75 research outputs found
Synthesis of nitric oxide modulating L-arginine derivatives and prodrugs of hydroxyguanidines
Considering the versatile functions of nitric oxide (NO), it is not surprising that dysregulation of endogenous NO-levels contributes to the pathogenesis of various diseases. Within this work different concepts were pursued in order to modulate the NO-generating system.
One common synthetic scheme was developed to afford optically pure Nδ-methylated L-arginine besides Nω-hydroxy-Nδ-methyl-L-arginine (NHAM), Nδ-methyl-L-citrulline und Nδ-cyano-Nδ-methyl-L-ornithine as possible metabolites of NO-synthase catalysis.
Furthermore, a series of Nω-substituted L-arginines and simple guanidines were synthesized to gain new insights in structure-activity relationships of the dimethylarginine dimethylaminohydrolase (DDAH).
Additionally, a number of different prodrugs of Nω-hydroxy-L-arginine were synthesized as potential NO-donors or arginase-inhibitors, respectively. In this context a novel bioactivation concept was investigated: The peptidylglycine α-amidating monooxygenase
Cell permeable stapled peptide inhibitor of Wnt signaling that targets β-catenin protein‒protein interactions
The Wnt signaling pathway plays a critical role in cell proliferation and differentiation, thus it is often associated with diseases such as cancers. Unfortunately, although attractive, developing anti-cancer strategy targeting Wnt signaling has been challenging given that the most attractive targets are involved in protein-protein interactions (PPIs). Here, we develop a stapled peptide inhibitor that targets the interaction between β-catenin and T cell factor/lymphoid enhancer-binding factor transcription factors, which are crucially involved in Wnt signaling. Our integrative approach combines peptide stapling to optimize proteolytic stability, with lessons learned from cell-penetrating peptide (CPP) design to maximize cellular uptake resulting in NLS-StAx-h, a selective, cell permeable, stapled peptide inhibitor of oncogenic Wnt signaling that efficiently inhibits β-catenin-transcription factor interactions. We expect that this type of integrative strategy that endows stapled peptides with CPP features will be generally useful for developing inhibitors of intracellular PPIs
Crataegus Extract WS®1442 Stimulates Cardiomyogenesis and Angiogenesis From Stem Cells: A Possible New Pharmacology for Hawthorn?
Extracts from the leaves and flowers of Crataegus spp. (i.e., hawthorn species) have been traditionally used with documented preclinical and clinical activities in cardiovascular medicine. Based on reported positive effects on heart muscle after ischemic injury and the overall cardioprotective profile, the present study addressed potential contributions of Crataegus extracts to cardiopoietic differentiation from stem cells. The quantified Crataegus extract WS®1442 stimulated cardiomyogenesis from murine and human embryonic stem cells (ESCs). Mechanistically, this effect was found to be induced by promoting differentiation of cardiovascular progenitor cell populations but not by proliferation. Bioassay-guided fractionation, phytochemical and analytical profiling suggested high-molecular weight ingredients as the active principle with at least part of the activity due to oligomeric procyanidines (OPCs) with a degree of polymerization between 3 and 6 (DP3–6). Transcriptome profiling in mESCs suggested two main, plausible mechanisms: These were early, stress-associated cellular events along with the modulation of distinct developmental pathways, including the upregulation of brain-derived neurotrophic factor (BDNF) and retinoic acid as well as the inhibition of transforming growth factor β/bone morphogenetic protein (TGFβ/BMP) and fibroblast growth factor (FGF) signaling. In addition, WS®1442 stimulated angiogenesis ex vivo in Sca-1+ progenitor cells from adult mice hearts. These in vitro data provide evidence for a differentiation promoting activity of WS®1442 on distinct cardiovascular stem/progenitor cells that could be valuable for therapeutic heart regeneration after myocardial infarction. However, the in vivo relevance of this new pharmacological activity of Crataegus spp. remains to be investigated and active ingredients from bioactive fractions will have to be further characterized
Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.
Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability
The Mediterranean diet: Effects on proteins that mediate fatty acid metabolism in the colon
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88101/1/j.1753-4887.2011.00439.x.pd
Higher carbon analogues of 1,4-dihydropyridines as potent TGFβ/Smad inhibitors
The C to Si and Ge exchange in bioactive compounds has often led to positive changes in the molecular properties, whereby Ge analogues are underrepresented. This is only possible at tetrahedral positions, and it is necessary for the analogue building blocks to withstand the synthetic conditions. Here, we present the synthesis of Si and Ge analogues of a TGFβ inhibiting 1,4‐dihydropyridine, which has a tetrahedral carbon in an important position for its activity. The molecular properties are compared by the discussion of the single X‐ray crystal structures and the electrostatic potential on the molecule surface which could play a role in the target interaction. Biological activities show that the C to Si and Ge exchange goes with full preservation of the potency, thus representing good starting points to modify physicochemical features and pharmacokinetics of these TGFβ inhibitors
Design, Synthesis, and Bioactivation of <i>O</i>‑Glycosylated Prodrugs of the Natural Nitric Oxide Precursor <i>N</i><sup>ω</sup>‑Hydroxy‑l‑arginine
Naturally occurring <i>N</i><sup>ω</sup>-hydroxy-l-arginine (NOHA, <b>1</b>) is the best substrate of NO synthases (NOS). The development of
stable and bioavailable prodrugs would provide a pharmacologically
valuable strategy for the treatment of cardiovascular diseases that
are associated with endothelial dysfunction. To improve NOHAs druglike
properties, we demonstrate that <i>O</i>-substitution by
(glycosylic) acetal formation greatly increased the chemical stability
of the hydroxyguanidine moiety and provided a nontoxic group that
could be easily bioactivated by glycosidases. A straightforward synthetic
concept was devised and afforded a series of diversely substituted
prodrugs by <i>O</i>-conjugation of the hydroxyguanidine
moiety with different monosaccharides. Systematic exploration of their
bioactivation profile revealed that glucose-based prodrugs were more
efficiently bioactivated than their galactose counterparts. NOS-dependent
cytosolic NO release was quantified by automated fluorescence microscopy
in a cell-based assay with murine macrophages. Glucose-based prodrugs
performed particularly well and delivered cellular NO levels comparable
to <b>1</b>, demonstrating proof-of-concept
Identification of Maleimide-Fused Carbazoles as Novel Noncanonical Bone Morphogenetic Protein Synergizers
Morphogenic signaling pathways govern embryonic development
and
tissue homeostasis on the cellular level. Precise control of such
signaling events paves the way for innovative therapeutic approaches
in the field of regenerative medicine. In line with these notions,
bone morphogenic protein (BMP) is a major osteogenic driver and pharmacological
stimulation of BMP signaling holds supreme potential for diseases
and defects of the skeleton. Efforts to identify small-molecule modalities
that activate or potentiate the BMP pathway have primarily been focused
on the canonical signaling cascade. Here, we describe the phenotypic
identification and development of specific carbazolomaleimides 2 as novel noncanonical BMP synergizers with submicromolar
osteogenic cellular potency. The devised chemical tools are characterized
to specifically regulate Id gene expression in a
SMAD-independent, yet highly BMP-dependent fashion. Mechanistic studies
revealed that GSK3 inhibition and increased β-catenin levels
are partly responsible for this activity. The utility of the new BMP
synergizer profile was further exemplified by showing how the synergistic
action of canonical and noncanonical BMP enhancers additively amplifies
BMP-dependent osteogenic outputs. Carbazolomaleimide 2b serves as a new and unique pharmacological tool for the modulation
and study of the BMP pathway
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