-based technology in characterizing viral sequence variations that overcomes these problems, and we apply it retrospectively to the severe acute respiratory syndrome (SARS) outbreak in Singapore. METHODS AND FINDINGS: The success rate of the MS-based analysis for detecting SARS coronavirus (SARS-CoV) sequence variations was determined to be 95% with 75 copies of viral RNA per reaction, which is sufficient to directly analyze both clinical and cultured samples. Analysis of 13 SARS-CoV isolates from the different stages of the Singapore outbreak identified nine sequence variations that could define the molecular relationship between them and pointed to a new, previously unidentified, primary route of introduction of SARS-CoV into the Singapore population. Our direct determination of viral sequence variation from a clinical sample also clarified an unresolved epidemiological link regarding the acquisition of SARS in a German patient. We were also able to detect heterogeneous viral sequences in primary lung tissues, suggesting a possible coevolution of quasispecies of virus within a single host. CONCLUSION: This study has further demonstrated the importance of improving clinical and epidemiological studies of pathogen transmission through the use of genetic analysis and has revealed the MS-based analysis to be a sensitive and accurate method for characterizing SARS-CoV genetic variations in clinical samples. We suggest that this approach should be used routinely during outbreaks of a wide variety of agents, in order to allow the most effective control.

DNA, Viral↗
PubMed2000

Toxicity and residual effectiveness of insecticides on insecticide-treated spheres for controlling females of Rhagoletis pomonella (Diptera: Tephritidae).

This study evaluated the toxicity of five technical-grade insecticides of four different classes to apple maggot females, Rhagoletis pomonella (Walsh), following a 10-min exposure period in insecticide-coated glass jars, with or without a feeding stimulant (sucrose) present. According to LC90 values for toxicity by ingestion and tarsal contact, imidacloprid was 1.5 times more toxic than dimethoate or abamectin, diazinon was less toxic, and phloxine B (a phototoxic dye) least toxic. Based on LC90 values for tarsal contact alone, dimethoate was 2.3, 4.0, and 18.4 times more toxic than imidacloprid, abamectin, and diazinon, respectively. Contact alone with phloxine B caused no mortality. When exposure was assessed using spheres coated with a latex paint mixture containing sucrose and formulated dimethoate (Digon 400 EC) or imidacloprid (Provado 1.6 F) at concentrations ranging from 5 to 70 g (AI)/cm2, both insecticides showed reduced effectiveness compared with toxicities from glass jar tests, with Digon two times more toxic than Provado. After exposure to artificial rainfall and retreatment with sucrose, Digon- and Provado-treated spheres exhibited greatest residual effectiveness, with diazinon-treated spheres less effective. Spheres treated with formulated abamectin (Agri-Mek 0.15 EC) at 1.0% (AI) performed only slightly better than phloxine B-treated spheres, which completely lost effectiveness after exposure to rainfall. Spheres treated with formulated imidacloprid (Merit 75 WP) at 1.5% (AI) showed equal or better residual efficacy in killing apple maggot flies (> 80% mortality, shorter lethal duration of feeding) over a 12-wk exposure period to outdoor weather than spheres treated with Digon at 1.0% (AI) after both types were retreated with sucrose. Our results indicate that imidacloprid is a promising safe substitute for dimethoate as a fly killing agent on lure-kill spheres. Imidacloprid formulated as Merit 75 WP had greater residual efficacy than imidacloprid formulated as Provado 1.6 F.

Animals↗
PubMed2004

Effect of 2-(3-carboxy-1-oxopropyl) amino-2-deoxy-D-glucose on human esophageal cancer cell line.

AIM: To determine whether 2-(3-carboxy-1-oxopropy1) amino-2-deoxy-D-glucose (COPADG), a derivative of D-amino-glucose, inhibited the growth of human esophageal cancer cell line Eca-109. METHODS: Effects of COPADG on Eca-109 cells cultured in RPMI 1640 medium were examined by a tetrazolium-based colorimetric assay (MTT assay). RESULTS: COPADG inhibited the growth of Eca-109 cells in a dose- and time-dependent manner; the maximum inhibition rate was 83.75%. CONCLUSION: COPADG can directly inhibit the proliferation of Eca-109 cells, which may serve as the experimental evidence for development of new drugs for esophageal cancer therapy.

Antineoplastic Agents↗
PubMed2001

[Developments of hormonal agents for breast cancer].

Endocrine therapy for breast cancer, which began with ovariectomy, has a history of more than 100 years. Tamoxifen has been an epoch-making drug during the late 20th century. Recently LHRH analogues which work as downregulators of estrogen production and many aromatase inhibitors (AI), both non-steroidal and steroidal have been developed in Japan. Fadrozole was the only AI until anastrozole was approved a few months ago. Letrozole was shown to be a better AI than fadrozole by prospective randomized double blind examination; however, it is not licenced yet. The reason is that the appropriate dosage is not identical to that of Western countries. We have reached a time when order-made medicine should take into consideration such differences as race and individuality.

Adult↗
PubMed2001

The role of tamoxifen and aromatase inhibitors/inactivators in postmenopausal patients.

