The potassium channel Kcne3 is a VEGFA-inducible gene selectively expressed by vascular endothelial tip cells.

Angiogenesis is largely driven by motile endothelial tip-cells capable of invading avascular tissue domains and enabling new vessel formation. Highly responsive to Vascular Endothelial Growth-Factor-A (VEGFA), endothelial tip-cells also suppress angiogenic sprouting in adjacent stalk cells, and thus have been a primary therapeutic focus in addressing neovascular pathologies. Surprisingly, however, there remains a paucity of specific endothelial tip-cell markers. Here, we employ transcriptional profiling and a lacZ reporter allele to identify Kcne3 as an early and selective endothelial tip-cell marker in multiple angiogenic contexts. In development, Kcne3 expression initiates during early phases of angiogenesis (E9) and remains specific to endothelial tip-cells, often adjacent to regions expressing VEGFA. Consistently, Kcne3 activation is highly responsive to exogenous VEGFA but maintains tip-cell specificity throughout normal retinal angiogenesis. We also demonstrate endothelial tip-cell selectivity of Kcne3 in several injury and tumor models. Together, our data show that Kcne3 is a unique marker of sprouting angiogenic tip-cells and offers new opportunities for investigating and targeting this cell type.

Modulation of Energy Transfer into Sequential Electron Transfer upon Axial Coordination of Tetrathiafulvalene in an Aluminum(III) Porphyrin-Free-Base Porphyrin Dyad.

Axially assembled aluminum(III) porphyrin based dyads and triads have been constructed to investigate the factors that govern the energy and electron transfer processes in a perpendicular direction to the porphyrin plane. In the aluminum(III) porphyrin-free-base porphyrin (AlPor-Ph-H2Por) dyad, the AlPor occupies the basal plane, while the free-base porphyrin (H2Por) with electron withdrawing groups resides in the axial position through a benzoate spacer. The NMR, UV-visible absorption, and steady-state fluorescence studies confirm that the coordination of pyridine appended tetrathiafulvalene (TTF) derivative (TTF-py or TTF-Ph-py) to the dyad in noncoordinating solvents afford vertically arranged supramolecular self-assembled triads (TTF-py→AlPor-Ph-H2Por and TTF-Ph-py→AlPor-Ph-H2Por). Time-resolved studies revealed that the AlPor in dyad and triads undergoes photoinduced energy and/or electron transfer processes. Interestingly, the energy and electron donating/accepting nature of AlPor can be modulated by changing the solvent polarity or by stimulating a new competing process using a TTF molecule. In modest polar solvents (dichloromethane and o-dichlorobenzene), excitation of AlPor leads singlet-singlet energy transfer from the excited singlet state of AlPor ((1)AlPor*) to H2Por with a moderate rate constant (k(EnT)) of 1.78 × 10(8) s(-1). In contrast, excitation of AlPor in the triad results in ultrafast electron transfer from TTF to (1)AlPor* with a rate constant (k(ET)) of 8.33 × 10(9)-1.25 × 10(10) s(-1), which outcompetes the energy transfer from (1)AlPor* to H2Por and yields the primary radical pair TTF(+•)-AlPor(-•)-H2Por. A subsequent electron shift to H2Por generates a spatially well-separated TTF(+•)-AlPor-H2Por(-•) radical pair.

Isolation of steroidal glycosides from the Caribbean sponge Pandaros acanthifolium.

Four new steroidal glycosides, acanthifoliosides G-J (1-4), were isolated as minor constituents from the Caribbean marine sponge Pandaros acanthifolium. These metabolites are characterized by a highly oxygenated D ring and the presence of a disaccharide rhamnose-glucose residue and a rhamnose at positions C-3 and C-15, respectively. Their structures were established on the basis of extensive interpretation of 1D and 2D NMR data and HRESIMS analyses. The absolute configurations of the glucose and rhamnose sugars were determined by preparing aldose o-tolylthiocarbamate derivatives and comparison to authentic standards by LC/HRESIMS. Acanthifolioside G (1) exhibited antioxidant and cytoprotective activities.

