New aspects of cellular cholesterol regulation on blood glucose control- review and perspective on the impact of statin medications on metabolic health

Cholesterol is an essential component of cell membranes, and during the past several years, diabetes researchers have found that membrane cholesterol levels in adipocytes, skeletal muscle fibers and pancreatic beta cells influence insulin action and insulin secretion. Consequently, it is thought that dysregulated cell cholesterol homeostasis could represent a determinant of type 2 diabetes (T2D). Recent clinical findings compellingly add to this notion by finding increased T2D susceptibility in individuals with alterations in a variety of cholesterol metabolism genes. While it remains imperfectly understood how statins influence glucose metabolism, the fact that they display an influence on blood glucose levels and diabetes susceptibility seems to intensify the emerging importance of understanding cellular cholesterol in glucose metabolism. Taking this into account, this review first presents cell system and animal model findings that demonstrate the negative impact of cellular cholesterol accumulation or diminution on insulin action and insulin secretion. With this framework, a description of how changes in cholesterol metabolism genes are associated with T2D susceptibility will be presented. In addition, the connection between statins and T2D risk will be reviewed with expanded information on pitavastatin, a newer statin medication that displays actions favoring metabolic healt

Feasibility of multiphoton microscopy-based quantification of antibiotic uptake into neutrophil granulocytes

Antibiotic levels in livestock are usually evaluated through destructive analysis. Taking advantage of the fluorescent properties of marbofloxacin (MBX) and trovafloxacin (TVX), multiphoton microscopy (MPM) was evaluated as a minimally invasive and nondestructive method to determine the penetration of TVX and MBX into sheep neutrophils. Standard curves were measured with drug-only solutions and suggested that MBX was more suited for this type of analysis. The intracellular concentration of both TVX and MBX was higher than the extracellular concentration after incubating neutrophils for 30 min at concentrations ranging from 0.1 to 100 mu g/ml for both the drugs. The intracellular concentration of TVX increased with the extracellular concentration but was always greater than the extracellular concentration, suggesting active internalization. On the other hand, intracellular/extracellular ratio (I/E) peaked at 1.6-fold I/E for 1 mu g/ml and then gradually decreased with increased concentration to 1.2-fold I/E at 100 mu g/ml. For the first time, this study showed the use of MPM to quantify antibiotic uptake by sheep neutrophils and observed that both antibiotics were taken up by sheep neutrophils beyond extracellular levels. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI

Changes in the redox state and endogenous fluorescence of in vivo human skin due to intrinsic and photo-aging, measured by multiphoton tomography with fluorescence lifetime imaging

Ultraviolet radiation from solar exposure is a key extrinsic factor responsible for premature skin aging (i.e., photo-aging). Recent advances using in vivo multiphoton tomography (MPT) demonstrate the efficacy of this approach to assess intrinsic and extrinsic skin aging as an alternative to existing invasive techniques. In this study, we measured changes in epidermal autofluorescence, dermal collagen second harmonic generation (SHG), and the redox state of solar-exposed and solar-protected human skin by MPT with fluorescence lifetime imaging (MPT-FLIM). Twenty-four volunteers across four age categories (20 to 29, 30 to 39, 40 to 49, and 50 to 59 years old; six volunteers each) were recruited for MPT-FLIM imaging of the dorsal (solar-exposed; photo-damaged) and volar (solar-protected) forearm. We demonstrate a higher intensity of dermal collagen SHG within the volar forearm compared to dorsal solar-exposed skin. Redox imaging of each epidermal skin stratum by FLIM demonstrates an increase in fluorescence lifetime in the solar-exposed dorsal forearm that is more apparent in aged skin. The results of this study suggest the redox state of the viable epidermis is a key marker in assessing intrinsic and photo-damage skin aging, in combination with changes in autofluorescence and SHG

Climate simulation of the latest Permian: Implications for mass extinction

This report presents the results of climate modeling research which indicates that elevated levels of carbon dioxide in the atmosphere at the end of the Permian period led to climatic conditions inhospitable to both marine and terrestrial life. The Permian-Triassic boundary (about 251 million years ago) was the time of the largest known mass extinction in Earth's history, when greater than ninety percent of all marine species, and approximately seventy percent of all terrestrial species, died out. The model, which used paleogeography and paleotopography correct for the time period, indicated that warm high-latitude surface air temperatures and elevated carbon dioxide levels may have resulted in slowed circulation and stagnant, anoxic conditions in Earth's oceans. The report also suggests that the excess carbon dioxide (and sulfur dioxide) may have originated from volcanic activity associated with eruption of the Siberian Trap flood basalts, which took place at the same time. Educational levels: Undergraduate lower division, Undergraduate upper division, Graduate or professional

Relative uptake of minoxidil into appendages and stratum corneum and permeation through human skin in vitro

