Natural products in modern life science

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science

Lysosomes in iron metabolism, ageing and apoptosis

The lysosomal compartment is essential for a variety of cellular functions, including the normal turnover of most long-lived proteins and all organelles. The compartment consists of numerous acidic vesicles (pH ∼4 to 5) that constantly fuse and divide. It receives a large number of hydrolases (∼50) from the trans-Golgi network, and substrates from both the cells’ outside (heterophagy) and inside (autophagy). Many macromolecules contain iron that gives rise to an iron-rich environment in lysosomes that recently have degraded such macromolecules. Iron-rich lysosomes are sensitive to oxidative stress, while ‘resting’ lysosomes, which have not recently participated in autophagic events, are not. The magnitude of oxidative stress determines the degree of lysosomal destabilization and, consequently, whether arrested growth, reparative autophagy, apoptosis, or necrosis will follow. Heterophagy is the first step in the process by which immunocompetent cells modify antigens and produce antibodies, while exocytosis of lysosomal enzymes may promote tumor invasion, angiogenesis, and metastasis. Apart from being an essential turnover process, autophagy is also a mechanism by which cells will be able to sustain temporary starvation and rid themselves of intracellular organisms that have invaded, although some pathogens have evolved mechanisms to prevent their destruction. Mutated lysosomal enzymes are the underlying cause of a number of lysosomal storage diseases involving the accumulation of materials that would be the substrate for the corresponding hydrolases, were they not defective. The normal, low-level diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow formation of lipofuscin in long-lived postmitotic cells, where it occupies a substantial part of the lysosomal compartment at the end of the life span. This seems to result in the diversion of newly produced lysosomal enzymes away from autophagosomes, leading to the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. If autophagy were a perfect turnover process, postmitotic ageing and several age-related neurodegenerative diseases would, perhaps, not take place

Opening of small and intermediate calcium-activated potassium channels induce relaxation mainly mediated by NO release in large arteries and EDHF in small arteries from rat Number of text pages: 22 Number of tables: 0 Number of figures: 5 Number of refere

Abstract This study was designed to investigate whether calcium-activated potassium channels of small (SK Ca or K Ca 2) and intermediate (IK Ca or K Ca 3.1) conductance activated by NS309 are involved in both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) type relaxation in large and small rat mesenteric arteries. Segments of rat superior and small mesenteric arteries were mounted in myographs for functional studies. NO was recorded using NO microsensors. SK Ca and IK Ca channel-currents, and mRNA expression were investigated in human umbilical vein endothelial cells (HUVECs), and calcium concentrations both in HUVEC and mesenteric arterial endothelial cells. In both superior (~1093 µm) and small mesenteric (~300 µm) arteries, NS309, evoked endothelium-and concentration-dependent relaxations. In superior mesenteric arteries, NS309 relaxations and NO release were inhibited both by asymmetric dimethylarginine (ADMA, 300 µM), an inhibitor of NO synthase, and by apamin (0.5 µM) plus TRAM 34 (1 µM), blockers of SK Ca and IK Ca channels, respectively. In small mesenteric arteries, NS309 relaxations were slightly reduced by ADMA, whereas apamin plus an IK Ca channel blocker almost abolished the relaxation. Iberiotoxin did not change NS309 relaxation. HUVECs expressed mRNA for SK Ca and IK Ca channels, and NS309 induced increases in calcium, outward current, and NO release that was blocked by apamin and TRAM 34 or charybdotoxin. These findings suggest that opening of SK Ca and IK Ca channels leads to endothelium-dependent relaxation that is mainly mediated by NO in large mesenteric arteries and by EDHF-type relaxation in small mesenteric arteries. NS309-induced calcium influx appears to contribute to formation of NO. JPET #179242