Environmental exposure and preventive measures in Sweden and EU*

Environmental exposure to cadmium (Cd) gives rise to renal tubular dysfunction at low cumulative doses of Cd. A possible role of Cd in influencing the occurrence of diseases, e.g., bone, reproductive and cancer in the general population groups environmentally exposed to Cd has been reported from Japan, Belgium, Sweden and China. Authorities have to pay attention to this fact and to act in order to prevent serious outcomes and personal suffering in the population groups at risk. A general approach in setting recommended health based limits and to regulate the occurrence of a substance existing in food stuff is to keep low levels -better to be on the safer side than on the risk side. In the case of cadmium it should be most clear that since cadmium has a very long biological half-life of 20 years in humans, increased cadmium exposure due to human activities can never be accepted. In cases where cadmium exposure can not be avoided the approach should be to limit and decrease exposure. Presently FAO/WHO Expert Committee on Food Additives and Food has a PTWI (provisional tolerable weekly intake) value for adult persons of 7 microg/kg body weight for Cd (WHO 2003) a value corresponding to 1 microg/kg body weight for each day of a week. For children and pregnant or lactating women daily intakes should not exceed 1 microg/kg body weight.     

Seeking new antibiotics in nature's backyard

As the pipeline of new antibiotics slows to a trickle, scientists are developing innovative strategies to unearth antibacterial compounds in unexpected places.     

Basic principles of developing national standards for antibiotics

The main principles in preparation of national standards of the antibiotics manufacture in the USSR are compared with those of the World Health Organization. The characteristics of preparing standards of mono- and multicomponent antibiotics, as well as the requirements for optimal packing of the standards are presented.     

Activated Met signalling in the developing mouse heart leads to cardiac disease

Background

The Hepatocyte Growth Factor (HGF) is a pleiotropic cytokine involved in many physiological processes, including skeletal muscle, placenta and liver development. Little is known about its role and that of Met tyrosine kinase receptor in cardiac development.

Methodology/Principal Findings

In this study, we generated two transgenic mice with cardiac-specific, tetracycline-suppressible expression of either Hepatocyte Growth Factor (HGF) or the constitutively activated Tpr-Met kinase to explore: i) the effect of stimulation of the endogenous Met receptor by autocrine production of HGF and ii) the consequence of sustained activation of Met signalling in the heart. We first showed that Met is present in the neonatal cardiomyocytes and is responsive to exogenous HGF. Exogenous HGF starting from prenatal stage enhanced cardiac proliferation and reduced sarcomeric proteins and Connexin43 (Cx43) in newborn mice. As adults, these transgenics developed systolic contractile dysfunction. Conversely, prenatal Tpr-Met expression was lethal after birth. Inducing Tpr-Met expression during postnatal life caused early-onset heart failure, characterized by decreased Cx43, upregulation of fetal genes and hypertrophy.

Conclusions/Significance

Taken together, our data show that excessive activation of the HGF/Met system in development may result in cardiac damage and suggest that Met signalling may be implicated in the pathogenesis of cardiac disease.     

Leptin leads hypothalamic feeding circuits in a new direction

A decade ago, leptin (from the greek lepto meaning 'thin') was identified as the product of the ob gene.1 This adipocyte-derived hormone was found to suppress feeding and stimulate thermogenesis, and was thus proposed as a mediator in a negative feedback loop that controls body adiposity. This discovery led to a rapid revolution in the understanding of neurobiological mechanisms regulating obesity. However, while leptin's first life was as an adipostat, it is now known to have a wide range of additional neuroendocrine, metabolic and behavioural functions in the CNS and periphery. Remarkably, the pleiotropic nature of the hormone continues to be extended with the recent publication of two papers that expand on leptin's neurobiological actions in the CNS.2,3 They indicate novel regulatory roles for the hormone in both synaptic plasticity and axon guidance. Crucially, in light of the rising incidence of obesity in modern society, both of the studies reveal leptin-mediated links between nutrition and neurodevelopment, findings that have further implications for leptin's role in the regulation of energy homeostasis.     

Bis-alkylamine quindolone derivatives as new antimalarial leads

Quindolone derivatives, designed to target the malaria parasite digestive vacuole and heme detoxification pathway, have been synthesized by reaction with 2-chloro-N,N-diethylethanamine. This reaction gave N,O-, N,N- and O-alkylated products containing one or two basic side-chains. The compounds were evaluated for antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum W2 strain and for cytotoxicity in HepG2 A16 hepatic cells. By incorporating alkylamine side chains and chlorine atoms in the quindolone nucleus we transformed the inactive tetracyclic parent quindolones into moderate or highly active and selective antimalarial compounds. The most active and selective compound, 5c, showed an IC₅₀ = 51 nM for P. falciparum and a selectivity ratio of 98.     

Dihydropyrimidinones--a new class of anti-staphylococcal antibiotics

We report the synthesis and pharmacological evaluation of new derivatives of natural dipeptide antibiotic TAN-1057 A, B. In the course of this program, we identified novel analogues of the natural product that display similar antibacterial activity and showed improved tolerability.     

Modifying quinolone antibiotics yields new anxiolytics

Patients taking fluoroquinolone antibiotics such as norfloxacin exhibit a low incidence of convulsions and anxiety. These side effects probably result from antagonism of the neurotransmitter gamma-aminobutyric acid (GABA) at the brain GABA(A) receptor complex (GRC). Modification of norfloxacin yields molecules such as compound 4 that potentiate GABA action with alpha(2) subunit selectivity. Compound 4 is anxiolytic but does not cause sedation, and may represent a new class of ligands that have anxiolytic activity without sedative liability.     

Isoprenoid flavonoids are new leads in the modulation of chemoresistance

Flavonoid compounds are able to bind to P-glycoprotein (P-gp), a transporter involved in chemoresistance of cancer cells. This interaction involves, at least in part, two overlapping sites in the cytosolic domains of P-gp, the ATP site and a hydrophobic steroid-binding site. We have studied the structure-activity relationships toward binding to P-gp. Modification of the substitution pattern of the flavonoid ring by hydroxylation, methoxylation or introduction of nitrogen-containing substituents had little effect. On the contrary, the presence of a 3-hydroxyl (flavonols), and especially of a C-isoprenoid chain increased the affinity of flavonoids towards P-gp. More detailed examination of the interaction with the ATP site was conducted through inhibition by flavonoids of the photolabeling by radioactive 8-azido-TNP-ATP. Only simple flavonols were demonstrated to bind to the ATP site. When position 3 was free (flavones) or when a hydrophobic C-prenyl substituent was present, interaction was rather directed to the hydrophobic site. A number of flavonoid compounds were tested for their ability to modulate multidrug resistance in resistant leukemic K562/R7 cells. Again, prenyl flavonoids were potent modulators. Simple flavonoids were ineffective in this model. The beneficial effect of prenylation was lower in polyhydroxylated compounds, suggesting a crucial role of hydrophobicity in P-gp modulation. This revised version was published online in June 2006 with corrections to the Cover Date.     

Discovery of new selective glucocorticoid receptor agonist leads

We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro.