Phosphatidylinositol 3-kinase (PI3-K) phosphorylates the 3-position of phosphatidylinositol to give rise to three signaling phospholipids. Binding of the pleckstrin homology (PH) domain of Akt to membrane PI(3)P's causes the translocation of Akt to the plasma membrane bringing it into contact with membrane-bound Akt kinase (PDK1 and 2), which phosphorylates and activates Akt. Akt inhibits apoptosis by phosphorylating Bad, thus promoting its binding to and blockade of the activity of the cell survival factor Bcl-x. Herein we present the synthesis and biological activity of several novel phosphatidylinositol analogues and demonstrate the ability of the carbonate group to function as a surrogate for the phosphate moiety. Due to a combination of their PI3-K and Akt inhibitory activities, the PI analogues 2, 3, and 5 proved to be good inhibitors of the growth of various cancer cell lines with IC(50) values in the 1-10 microM range. The enhanced Akt inhibitory activity of the axial hydroxymethyl-bearing analogue 5 compared to its equatorial counterpart 6 is rationalized based upon postulated differences in the H-bonding patterns of these compounds in complex with a homology modeling generated structure of the PH domain of Akt. This work represents the first attempt to examine the effects of 3-modified PI analogues on these two crucial cell signaling proteins, PI3-K and Akt, in an effort to better understand their cell growth inhibitory properties.
Accumulating evidence suggests that formation of peroxynitrite (ONOO(-)) in the cerebral vasculature contributes to the progression of ischemic damage, while the underlying molecular mechanisms remain elusive. To fully understand ONOO(-) biology, efficient tools that can realize the real-time tracing of endogenous ONOO(-) fluxes are indispensable. While a few ONOO(-) fluorescent probes have been reported, direct visualization of ONOO(-) fluxes in the cerebral vasculature of live mice remains a challenge. Herein, we present a fluorescent switch-on probe (NP3) for ONOO(-) imaging. NP3 exhibits good specificity, fast response, and high sensitivity toward ONOO(-) both in vitro and in vivo. Moreover, NP3 is two-photon excitable and readily blood-brain barrier penetrable. These desired photophysical and pharmacokinetic properties endow NP3 with the capability to monitor brain vascular ONOO(-) generation after injury with excellent temporal and spatial resolution. As a proof of concept, NP3 has enabled the direct visualization of neurovascular ONOO(-) formation in ischemia progression in live mouse brain by use of two-photon laser scanning microscopy. Due to these favorable properties, NP3 holds great promise for visualizing endogenous peroxynitrite fluxes in a variety of pathophysiological progressions in vitro and in vivo.
With accumulating evidence suggesting that amyloid-β (Aβ) deposition is a good diagnostic biomarker for Alzheimer's disease (AD), the discovery of active Aβ probes has become an active area of research. Among the existing imaging methods, optical imaging targeting Aβ aggregates (fibrils or oligomers), especially using near-infrared (NIR) fluorescent probes, is increasingly recognized as a promising approach for the early diagnosis of AD due to its real time detection, low cost, lack of radioactive exposure and high-resolution. In the past decade, a variety of fluorescent probes have been developed and tested for efficiency in vitro, and several probes have shown efficacy in AD transgenic mice. This review classifies these representative probes based on their chemical structures and functional modes (dominant solvent-dependent mode and a novel solvent-independent mode). Moreover, the pharmaceutical characteristics of these representative probes are summarized and discussed. This review provides important perspectives for the future development of novel NIR Aβ diagnostic probes.
