Isoprenoid biosynthesis as a novel target for antibacterial and antiparasitic drugs

The mevalonate-independent methylerythritol phosphate pathway is a long overlooked metabolic pathway for isoprenoid biosynthesis. It is present in most bacteria, including pathogens and opportunistic pathogens, in some unicellular eukaryotes, including the parasite responsible for malaria, and in the chloroplasts of all phototrophic organisms. It represents an alternative to the mevalonate pathway, which is only present in animals, fungi, the plant cytoplasm, archaebacteria and some eubacteria. This biosynthetic pathway is thus a potential target for antibacterial and antiparasitic drugs. An isopentenyl diphosphate isomerase that differs from the previously known isopentenyl diphosphate isomerase found in all other organisms, including animals, was discovered in several Gram-positive bacteria possessing the mevalonate pathway, adding another target related to isoprenoid biosynthesis.     

Estrogenic and anticarcinogenic properties of kurarinone, a lavandulyl flavanone from the roots of Sophora flavescens

Kurarinone, a lavandulyl flavanone, was isolated from a polyphenolic extract of the roots of Sophora flavescens using fractionation guided by estrogenic activity, which was determined by recombinant yeast and Ishikawa Var-I bioassays. Kurarinone showed weak estrogenic activity both in the yeast screen and in the Ishikawa Var-I assay with EC(50) values of 4.6 and 1.66 microM, respectively. Furthermore, kurarinone was found to have potent cytotoxic activity (IC(50) value = 22.2 microM) against human MCF-7/6 breast cancer cells in the sulforhodamine-B assay.     

Involvement of the PI 3-kinase signaling pathway in progression of colon adenocarcinoma

The phosphoinositide 3-kinase (PI 3-kinase) signaling pathway has been shown to play a pivotal role in intracellular signal transduction pathways involved in cell growth, cellular transformation and tumorigenesis. Analysis of several colon adenocarcinoma cell lines indicates that the PI 3-kinase signaling pathway is up-regulated in colon cancers. In particular, the protein levels and phosphorylation status of Akt and p70 S6 kinase are up-regulated in colon adenocarcinoma cell lines. More significantly, we have demonstrated for the first time that the phosphorylation of FKHR, a downstream target of Akt, is increased in these cell lines. Intriguingly, phosphorylation of three components of the PI 3-kinase signaling pathway, namely Akt, p70 S6 kinase and FKHR, are in direct correlation with the degree of tumorigenic potential of the colon cell lines tested. No differences in the protein levels of the two subunits of PI 3-kinase, p85 and p110alpha, and PTEN were noted. Real-time quantitative PCR indicated an increase in levels of Akt message only, and not of the other signaling pathway components. Inhibition of the PI 3-kinase with wortmannin decreased the anchorage-independent growth of colon cells in a soft agar assay. Hence, the components of the PI 3-kinase signaling pathway could serve as potential candidates for drug development in treatment of colon cancer.     

Thromboembolic events occur despite sinus rhythm maintenance in patients treated for atrial fibrillation: The Canadian Trial of Atrial Fibrillation experience

BACKGROUND: Anticoagulation reduces the risk of stroke in patients with atrial fibrillation. It is not clear whether patients who revert and are maintained in sinus rhythm should continue to receive warfarin. The recommendation is to anticoagulate these patients for a minimum of four weeks after cardioversion. Whether warfarin should be maintained for a longer period of time is unknown. METHODS AND RESULTS: To address this question, data from the Canadian Trial of Atrial Fibrillation were reviewed. Among the 403 patients, 81.9% had at least one risk factor for stroke, of whom only 60% were on warfarin. Nine thromboembolic events occurred in nine patients (2.2%): all had at least one risk factor for stroke. Six events occurred in patients who were either not anticoagulated (n=4) or for whom the international normalization ratio was subtherapeutic (n=2). Eight of the nine patients were in sinus rhythm at the last follow-up visit before and at the time of evaluation of the thromboembolic event. CONCLUSIONS: Anticoagulants are underused in atrial fibrillation patients at risk of stroke. Thromboembolic events are most often associated with suboptimal levels of anticoagulation and they occur despite the appearance of sinus rhythm maintenance.     

The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals

BACKGROUND: It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer. To date, however, the published results of randomized, placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect. We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population. METHODS: The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study is a randomized, double-blind, placebo-controlled primary prevention trial. A total of 13 017 French adults (7876 women aged 35-60 years and 5141 men aged 45-60 years) were included. All participants took a single daily capsule of a combination of 120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 mug of selenium, and 20 mg of zinc, or a placebo. Median follow-up time was 7.5 years. RESULTS: No major differences were detected between the groups in total cancer incidence (267 [4.1%] for the study group vs 295 [4.5%] for the placebo group), ischemic cardiovascular disease incidence (134 [2.1%] vs 137[2.1%]), or all-cause mortality (76 [1.2%] vs 98 [1.5%]). However, a significant interaction between sex and group effects on cancer incidence was found (P = .004). Sex-stratified analysis showed a protective effect of antioxidants in men (relative risk, 0.69 [95% confidence interval [CI], 0.53-0.91]) but not in women (relative risk, 1.04 [95% CI, 0.85-1.29]). A similar trend was observed for all-cause mortality (relative risk, 0.63 [95% CI, 0.42-0.93] in men vs 1.03 [95% CI, 0.64-1.63] in women; P = .11 for interaction). CONCLUSIONS: After 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants, especially of beta carotene.     

Equivocal roles of tissue-type plasminogen activator in stroke-induced injury

Stroke represents a major health problem in the ever-ageing population of industrialized nations. Each year, over three million people in the USA alone suffer from this affliction. Stroke, which results from the obstruction of an intra- or extra-cerebral artery, induces irreversible neuronal damage. The clot-busting drug tissue-type plasminogen activator (tPA) is the only FDA-approved therapy for acute stroke. Although tPA has been successfully used to treat myocardial infarction due to clot formation, its use in the treatment of occlusive cerebrovascular diseases remains controversial. Indeed, tPA is clearly beneficial as a thrombolytic agent. However, increasing evidence suggests that tPA could have direct and deleterious effects on neurons and glial cells.     

Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection

Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm³/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p=0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model.