In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors

The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 (SLC47A1) and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and in vivo pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice. Of 57 TKIs evaluated, 37 potently inhibited MATE1 function by >80% through a non-competitive, reversible, substrate-independent mechanism. The urinary excretion of oxaliplatin was reduced by about 2-fold in mice with a deficiency of MATE1 or both OCT2 and MATE1 (p < 0.05), without impacting markers of acute renal injury. In addition, genetic or pharmacological inhibition of MATE1 did not significantly alter plasma levels of oxaliplatin, suggesting that MATE1 inhibitors are unlikely to influence the safety or drug-drug interaction liability of oxaliplatin-based chemotherapy.

Beyond the Human? A Critique of Transhumanism

According to transhumanists, the human being in its current shape is fundamentally imperfect. Consequently, they propagate possibilities of enhancing and reshaping one’s body, culminating in the idea of virtual immortality, i.e., transferring one’s mind as software onto more durable substrates (“mind uploading”). Such ideas are based on a blatant mind-body dualism: the body is regarded as a material vehicle, which is at our free disposal; the mind is considered to be a substrate-independent information structure. In contrast, the chapter argues that humans are neither natural machines nor pure minds but living beings in the first place. The idea of mind uploading is thus based on an untenable neuro-reductionism, which wrongly assumes the brain to be the only substrate of the mind. Similarly, the ideas of optimizing the body overlook the necessary balance of functions that has evolved in human evolution.

Development of an Anti-infective Coating on the Surface of Intraosseous Implants Responsive to Enzymes and Bacteria

BackgroundBacterial proliferation on the endosseous implants surface presents a new threat to the using of the bone implants. Unfortunately, there is no effective constructed antibacterial coating which is bacterial anti-adhesion substrate-independent or have long-term biofilm inhibition functions. MethodsDrug release effect was tested in CMS solution and S. aureus. We used bacterial inhibition rate assays and protein leakageexperiment to analyze the in vitro antibacterial effect of (MMT/PLL-CHX)10 multilayer film. We used the CCK-8 assay to analyze the effect of (MMT/PLL-CHX)10 multilayer films on the growth and proliferation of rat osteoblasts. Rat orthopaedic implant-related infections model was constructed to test the antimicrobial activity effect of (MMT/PLL-CHX)10 multilayer films in vivo.ResultsIn this study, the (MMT/PLL-CHX)10 multilayer films structure were progressively degraded and showed well concentration-dependent degradation characteristics following incubation with Staphylococcus aureus and CMS solution. Bacterial inhibition rate assays and protein leakageexperiment showed high levels of bactericidal activity. While the CCK-8 analysis proved that the (MMT/PLL-CHX)10 multilayer films possess perfect biocompatibility. It is somewhat encouraging that in the in vivo antibacterial tests, the K-wires coated with (MMT/PLL-CHX)10 multilayer films showed lower infections incidence and inflammation than the unmodified group, and all parameters are close to SHAM group. Conclusion(MMT/PLL-CHX)10 multilayer films provides a potential therapeutic method for orthopaedic implant-related infections.