We present the use of functionalized gold nanoparticles (AuNPs) to combat multi-drug-resistant pathogenic bacteria. Tuning of the functional groups on the nanoparticle surface provided gold nanoparticles that were effective against both Gram-negative and Gram-positive uropathogens, including multi-drug-resistant pathogens. These AuNPs exhibited low toxicity to mammalian cells, and bacterial resistance was not observed after 20 generations. A strong structure–activity relationship was observed as a function of AuNP functionality, providing guidance to activity prediction and rational design of effective antimicrobial nanoparticles.

The novel hormone ghrelin is a potent orexigen that may counterbalance leptin. Ghrelin is the only secreted molecule requiring post-translational acylation with octanoic acid to ensure bioactivity. Ghrelin, predominantly derived from the stomach, may target neuroendocrine networks within the central nervous system (CNS) to regulate energy homeostasis. This would require ghrelin to cross the blood-brain barrier (BBB). In mice, we examined whether ghrelin crosses the BBB and whether its lipophilic side chain is involved in this process. We found that saturable systems transported human ghrelin from brain-to-blood and from bloodto-brain. Mouse ghrelin, differing from human ghrelin by two amino acids, was a substrate for the brain-to-blood but not for the blood-to-brain transporter and so entered the brain to a far lesser degree. des-Octanoyl ghrelin entered the brain by nonsaturable transmembrane diffusion and was sequestered once within the CNS. In summary, we show that ghrelin transport across the BBB is a complex, highly regulated bidirectional process. The direction and extent of passage are determined by the primary structure of ghrelin, defining a new role for the unique post-translational octanoylation.Ghrelin, a novel 28 residue peptide hormone, has recently been identified as an endogenous ligand of the growth-hormone secretagogue receptor and is characterized by a novel posttranslational acylation that ensures bioactivity (Kojima et al., 1999). Ghrelin is secreted in substantial amounts into circulation by the stomach and the intestine, whereas the CNS, as well as kidneys, placenta, pancreas, and pituitary, might produce miniscule amounts of ghrelin (Horvath et al., 2001).Ghrelin acts peripherally and in the brain to regulate growth hormone secretion (Arvat et al., 2001), energy homeostasis (Tschop et al., 2000), and other physiological processes (Bowers, 2001). Crucial targets of the anabolic action of ghrelin are agouti-related protein/neuropeptide Y neurons located in the arcuate nucleus (Tschop et al., 2002). It is debatable if substances entering the nearby median eminence, a circumventricular organ (CVO) with a deficient blood-brain barrier (BBB), could leak into the arcuate nucleus (Horvath et al., 2001). Some evidence, however, shows that the outer layer of cells comprising the CVOs form a barrier preventing diffusion between CVOs and the rest of the brain (Maness et al., 1995).Other neurons regulating energy balance that are targeted by ghrelin are located in CNS areas that are clearly protected by the BBB (Guan et al., 1997). This has raised the question of whether ghrelin is readily transported across BBB. It was once widely assumed that peptides and proteins could not cross the BBB. However, a number of peripheral hormones that participate in the regulation of energy have been shown to cross the BBB by saturable or nonsaturable mechanisms. Examples include leptin, insulin, and amylin (Baura et al., 1993;Banks et al., 1996;Banks and Kastin, 1998). Current efforts to better understand th...

Obesity is associated with leptin resistance as evidenced by hyperleptinemia. Resistance arises from impaired leptin transport across the blood-brain barrier (BBB), defects in leptin receptor signaling, and blockades in downstream neuronal circuitries. The mediator of this resistance is unknown. Here, we show that milk, for which fats are 98% triglycerides, immediately inhibited leptin transport as assessed with in vivo, in vitro, and in situ models of the BBB. Fat-free milk and intralipid, a source of vegetable triglycerides, were without effect. Both starvation and diet-induced obesity elevated triglycerides and decreased the transport of leptin across the BBB, whereas short-term fasting decreased triglycerides and increased transport. Three of four triglycerides tested intravenously inhibited transport of leptin across the BBB, but their free fatty acid constituents were without effect. Treatment with gemfibrozil, a drug that specifically reduces triglyceride levels, reversed both hypertriglyceridemia and impaired leptin transport. We conclude that triglycerides are an important cause of leptin resistance as mediated by impaired transport across the BBB and suggest that triglyceride-mediated leptin resistance may have evolved as an anti-anorectic mechanism during starvation. Decreasing triglycerides may potentiate the anorectic effect of leptin by enhancing leptin transport across the BBB. Diabetes 53

LPS given peripherally or into the brain induces a neuroinflammatory response. How peripheral LPS induces its effects on brain is not clear, but one mechanism is that LPS crosses the blood-brain barrier (BBB). Alternatively, LPS acts outside the BBB by stimulating afferent nerves, acting at circumventricular organs, and altering BBB permeabilities and functions. Here, we labeled LPS with radioactive iodine (I-LPS) and co-injected it with radioactively labeled albumin (I-Alb) which acted as a vascular space marker. Measurable amounts of I-LPS associated with the BBB, most reversibly bound to brain endothelia. Brain endothelia also sequestered small amounts of I-LPS and about 0.025% of an intravenously injected dose of I-LPS crossed the BBB to enter the CNS. Disruption of the BBB with repeated injections of LPS did not enhance I-LPS uptake. Based on dose-response curves in the literature of the amounts of LPS needed to stimulate brain neuroimmune events, it is unlikely that enough peripherally administered LPS enters the CNS to invoke those events except possibly at the highest doses used and for the most sensitive brain functions. I-LPS injected into the lateral ventricle of the brain entered the circulation with the reabsorption of cerebrospinal fluid (bulk flow) as previously described. In conclusion, brain uptake of circulating I-LPS is so low that most effects of peripherally administered LPS are likely mediated through LPS receptors located outside the BBB.