Hepatoselectivity of statins: design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors

4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.     

Genetics and genomics converge on the human blood fluke

The construction of a genetic map of the human infective blood fluke (Schistosoma mansoni), coupled with the availability of the genome sequence, offers new approaches for research on this important parasitic worm.     

The antidepressant-like effect of Ocimum basilicum in an animal model of depression

We investigated the efficacy of Ocimum basilicum (OB) essential oils for treating depression related behavioral, biochemical and histopathological changes caused by exposure to chronic unpredictable mild stress (CUMS) in mice and to explore the mechanism underlying the pathology. Male albino mice were divided into four groups: controls; CUMS; CUMS plus fluoxetine, the antidepressant administered for pharmacological validation of OB; and CUMS plus OB. Behavioral tests included the forced swim test (FST), elevated plus-maze (EPM) and the open ?eld test (OFT); these tests were performed at the end of the experiment. We assessed serum corticosterone level, protein, gene and immunoexpression of brain-derived neurotropic factor (BDNF) and glucocorticoid receptors (GRs) as well as immunoexpression of glial fibrillary acidic protein (GFAP), Ki67, caspase-3 in the hippocampus. CUMS caused depression in the mice as evidenced by prolonged immobility in the FST, prolonged time spent in the open arms during the EPM test and reduction of open field activity in the OFT. OB ameliorated the CUMS induced depressive status. OB significantly reduced the corticosterone level and up-regulated protein and gene expressions of BDNF and GR. OB reduced CUMS induced hippocampal neuron atrophy and apoptosis, and increased the number of the astrocytes and new nerve cells. OB significantly increased GFAP-positive cells as well as BDNF and GR immunoexpression in the hippocampus.     

Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity

During macroautophagy, conjugation of ATG12 to ATG5 is essential for LC3 lipidation and autophagosome formation. Additionally, ATG12 has ATG5-independent functions in diverse processes including mitochondrial fusion and mitochondrial-dependent apoptosis. In this study, we investigated the regulation of free ATG12. In stark contrast to the stable ATG12–ATG5 conjugate, we find that free ATG12 is highly unstable and rapidly degraded in a proteasome-dependent manner. Surprisingly, ATG12, itself a ubiquitin-like protein, is directly ubiquitinated and this promotes its proteasomal degradation. As a functional consequence of its turnover, accumulation of free ATG12 contributes to proteasome inhibitor-mediated apoptosis, a finding that may be clinically important given the use of proteasome inhibitors as anticancer agents. Collectively, our results reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12.     

Shining Light on Benthic Macroalgae: Mechanisms of Complementarity in Layered Macroalgal Assemblages

Phototrophs underpin most ecosystem processes, but to do this they need sufficient light. This critical resource, however, is compromised along many marine shores by increased loads of sediments and nutrients from degraded inland habitats. Increased attenuation of total irradiance within coastal water columns due to turbidity is known to reduce species'' depth limits and affect the taxonomic structure and architecture of algal-dominated assemblages, but virtually no attention has been paid to the potential for changes in spectral quality of light energy to impact production dynamics. Pioneering studies over 70 years ago showed how different pigmentation of red, green and brown algae affected absorption spectra, action spectra, and photosynthetic efficiency across the PAR (photosynthetically active radiation) spectrum. Little of this, however, has found its way into ecological syntheses of the impacts of optically active contaminants on coastal macroalgal communities. Here we test the ability of macroalgal assemblages composed of multiple functional groups (including representatives from the chlorophyta, rhodophyta and phaeophyta) to use the total light resource, including different light wavelengths and examine the effects of suspended sediments on the penetration and spectral quality of light in coastal waters. We show that assemblages composed of multiple functional groups are better able to use light throughout the PAR spectrum. Macroalgal assemblages with four sub-canopy species were between 50–75% more productive than assemblages with only one or two sub-canopy species. Furthermore, attenuation of the PAR spectrum showed both a loss of quanta and a shift in spectral distribution with depth across coastal waters of different clarity, with consequences to productivity dynamics of diverse layered assemblages. The processes of light complementarity may help provide a mechanistic understanding of how altered turbidity affects macroalgal assemblages in coastal waters, which are increasingly threatened by diminishing light quantity and altered spectral distributions through sedimentation and eutrophication.     

Microbiome mediating methane and nitrogen transformations in a subterranean estuary

Subterranean estuaries (STEs) are important coastal biogeochemical reactors facilitating unique niches for microbial communities. A common approach in determining STE greenhouse gas and nutrient fluxes is to use terrestrial endmembers, not accounting for microbially mediated transformations throughout the STE. As such, the microbial ecology and spatial distribution of specialists that cycle compounds in STEs remain largely underexplored. In this study, we applied 16S rRNA amplicon sequencing with paired biogeochemical characterisations to spatially evaluate microbial communities transforming greenhouse gases and nutrients in an STE. We show that methanogens are most prevalent at the terrestrial end (up to 2.81% relative abundance) concomitant to the highest porewater methane, carbon dioxide and dissolved organic carbon concentrations (0.41 ± 0.02 μM, 273.31 ± 6.05 μM and 0.51 ± 0.02 mM, respectively). Lower ammonium concentrations corresponded with abundant nitrifying and ammonia-oxidising prokaryotes in the mixing zone (up to 11.65% relative abundance). Methane, ammonium and dissolved organic carbon concentrations all decreased by >50% from the terrestrial to the oceanic end of the 15 m transect. This study highlights the STE's hidden microbiome zonation, as well as the importance of accounting for microbial transformations mitigating nutrient and greenhouse gas fluxes to the coastal ecosystems.