Embryonic stem cell tumor model reveals role of vascular endothelial receptor tyrosine phosphatase in regulating Tie2 pathway in tumor angiogenesis.

Inhibiting angiogenesis has become an effective approach for treating cancer and other diseases. However, our understanding of signaling pathways in tumor angiogenesis has been limited by the embryonic lethality of many gene knockouts. To overcome this limitation, we used the plasticity of embryonic stem (ES) cells to develop a unique approach to study tumor angiogenesis. Murine ES cells can be readily manipulated genetically; in addition, ES cells implanted subcutaneously in mice develop into tumors that contain a variety of cell types (teratomas). We show that ES cells differentiate into bona fide endothelial cells within the teratoma, and that these ES-derived endothelial cells form part of the functional tumor vasculature. Using this powerful and flexible system, the Angiopoietin/Tie2 system is shown to have a key role in the regulation of tumor vessel size. Endothelial differentiation in the ES teratoma model allows gene-targeting methods to be used in the study of tumor angiogenesis.

Iron oxides in novel skin care formulations attenuate blue light for enhanced protection against skin damage.

BACKGROUND: Ultraviolet (UV) radiation is a main cause of aging of sun-exposed skin, but greater attention is being focused on the damaging effects of high-energy visible (HEV) light (400 and 500 nm). HEV light exposure has increased with expanding use of consumer electronics, such as smartphones, which have a peak emission in the 400-490 nm range. Sunscreens containing titanium dioxide and zinc oxide protect against UVA and UVB radiation but provide limited protection against HEV light. AIM: Iron oxides including red iron oxide (Fe2 O3 ), yellow iron oxide (Fe(OH)3 /FeOOH), and black iron oxide (Fe3 O4 ) effectively block HEV light, each with a different attenuation profile. Zinc oxide, titanium dioxide, and iron oxides with patented skin care ingredients have been incorporated into several formulations to provide enhanced skin protection (Colorescience, Inc). METHODS: The percent of HEV light attenuation from 400 nm to 490 nm light was measured in vitro using a technique known as diffuse transmittance spectroscopy using a Perkin Elmer Lambda™ 750 UV/Vis/NIR Spectrophotometer equipped with a 100-mm integrating Labsphere® and PbS detector. RESULTS: Products formulated with zinc oxide, titanium dioxide, and iron oxides demonstrated 71.9%-85.6% attenuation across the tested wavelengths of 415-465 nm. CONCLUSION: Sunscreens formulated with iron oxides provide enhanced protection against blue light, especially when combined with zinc oxide. To our knowledge, similar studies with iron oxides have not been performed.

Beyond sun protection factor: An approach to environmental protection with novel mineral coatings in a vehicle containing a blend of skincare ingredients.

BACKGROUND: Premature skin aging results from exposure to a range of environmental factors, primarily ultraviolet radiation, but also high-energy visible light in the blue spectrum, infrared radiation, and environmental pollution. These extrinsic factors result in the generation of reactive oxygen species which promote photoaging and DNA damage resulting in skin cancers. AIMS: To formulate skincare products utilizing a new coating applied to zinc oxide and titanium dioxide particles and complimentary skincare ingredients to provide broad protection against a range of environmental insults. METHODS: A cross-polymer, multifunctional coating of silicate, polyalkylsilsesquioxane, and polydimethylsiloxane moieties increases the photostability and decreases the reactivity of mineral sunscreen agents when interacting with energy sources. These products are also formulated with antioxidants to minimize free radical propagation. Additionally, this coating improves the esthetic feel of mineral sunscreens, while the appearance is enhanced by formulating products with a blend of iron oxides. RESULTS: A series of in vitro and ex vivo studies demonstrated the ability of mineral-based products formulated with the new multifunctional coating to provide protection against ultraviolet radiation, high-energy visible light, infrared radiation, and environmental pollution. CONCLUSION: Newly formulated mineral-based skincare products provide environmental protection, are ecologically safe, and can replace chemical-based sunscreen ingredients.

A cucurbit[6]uril analogue: host properties monitored by fluorescence spectroscopy.

