Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells

A single-site modification of paclitaxel analogs at the C10 position on the baccatin III core that reduces interaction with P-glycoprotein in bovine brain microvessel endothelial cells is described. Modification and derivatization of the C10 position were carried out using a substrate controlled hydride addition to a key C9 and C10 diketone intermediate. The analogs were tested for tubulin assembly and cytotoxicity, and were shown to retain potency similar to paclitaxel. P-glycoprotein interaction was examined using a rhodamine assay and it was found that simple hydrolysis or epimerization of the C10 acetate of paclitaxel and Taxol C can reduce interaction with the P-glycoprotein transporter that may allow for increased permeation of taxanes into the brain.     

Inducible defences prevent strong population fluctuations in bi- and tritrophic food chains

Recent theoretical work ( Vos et al. 2004 ) predicts that inducible defences prevent strong population fluctuations under high levels of nutrient enrichment. Here we evaluate this model prediction and show that inducible defences in algae stabilize the dynamics of experimentally assembled bi‐ and tritrophic planktonic food chains. At high phosphorus levels, we observed strong population fluctuations in all food chains with undefended algae. These fluctuations did not occur when algae had inducible defences. At low phosphorus levels, we observed deterministic consumer extinctions, as predicted by stoichiometric theory. Our study thus shows that both biotically and abiotically induced changes in algal food quality affect the stability and persistence of planktonic food chains.     

Inhibition of protein kinase CbetaII increases glucose uptake in 3T3-L1 adipocytes through elevated expression of glucose transporter 1 at the plasma membrane

The mechanism via which diacylglycerol-sensitive protein kinase Cs (PKCs) stimulate glucose transport in insulin-sensitive tissues is poorly defined. Phorbol esters, such as phorbol-12-myristate-13-acetate (PMA), are potent activators of conventional and novel PKCs. Addition of PMA increases the rate of glucose uptake in many different cell systems. We attempted to investigate the mechanism via which PMA stimulates glucose transport in 3T3-L1 adipocytes in more detail. We observed a good correlation between the rate of disappearance of PKCbetaII during prolonged PMA treatment and the increase in glucose uptake. Moreover, inhibition of PKCbetaII with a specific myristoylated PKCbetaC2-4 peptide inhibitor significantly increased the rate of glucose transport. Western blot analysis demonstrated that both PMA treatment and incubation with the myristoylated PKCbetaC2-4 pseudosubstrate resulted in more glucose transporter (GLUT)-1 but not GLUT-4 at the plasma membrane. To our knowledge, we are the first to demonstrate that inactivation of PKC, most likely PKCbetaII, elevates glucose uptake in 3T3-L1 adipocytes. The observation that PKCbetaII influences the rate of glucose uptake through manipulation of GLUT-1 expression levels at the plasma membrane might reveal a yet unidentified regulatory mechanism involved in glucose homeostasis.     

Downregulation of GABA Transporter 3 (GAT3) is Associated with Deficient Oxidative GABA Metabolism in Human Induced Pluripotent Stem Cell-Derived Astrocytes in Alzheimer's Disease

Neurochemical Research - Alterations in neurotransmitter homeostasis, primarily of glutamate and GABA, is strongly implicated in the pathophysiology of Alzheimer’s disease (AD). Homeostasis...     

Effects of artificial ultraviolet-B radiation on experimental aquatic microcosms

1. The effects of prolonged ultraviolet-B (UVB) radiation on freshwater communities were studied in indoor microcosms (600 L) with artificial light sources, simulating a clear, shallow, mesotrophic aquatic ecosystem. A range of six intensities (in duplicate) of UVB radiation, ranging from 0 (control) to 9.56 kJ m⁻² day⁻¹ at the water surface, was applied for 8 weeks. The UVB radiation levels, attenuation, shading and scattering were comparable to those in Dutch shallow freshwater systems. Physical, chemical and biological variables were monitored weekly.
2. The UVB treatment did not affect the abundance, species composition or biovolume of the phytoplankton or zooplankton communities, nor did it affect the periphyton or the macroinvertebrate community. A few species showed a significant response on some of the sampling dates, but there was no negative UVB effect at the community level. Overall, the ecosystems in the microcosms were not affected by the UVB treatment.
3. In a bio-assay, a laboratory clone of Daphnia pulex , not subjected to UVB radiation, was fed with seston from the microcosms. Daphnia pulex feeding on seston from the control microcosms grew faster, had better survival and better reproduction than D. pulex feeding on seston from the UVB treated microcosms. The phytoplankton–zooplankton interaction may have been influenced by the UVB treatment.
4. The dissolved oxygen content (DOC) concentrations in the microcosms were around 5 mg L^−1. The DOC levels in Dutch systems rarely fall below 10 mg L^−1. This might provide sufficient protection against the detrimental effects of increased UVB radiation.