1-Laurin-3-Palmitin as a Novel Matrix of Solid Lipid Particles: Higher Loading Capacity of Thymol and Better Stability of Dispersions Than Those of Glyceryl Monostearate and Glyceryl Tripalmitate

To develop solid lipid nanoparticles (SLNs) with a new lipid matrix for delivery of hydrophobic bioactive molecules, high purity 1-laurin-3-palmitin (1,3-LP) was synthesized and the prepared 1,3-LP SLNs were compared with those of two common SLN matrices in glyceryl monostearate (GMS) and glyceryl tripalmitate (PPP). Conditions of preparing SLNs were first optimized by evaluating the particle size, polydispersity index (PDI), zeta-potential, and stability. Thereafter, the performance of SLN loading of a model compound in thymol was studied. The loading capacity of thymol in 1,3-LP SLNs was 16% of lipids and higher than 4% and 12% for GMS- and PPP-SLNs, respectively. The 1,3-LP SLNs also had the best efficiency to entrapment thymol during the prolonged storage. X-ray diffraction (XRD) analyses confirmed the excellent crystalline stability of 1,3-LP leading to the stable entrapment efficiency and better stability of thymol-loaded SLNs. Conversely, the polymorphic transformation of GMS and PPP resulted in the declined entrapment efficiency of thymol in the corresponding SLNs. This work indicated the 1,3-diacylglycerol (DAG) SLNs could be used as a promising delivery system for the encapsulation of hydrophobic bioactive molecules with high loading capacity and stability

Core-Shell Nanoencapsulation of α-Tocopherol by Blending Sodium Oleate and Rebaudioside A: Preparation, Characterization, and Antioxidant Activity

Nanoencapsulation of α-tocopherol (α-TOC) by blending sodium oleate (NaOl) and rebaudioside A (RebA) was successfully prepared by self-assembly method under mild conditions. The optimized nanoemulsion showed the loading capacity of α-TOC was 30 wt% of sodium oleate. FTIR analysis suggested that hydrogen bonds and hydrophobic interactions were the major forces in α-TOC-NaOl/RebA complexes that were spherical and possessed well-distinguishable core-shell structures. The freeze-dried α-TOC-NaOl/RebA complexes had great stability under ambient conditions. The release profile of α-TOC showed a first-order kinetics reaching around 67.9% after 90 h at 25 °C. Nanoencapsulation improved dispersibility and greatly increased the antioxidant activity of α-TOC. Therefore, the stable α-TOC-NaOl/RebA core-shell complexes prepared from “generally recognized as safe„ (GRAS) ingredients have great potential to supplement α-TOC in food and cosmetic products

SIRT6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer

SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability, and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here, we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis. SIRT6 promoted expression of COX-2 by repressing AMPK signaling, thereby increasing cell proliferation and survival in the skin epidermis. SIRT6 expression in skin keratinocytes was increased by exposure to UVB light through activation of the AKT pathway. Clinically, we found that SIRT6 was upregulated in human skin squamous cell carcinoma. Taken together, our results provide evidence that SIRT6 functions as an oncogene in the epidermis and suggest greater complexity to its role in epithelial carcinogenesis. (C) 2014 AACR

Translational profiling identifies sex-specific metabolic and epigenetic reprogramming of cortical microglia/macrophages in APPPS1-21 mice with an antibiotic-perturbed-microbiome

Background: Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining homeostasis. In preceding studies, we showed that antibiotic-induced perturbations of the gut microbiome of APPPS1-21 mice resulted in significant attenuation in Aβ amyloidosis and altered microglial phenotypes that are specific to male mice. The molecular events underlying microglial phenotypic transitions remain unclear. Here, by generating ‘APPPS1-21-CD11br’ reporter mice, we investigated the translational state of microglial/macrophage ribosomes during their phenotypic transition and in a sex-specific manner. Methods: Six groups of mice that included WT-CD11br, antibiotic (ABX) or vehicle-treated APPPS1-21-CD11br males and females were sacrificed at 7-weeks of age (n = 15/group) and used for immunoprecipitation of microglial/macrophage polysomes from cortical homogenates using anti-FLAG antibody. Liquid chromatography coupled to tandem mass spectrometry and label-free quantification was used to identify newly synthesized peptides isolated from polysomes. Results: We show that ABX-treatment leads to decreased Aβ levels in male APPPS1-21-CD11br mice with no significant changes in females. We identified microglial/macrophage polypeptides involved in mitochondrial dysfunction and altered calcium signaling that are associated with Aβ-induced oxidative stress. Notably, female mice also showed downregulation of newly-synthesized ribosomal proteins. Furthermore, male mice showed an increase in newly-synthesized polypeptides involved in FcγR-mediated phagocytosis, while females showed an increase in newly-synthesized polypeptides responsible for actin organization associated with microglial activation. Next, we show that ABX-treatment resulted in substantial remodeling of the epigenetic landscape, leading to a metabolic shift that accommodates the increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex-specific manner. While microglia in ABX-treated male mice exhibited a metabolic shift towards a neuroprotective phenotype that promotes Aβ clearance, microglia in ABX-treated female mice exhibited loss of energy homeostasis due to persistent mitochondrial dysfunction and impaired lysosomal clearance that was associated with inflammatory phenotypes. Conclusions: Our studies provide the first snapshot of the translational state of microglial/macrophage cells in a mouse model of Aβ amyloidosis that was subject to ABX treatment. ABX-mediated changes resulted in metabolic reprogramming of microglial phenotypes to modulate immune responses and amyloid clearance in a sex-specific manner. This microglial plasticity to support neuro-energetic homeostasis for its function based on sex paves the path for therapeutic modulation of immunometabolism for neurodegeneration.</p

Caffeine Promotes Ultraviolet B-induced Apoptosis in Human Keratinocytes without Complete DNA Repair*

In response to ultraviolet B damage, keratinocytes undergo apoptosis to eliminate damaged cells, thereby preventing tumorigenic transformation. Caffeine, the most widely consumed psychoactive substance, produces complex pharmacological actions; it has been shown to be chemopreventive in non-melamona skin cancer in mice through increasing apoptosis. Here we have investigated the molecular and cellular mechanisms in the pro-apoptotic effect of caffeine on UVB-irradiated human HaCaT keratinocytes. Pretreatment with caffeine increased UVB-induced apoptosis in HaCaT cells. Caffeine blocked UVB-induced Chk1 phosphorylation. In addition, similar to the effect of the PI3K inhibitor LY294002, caffeine also inhibited phosphorylation of AKT and up-regulation of COX-2, two critical oncogenic pathways in skin tumorigenesis. However, phosphorylation of EGFR or ERK was unaffected. Inhibiting ATR pathways by siRNA targeting ATR had little effect on UVB-induced apoptosis or AKT activation, indicating that the inhibitory effect of caffeine on apoptosis and the AKT pathway does not require the ATR pathway. Inhibiting AKT by caffeine blocked UVB-induced COX-2 up-regulation. Expression of constitutively active AKT that was not inhibited by caffeine was found to protect cells from caffeine-promoted apoptosis post-UVB irradiation, indicating that AKT is an essential inhibitory target for caffeine to promote apoptosis. Caffeine specifically sensitized cells with unrepaired DNA damage to UVB-induced apoptosis. These findings indicate that in HaCaT keratinocytes, inhibiting the AKT/COX-2 pathways through an ATR-independent pathway is a critical molecular mechanism by which caffeine promotes UVB-induced apoptosis of unrepaired keratinocytes for elimination