Aims/hypothesis Arctigenin is a natural compound that had never been previously demonstrated to have a glucoselowering effect. Here it was found to activate AMPactivated protein kinase (AMPK), and the mechanism by which this occurred, as well as the effects on glucose and lipid metabolism were investigated. Methods 2-Deoxyglucose uptake and AMPK phosphorylation were examined in L6 myotubes and isolated skeletal muscle. Gluconeogenesis and lipid synthesis were evaluated in rat primary hepatocytes. The acute and chronic effects of arctigenin on metabolic abnormalities were observed in C57BL/6J and ob/ob mice. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye, JC-1. Analysis of respiration of L6 myotubes or isolated mitochondria was conducted in a channel oxygen system. Results Arctigenin increased AMPK phosphorylation and stimulated glucose uptake in L6 myotubes and isolated skeletal muscles. In primary hepatocytes, it decreased gluconeogenesis and lipid synthesis. The enhancement of glucose uptake and suppression of hepatic gluconeogenesis and lipid synthesis by arctigenin were prevented by blockade of AMPK activation. The respiration of L6 myotubes or isolated mitochondria was inhibited by arctigenin with a specific effect on respiratory complex I. A single oral dose of arctigenin reduced gluconeogenesis in C57BL/6J mice. Chronic oral administration of arctigenin lowered blood glucose and improved lipid metabolism in ob/ob mice. Conclusions/interpretation This study demonstrates a new role for arctigenin as a potent indirect activator of AMPK via inhibition of respiratory complex I, with beneficial effects on metabolic disorders in ob/ob mice. This highlights the potential value of arctigenin as a possible treatment of type 2 diabetes.
See Huang and Gitler (doi:) for a scientific commentary on this article.Small molecule drugs that can reduce levels of the mutant huntingtin protein (mHTT) are sought for the treatment of Huntington’s disease. Song et al. demonstrate that deleting Gpr52, or inhibiting Gpr52 protein function with a novel small molecule antagonist, reduces mHTT levels and rescues Huntington’s disease-associated phenotypes in cellular and mouse models.
Oligomeric procyanidins containing 4alpha-linked epicatechin units are rare in nature and have hitherto not been accessible through stereoselective synthesis. We report herein the preparation of the prototypical dimer, epicatechin-4alpha,8-epicatechin (6), by reaction of the protected 4-ketones 11a,b with aryllithium reagents derived by halogen/metal exchange from the aryl bromides 26a,b. Removal of the 4-hydroxyl group from the resulting tertiary benzylic alcohols 27a,b was effected by tri-n-butyltin hydride and trifluoroacetic acid in a completely stereoselective manner, resulting in hydride delivery exclusively from the beta face. If benzyl was chosen for protection of the 3-hydroxyls, all protective groups could subsequently be removed in a single step by hydrogenolysis. tert-Butyldimethylsilyl groups, on the other hand, permitted selective deprotection of the 3-hydroxyls in preparation for their subsequent acylation with tri-O-benzylgalloyl chloride. Only monogalloylation at the "bottom" 3-hydroxyl took place when 28c was acylated under the previously reported conditions, reflecting the increased steric hindrance of the "top" 3-hydroxyl group in 28c compared with its 4beta,8-isomer 3. The preparation of compounds 14 and 17 containing phloroglucinol trimethyl ether in the 4alpha and 4beta linkages to epicatechin is also described. The 8-position of the bromine atom in 19, previously conjectured in analogy to the structurally characterized tetramethyl ether 20, was confirmed by transformation of both compounds into the common derivative 25.
The primary aim of this study was to investigate the outcomes of two different modes (active and passive) of balloon dilatation therapy on cricopharyngeal dysfunction (CPD). Thirty-eight CPD patients with neurological disorders were recruited between 2006 and 2010. Twenty-one of them received active balloon dilatation therapy, and the remaining 17 received passive dilatation therapy for an average of 4 weeks. The patients' swallowing function before and after the intervention was evaluated using the Functional Oral Intake Scale (FOIS) and the upper esophageal sphincter (UES) opening was studied with the videofluoroscopic swallow study. Both modes of balloon dilatation therapy yielded improvements in the FOIS (active group: z = -3.767, p < 0.001; passive group: z = -3.472, p < 0.001) and the UES opening (both groups: p < 0.01). Active dilatation showed a significantly better FOIS result (p = 0.028) than passive dilatation for CPD. Both active and passive balloon dilatation benefits patients with neurological disorders but active balloon dilatation is better.
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