Kurz zum Klima: Der Fluch der Ressourcen in Afrika

Die Rohstoffpreise klettern auf immer neue Höhen, aber dennoch hört man aus den rohstoffexportierenden Ländern – vor allem Afrikas – wenig von wirtschaftlicher Prosperität. Im Gegenteil: Es herrschen extreme Armut, hohe Arbeitslosigkeit, Gewalt, Korruption und Misswirtschaft. Der Beitrag geht der Frage nach, inwieweit negative Effekte von Ressourcenreichtum ausgehen

Kurz zum Klima: Der Fluch der Ressourcen in Afrika

Die Rohstoffpreise klettern auf immer neue Höhen, aber dennoch hört man aus den rohstoffexportierenden Ländern – vor allem Afrikas – wenig von wirtschaftlicher Prosperität. Im Gegenteil: Es herrschen extreme Armut, hohe Arbeitslosigkeit, Gewalt, Korruption und Misswirtschaft. Der Beitrag geht der Frage nach, inwieweit negative Effekte von Ressourcenreichtum ausgehen.Rohstoffressourcen Rohstoffpolitik Ressourcenökonomik Dutch Disease Afrika

Targeting oxidative stress: Novel coumarin-based inverse agonists of GPR55

Oxidative stress is associated with different neurological and psychiatric diseases. Therefore, development of new pharmaceuticals targeting oxidative dysregulation might be a promising approach to treat these diseases. The G-protein coupled receptor 55 (GPR55) is broadly expressed in central nervous tissues and cells and is involved in the regulation of inflammatory and oxidative cell homeostasis. We have recently shown that coumarin-based compounds enfold inverse agonistic activities at GPR55 resulting in the inhibition of prostaglandin E2. However, the antioxidative effects mediated by GPR55 were not evaluated yet. Therefore, we investigated the antioxidative effects of two novel synthesized coumarin-based compounds, KIT C and KIT H, in primary mouse microglial and human neuronal SK-N-SK cells. KIT C and KIT H show antioxidative properties in SK-N-SH cells as well as in primary microglia. In GPR55-knockout SK-N-SH cells, the antioxidative effects are abolished, suggesting a GPR55-dependent antioxidative mechanism. Since inverse agonistic GPR55 activation in the brain seems to be associated with decreased oxidative stress, KIT C and KIT H possibly act as inverse agonists of GPR55 eliciting promising therapeutic options for oxidative stress related diseases

Functional Selectivity of Coumarin Derivates Acting via GPR55 in Neuroinflammation

Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Clinical studies demonstrate a reduction of the mentioned diseases’ symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE$_{2}$-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE$_{2}$-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis

Leukoencephalopathy after prophylactic whole-brain irradiation with or without hippocampal sparing: a longitudinal magnetic resonance imaging analysis

PURPOSE Neurocognitive changes are well described after prophylactic or therapeutic whole-brain radiotherapy (WBRT) and have been reported as early as 3 months after radiotherapy (RT). Therefore, WBRT with protection of the hippocampal region (hippocampal avoidance, HA) has been proposed to preserve neurocognition. Our aim was to compare the risk of leukoencephalopathy after prophylactic cranial irradiation (PCI) with or without HA. METHODS Patients with small-cell lung cancer who received either lateral-opposed field PCI (non-HA-PCI; n = 9) or hippocampus avoidance PCI (HA-PCI; n = 9) with available magnetic resonance imaging (MRI) follow-up were identified and age matched. Pre-therapeutic and follow-up MRI after RT was analysed for leukoencephalopathy based on the Fazekas score. Bilateral cortical and subcortical brain structures were segmented and analysed for alterations in dosimetric parameters and volumes. RESULTS There was no significant difference of Fazekas scores between groups at baseline. Fazekas score differed in post-treatment with a median of 1 in the HA-PCI group and 2 in the non-HA-PCI group (p = 0.007). Significant increase of Fazekas score over time after RT was observed for HA-PCI patients (p = 0.001) but not for non-HA-PCI patients. Dmax (highest radiation dose) and brain volume receiving doses >25Gy were higher in HA-PCI patients. There were no significant volumetric differences for segmented brain structures between groups. CONCLUSION Radiological changes are more prominent after HA-PCI than after non-HA-PCI. Although no standardised neurocognitive testing was performed, the significantly increased Fazekas scores after HA-PCI are expected to interfere with neurocognitive function. Prospective long-term neurocognitive studies are warranted before HA-PCI is implemented in routine clinical practice

Evolution toward small molecule inhibitor resistance affects native enzyme function and stability, generating acarbose-insensitive cyclodextrin glucanotransferase variants

Small molecule inhibitors play an essential role in the selective inhibition of enzymes associated with human infection and metabolic disorders. Targeted enzymes may evolve toward inhibitor resistance through selective incorporation of mutations. Acquisition of insensitivity may, however, result in profound devolution of native enzyme function and stability. We therefore investigated the consequential effects on native function and stability by evolving a cyclodextrin glucanotransferase (CGTase) enzyme toward insensitivity to the small molecule inhibitor of the protein, acarbose. Error-prone PCR mutagenesis was applied to search the sequence space of CGTase for acarbose-insensitive variants. Our results show that all selected mutations were localized around the active site of the enzyme, and in particular, at the acceptor substrate binding sites, highlighting the regions importance in acarbose inhibition. Single mutations conferring increased resistance, K232E, F283L, and A230V, raised IC50 values for acarbose between 3,500- and 6,700-fold when compared with wild-type CGTase but at a significant cost to catalytic efficiency. In addition, the thermostability of these variants was significantly lowered. These results reveal not only the relative ease by which resistance may be acquired to small molecule inhibitors but also the considerable cost incurred to native enzyme function and stability, highlighting the subsequent constraints in the further evolutionary potential of inhibitor-resistant variants

Methyl Complexes of the Transition Metals

Organometallic chemistry can be considered as a wide area of knowledge that combines concepts of classic organic chemistry, that is, based essentially on carbon, with molecular inorganic chemistry, especially with coordination compounds. Transition-metal methyl complexes probably represent the simplest and most fundamental way to view how these two major areas of chemistry combine and merge into novel species with intriguing features in terms of reactivity, structure, and bonding. Citing more than 500 bibliographic references, this review aims to offer a concise view of recent advances in the field of transition-metal complexes containing M-CH fragments. Taking into account the impressive amount of data that are continuously provided by organometallic chemists in this area, this review is mainly focused on results of the last five years. After a panoramic overview on M-CH compounds of Groups 3 to 11, which includes the most recent landmark findings in this area, two further sections are dedicated to methyl-bridged complexes and reactivity.Ministerio de Ciencia e Innovación Projects CTQ2010–15833, CTQ2013-45011 - P and Consolider - Ingenio 2010 CSD2007 - 00006Junta de Andalucía FQM - 119, Projects P09 - FQM - 5117 and FQM - 2126EU 7th Framework Program, Marie Skłodowska - Curie actions C OFUND – Agreement nº 26722