The traditional hormonal cascade of the 1970s and 1980s used tamoxifen followed by megestrol acetate and subsequently by aminoglutethimide. In the 1990s, however, three trials of third-generation aromatase inhibitors (AIs) compared with megestrol acetate and two trials of third-generation AIs compared with aminoglutethimide showed improved efficacy and decreased toxicity for the newer AIs. Thus, the hormonal cascade changed in the late 1990s, to one in which tamoxifen, followed by a third-generation AI, followed by megestrol acetate, seemed more suitable. Now, however, several trials comparing anastrozole, letrozole, and exemestane to tamoxifen as first-line hormonal agents for metastatic breast cancer have shown that these drugs are at least equivalent and perhaps superior to tamoxifen in that setting in terms of response rate and time to progression. Results from 1021 patients randomized to receive anastrozole versus tamoxifen showed a slightly improved overall response rate (RR; 29% versus 26%), slightly improved clinical benefit (CB; 57% versus 52%), and a significantly improved time to progression (TTP; 8.5 months versus 7.0 months) in favor of anastrozole. In 907 women randomized to treatment with letrozole versus tamoxifen, significantly improved RR (30% versus 20%), CB (49% versus 38%), and TTP (9.4 months versus 6 months) have all been shown for those treated with letrozole. In addition, a randomized Phase II trial of 121 patients has shown nonsignificant benefits in favor of exemestane (RR 41% versus 14%; CB 56% versus 42%; TTP not available). To date, none of these trials has demonstrated any overall survival benefit. Additional follow-up in regard to survival in the trial of tamoxifen versus letrozole and an expanded Phase III trial of tamoxifen versus exemestane are ongoing.

Antineoplastic Agents, Hormonal↗
PubMedDate not supplied

Genetic response to farnesyltransferase inhibitors: proapoptotic targets of RhoB.

Knockout mouse studies have established that the transformation-selective death program triggered by farnesyltransferase inhibitor (FTI) requires a gain-of-function in the stress-regulated small GTPase RhoB. To gain insight into this death program, we compared the genetic response of cells with different RhoB genotypes to FTI treatment. The microarray hybridization strategy we employed focused specifically on events preceding the execution of RhoB-dependent apoptosis, which is crucial for effective antineoplastic responses in mouse, rather than on other aspects of the FTI response mediated by RhoB gain-of-function (e.g., growth inhibition). Genes that control cell adhesion and cell shape were represented prominently among upregulated targets, as were genes that control signal transduction, vesicle dynamics, transcription, and immunity. Genes that control cell cycle checkpoints and progression through S phase and mitosis were among the major downregulated targets. In support of the concept of RhoB as a negative regulator of Ras signaling pathways, the most strongly downregulated gene scored was farnesyl pyrophosphate synthetase, the enzyme that produces the substrate used by FT to farnesylate Ras proteins. Gene clustering revealed modules for MAPK signaling, cell cycle progression, and immune response as proapoptotic targets of RhoB. This report identifies genes that pertain to the transformation-selective apoptotic program triggered by FTI. Further study of this program may yield insights into the dramatic differences in efficacy and apoptotic prowess of most FTIs in human cancers, versus transgenic mouse models.

Alkyl and Aryl Transferases↗
PubMed2004

A new furobenzopyranone and other constituents from Anaphalis lactea.

Together with twenty-one known compounds, a new furobenzopyranone was isolated from the whole plant of Anaphalis lactea. Their structures were elucidated by spectroscopic methods MS, IR, UV, NMR, including 2D-NMR techniques. The anti-bacterial activity of compounds 1, 4-6, 14, 15 and the anti-tumor activity of compounds 4-6 were tested.

Anti-Bacterial Agents↗
PubMed1990

Flow and image cytometry for quality assessment of fresh and frozen human sperm samples.

A previous study reported that sperm mitochondrial activity and sperm motility can be evaluated by combined flow and image cytometry, suggesting their potential interest in fertility clinical applications and for studying the effect of physical and chemical agents that modify sperm motility and/or metabolism. This paper focuses on the effect of freezing sperm in liquid nitrogen, extensively used in artificial insemination (AI), combined with different sperm manipulations (washing, swim-up in capacitating medium, CM) using flow and image cytometry on sperm samples from three fertile donors. Rhodamine 123 (Rh123) uptake profiles were bimodal both for fresh and frozen/thawed samples. The mean value of fluorescence of active cells (m+) remained nearly similar after freezing while the percentage of active cells (%C+) was significantly decreased and the percentage of dead cells (%dc, revealed by propidium iodide uptake) significantly increased. In all experiments, the decrease of MOT (percentage of motile sperm) due to freezing was concomitant, to a smaller extent, with a drop in %C+ and an increase in %dc; there was a good relationship between velocity (VCL, VSL) or trajectory characteristics (ALH) and the mean fluorescence values of active cells (m+). Sperm immobilization was neither found related to a major decrease of Rh123 fluorescence nor to an increase in dead cells.

Cryopreservation↗