Effect of the Antioxidant Lipoic Acid in Aortic Phenotype in a Marfan Syndrome Mouse Model

Marfan syndrome (MFS) cardiovascular manifestations such as aortic aneurysms and cardiomyopathy carry substantial morbidity/mortality. We investigated the effects of lipoic acid, an antioxidant, on ROS production and aortic remodeling in a MFS mgΔloxPneo mouse model. MFS and WT (wild-type) 1-month-old mice were allocated to 3 groups: untreated, treated with losartan, and treated with lipoic acid. At 6 months old, echocardiography, ROS production, and morphological analysis of aortas were performed. Aortic ROS generation in 6-month-old MFS animals was higher at advanced stages of disease in MFS. An unprecedented finding in MFS mice analyzed by OCT was the occurrence of focal inhomogeneous regions in the aortic arch, either collagen-rich extremely thickened or collagen-poor hypotrophic regions. MFS animals treated with lipoic acid showed markedly reduced ROS production and lower ERK1/2 phosphorylation; meanwhile, aortic dilation and elastic fiber breakdown were unaltered. Of note, lipoic acid treatment associated with the absence of focal inhomogeneous regions in MFS animals. Losartan reduced aortic dilation and elastic fiber breakdown despite no change in ROS generation. In conclusion, oxidant generation by itself seems neutral with respect to aneurysm progression in MFS; however, lipoic acid-mediated reduction of inhomogeneous regions may potentially associate with less anisotropy and reduced chance of dissection/rupture

The Cryptosporidium parvum Kinome

<p>Abstract</p> <p>Background</p> <p>Hundreds of millions of people are infected with cryptosporidiosis annually, with immunocompromised individuals suffering debilitating symptoms and children in socioeconomically challenged regions at risk of repeated infections. There is currently no effective drug available. In order to facilitate the pursuit of anti-cryptosporidiosis targets and compounds, our study spans the classification of the <it>Cryptosporidium parvum </it>kinome and the structural and biochemical characterization of representatives from the CDPK family and a MAP kinase.</p> <p>Results</p> <p>The <it>C</it>. <it>parvum </it>kinome comprises over 70 members, some of which may be promising drug targets. These <it>C. parvum </it>protein kinases include members in the AGC, Atypical, CaMK, CK1, CMGC, and TKL groups; however, almost 35% could only be classified as OPK (other protein kinases). In addition, about 25% of the kinases identified did not have any known orthologues outside of <it>Cryptosporidium spp</it>. Comparison of specific kinases with their <it>Plasmodium falciparum </it>and <it>Toxoplasma gondii </it>orthologues revealed some distinct characteristics within the <it>C. parvum </it>kinome, including potential targets and opportunities for drug design. Structural and biochemical analysis of 4 representatives of the CaMK group and a MAP kinase confirms features that may be exploited in inhibitor design. Indeed, screening <it>Cp</it>CDPK1 against a library of kinase inhibitors yielded a set of the pyrazolopyrimidine derivatives (PP1-derivatives) with IC₅₀values of < 10 nM. The binding of a PP1-derivative is further described by an inhibitor-bound crystal structure of <it>Cp</it>CDPK1. In addition, structural analysis of <it>Cp</it>CDPK4 identified an unprecedented Zn-finger within the CDPK kinase domain that may have implications for its regulation.</p> <p>Conclusions</p> <p>Identification and comparison of the <it>C. parvum </it>protein kinases against other parasitic kinases shows how orthologue- and family-based research can be used to facilitate characterization of promising drug targets and the search for new drugs.</p

Optical coherence tomography imaging of the basal ganglia: feasibility and brief review

Optical coherence tomography (OCT) is a promising medical imaging technique that uses light to capture real-time cross-sectional images from biological tissues in micrometer resolution. Commercially available optical coherence tomography systems are employed in diverse applications, including art conservation and diagnostic medicine, notably in cardiology and ophthalmology. Application of this technology in the brain may enable distinction between white matter and gray matter, and obtainment of detailed images from within the encephalon. We present, herein, the in vivo implementation of OCT imaging in the rat brain striatum. For this, two male 60-day-old rats (Rattus norvegicus, Albinus variation, Wistar) were stereotactically implanted with guide cannulas into the striatum to guide a 2.7-French diameter high-definition OCT imaging catheter (Dragonfly™, St. Jude Medical, USA). Obtained images were compared with corresponding histologically stained sections to collect imaging samples. A brief analysis of OCT technology and its current applications is also reported, as well as intra-cerebral OCT feasibility on brain mapping during neurosurgical procedures

Small-molecule inhibition of pyruvate phosphate dikinase targeting the nucleotide binding site

Pyruvate phosphate dikinase (PPDK) is an essential enzyme of C4 photosynthesis in plants, catalyzing the ATP-driven conversion of pyruvate to phosphoenolpyruvate (PEP). It is further used by some bacteria and unicellular protists in the reverse, ATP-forming direction. Many weed species use C4 photosynthesis in contrast to world's major crops, which are C3 plants. Hence inhibitors of PPDK may be used as C4-specific herbicides. By screening a library of 80 commercially available kinase inhibitors, we identified compounds derived from bisindolylmaleimide (bisindolylmaleimide IV, IC50 = 0.76 ± 0.13 μM) and indirubin (indirubin-3'-monoxime, IC50 = 4.2 ± 0.9 μM) that showed high inhibitory potency towards PPDK and are among the most effective PPDK inhibitors described today. Physiological studies on leaf tissues of a C4 model plant confirmed in vivo inhibition of C4-driven photosynthesis by these substances. Moreover, comparative docking studies of non-inhibitory bisindolylmaleimide derivatives suggest that the selectivity towards PPDK may be increased by addition of functional groups to the core structure