We examined uptake of the model therapeutic agent, minoxidil, into appendages, stratum corneum (SC), and through human skin, under the influence of different vehicles. Quantitative estimation of therapeutic drug deposition into all three areas has not previously been reported. Finite doses of minoxidil (2%, w/v) in formulations containing varying amounts of ethanol, propylene glycol (PG), and water (60:20:20, 80:20:0, and 0:80:20 by volume, respectively) were used. Minoxidil in SC (by tape stripping), appendages (by cyanoacrylate casting), and receptor fluid was determined by liquid scintillation counting. At early times (30 min, 2 h), ethanol-containing formulations (60:20:20 and 80:20:0) caused significantly greater minoxidil retention in SC and appendages, compared to the formulation lacking ethanol (0:80:20). A significant increase in minoxidil receptor penetration occurred with the PG-rich 0:80:20 formulation after 12 h. We showed that deposition of minoxidil into appendages, SC, and skin penetration into receptor fluid were similar in magnitude. Transport by the appendageal route is likely to be a key determinant of hair growth promotion by minoxidil. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:712–718, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64562/1/21856_ftp.pd

Minoxidil skin delivery from nanoemulsion formulations containing eucalyptol or oleic acid: Enhanced diffusivity and follicular targeting

In this work, we examined enhanced skin delivery of minoxidil applied in nanoemulsions incorporating skin penetration enhancers. Aliquots of fully characterized oil-in-water nanoemulsions (1 mL), containing minoxidil (2%) and the skin penetration enhancer oleic acid or eucalyptol as oil phases, were applied to full-thickness excised human skin in Franz diffusion cells, while aqueous solutions (1 mL) containing minoxidil were used as controls. Minoxidil in the stratum corneum (SC), hair follicles, deeper skin layers, and flux through the skin over 24 h was determined, as well as minoxidil solubility in the formulations and in the SC. The nanoemulsions significantly enhanced the permeation of minoxidil through skin compared with control solutions. The eucalyptol formulations (NE) promoted minoxidil retention in the SC and deeper skin layers more than did the oleic acid formulations, while the oleic acid formulations (NO) gave the greatest hair follicle penetration. Minoxidil maximum flux enhancement was associated with increases in both minoxidil SC solubility and skin diffusivity in both nanoemulsion systems. The mechanism of enhancement appeared to be driven largely by increased diffusivity, rather than increased partitioning into the stratum corneum, supporting the concept of enhanced fluidity and disruption of stratum corneum lipids

Generating Entangled Two-Photon States with Coincident Frequencies

It is shown that parametric downconversion, with a short-duration pump pulse and a long nonlinear crystal that is appropriately phase matched, can produce a frequency-entangled biphoton state whose individual photons are coincident in frequency. Quantum interference experiments which distinguish this state from the familiar time-coincident biphoton state are described.Comment: Revised version (a typo was corrected) as published on PR

UVA and UVB formulation phototoxicity in a three-dimensional human skin model: photodegradation effect

In vitro three-dimensional human skin models are an innovative alternative to evaluate cytotoxicity and phototoxicity in the cosmetic industry. The aim of this study was to use a skin model to evaluate the potential toxicity of sunscreen formulations with or without exposure to UV radiation. In addition, the toxicity of these formulations was evaluated after exposure to photodegradation. The results showed toxicity with all formulations/conditions tested, including the control formulation, compared to PBS. Cell viability of photodegraded formulations - prior to the phototoxicity radiation process - was higher, indicating that some formulation components were degraded into products with reduced toxicity. The results also indicated that avobenzone was more unstable/toxic than octyl p-methoxycinnamate under the same test conditions. The sunscreens and their formulations were shown to be toxic to skin model cells to some extent, even when not exposed to UV irradiation; however the biological role of this toxicity is unclear. This result shows the importance of testing sunscreen formulations in real in-use conditions. Finally, since we used an in vitro assay based on a human cell model, this non-invasive technique represents a suitable alternative to animal models for phototoxicity tests in general and could have application in screening new sunscreen products

Microneedle Enhanced Delivery of Cosmeceutically Relevant Peptides in Human Skin

Peptides and proteins play an important role in skin health and well-being. They are also found to contribute to skin aging and melanogenesis. Microneedles have been shown to substantially enhance skin penetration and may offer an effective means of peptide delivery enhancement. The aim of this investigation was to assess the influence of microneedles on the skin penetration of peptides using fluorescence imaging to determine skin distribution. In particular the effect of peptide chain length (3, 4, 5 amino acid chain length) on passive and MN facilitated skin penetration was investigated. Confocal laser scanning microscopy was used to image fluorescence intensity and the area of penetration of fluorescently tagged peptides. Penetration studies were conducted on excised full thickness human skin in Franz type diffusion cells for 1 and 24 hours. A 2 to 22 fold signal improvement in microneedle enhanced delivery of melanostatin, rigin and pal-KTTKS was observed. To our knowledge this is the first description of microneedle enhanced skin permeation studies on these peptides