This paper describes the host properties of a new cucurbit[6]uril analogue, studied by fluorescence and 1H NMR spectroscopy. This host has an elongated cavity with oval-shaped portals. It is intrinsically fluorescent, and more importantly, this fluorescence is sensitive to guest encapsulation, allowing for the study of the inclusion of nonfluorescent guests by fluorescence spectroscopy. In the case of benzene as guest, significant enhancement of the cucurbit[6]uril analogue host fluorescence was observed upon addition of benzene; this allowed for the determination of the binding constant for 1:1 host-guest complexation, yielding a value of K = 6900 +/- 1100 M(-1). This complexation was also studied by 1H NMR, yielding a similar value of K = 8980 +/- 500 M(-1). The binding of a much larger guest, the dye Nile Red, was also studied, but in this case using guest fluorescence. Significant suppression of the Nile Red fluorescence was observed upon 1:1 complexation with the cucurbit[6]uril analogue, with an extremely large binding constant of 8.2 +/- 0.5 x 10(6) M(-1), indicating a very strong host-guest interaction and an excellent size and shape match. In both cases, binding was much stronger than in the case of the same guests with cucurbit[6]uril itself, and in the case of Nile Red, binding was also much stronger than with modified beta- or gamma-cyclodextrins. This is partly a result of the partial aromatic nature of the host walls, which allow for pi-pi interactions not possible in cucurbiturils or cyclodextrins. The ability to study its inclusion complexes using either host or guest fluorescence, and the very high binding constants observed, illustrates the versatility and potential usefulness of this new host compound.

Sea foam as a source of fungal inoculum for the isolation of biologically active natural products.

Due to a rate increase in the resistance of microbial pathogens to currently used antibiotics, there is a need in society for the discovery of novel antimicrobials. Historically, fungi are a proven source for antimicrobial compounds. The main goals of this study were to investigate the fungal diversity associated with sea foam collected around the coast of Prince Edward Island and the utility of this resource for the production of antimicrobial natural products. Obtained isolates were identified using ITS and nLSU rDNA sequences, fermented on four media, extracted and fractions enriched in secondary metabolites were screened for antimicrobial activity. The majority of the isolates obtained were ascomycetes, consisting of four recognized marine taxa along with other ubiquitous genera and many 'unknown' isolates that could not be identified to the species level using rDNA gene sequences. Secondary metabolite isolation efforts lead to the purification of the metabolites epolones A and B, pycnidione and coniothyrione from a strain of Neosetophoma samarorum; brefeldin A, leptosin J and the metabolite TMC-264 from an unknown fungus (probably representative of an Edenia sp.); and 1-hydroxy-6-methyl-8-hydroxymethylxanthone, chrysophanol and chrysophanol bianthrone from a Phaeospheria spartinae isolate. The biological activity of each of these metabolites was assessed against a panel of microbial pathogens as well as several cell lines.

VEGF-Trap: a VEGF blocker with potent antitumor effects.

Vascular endothelial growth factor (VEGF) plays a critical role during normal embryonic angiogenesis and also in the pathological angiogenesis that occurs in a number of diseases, including cancer. Initial attempts to block VEGF by using a humanized monoclonal antibody are beginning to show promise in human cancer patients, underscoring the importance of optimizing VEGF blockade. Previous studies have found that one of the most effective ways to block the VEGF-signaling pathway is to prevent VEGF from binding to its normal receptors by administering decoy-soluble receptors. The highest-affinity VEGF blocker described to date is a soluble decoy receptor created by fusing the first three Ig domains of VEGF receptor 1 to an Ig constant region; however, this fusion protein has very poor in vivo pharmacokinetic properties. By determining the requirements to maintain high affinity while extending in vivo half life, we were able to engineer a very potent high-affinity VEGF blocker that has markedly enhanced pharmacokinetic properties. This VEGF-Trap effectively suppresses tumor growth and vascularization in vivo, resulting in stunted and almost completely avascular tumors. VEGF-Trap-mediated blockade may be superior to that achieved by other agents, such as monoclonal antibodies targeted against the VEGF receptor.