76 research outputs found
Prevention of UV-Induced Skin Damages by 11,14,17-Eicosatrienoic Acid in Hairless Mice In Vivo
Polyunsaturated fatty acids (PUFAs) are known to play important roles in various physiological and pathological processes. Recent studies have shown that some omega-3 (Ï-3) PUFAs, such as eicosapentaenoic acid (EPA) and dodecahexaenoic acid (DHA), have protective effects on acute and chronic UV-induced changes. However, the effects of other Ï-3 PUFAs including 11,14,17-eicosatrienoic acid (20:3) (ETA) on UV-induced skin damages are poorly understood. In this study, we investigated the cutaneous photoprotective effects of ETA in hairless mice in vivo. Female HR-1 hairless mice were topically treated with vehicle (ethanol:polyethylene glycol=30:70) only, 0.1% ETA, or 1% ETA once a day for 3 successive days after one time UV irradiation (200 mJ/cm2) on dorsal skins. Skin biopsy was carried out on the fourth day (72 hr after UV irradiation). We found that topical treatment with ETA attenuated UV-induced epidermal and dermal thickness and infiltration of inflammatory cells, and impairment of skin barrier function. In addition, ETA suppressed the expression of IL-1ÎČ, COX-2, and MMP-13 induced by UV irradiation. Our results show that the topical application of ETA protects against UV-induced skin damage in hairless mice and suggest that ETA can be a potential agent for preventing and/or treating UV-induced inflammation and photoaging
Systemic multilineage engraftment in mice after in utero transplantation with human hematopoietic stem cells
In utero hematopoietic cell transplantation (IUHCT) is a potential therapy for the treatment of numerous
genetic diseases such as hemoglobinopathies, immunodeficiencies, and inborn errors of metabolism.1 In
utero therapy offers the benefit of avoiding host myeloablation and immunosuppression and has been
shown to be successful in multiple animal models, including mice,2-5 dogs,6,7 pigs,8,9 and sheep.10-12
The timing of IUHCT exposes the transplanted human cells to the normal fetal migratory and
developmental cues that facilitate proper stem cell distribution and differentiation.11,12 Clinically, IUHCT
has been successful for fetuses with severe combined immunodeficiency (SCID),13,14 but therapeutic
uses for other diseases, including hemoglobinopathies, have seen limited success.15 Further
investigations identified multiple barriers to successful engraftment, including lack of space within the
hematopoietic niche16,17 and the maternal immune system.2,18 Among available animal models of
IUHCT, the fetal mouse remains an efficient and reproducible model to study the differentiation of stem
cells in a nonirradiated host. NSG (NOD-SCID IL2Rg-null) mice, which are developed with SCID and
IL-2Rg-null chain mutations, are a robust platform for the engraftment of human hematopoietic cells
because they have no endogenous T, B, or natural killer cells.19-22 In this study, we used IUHCT of
human CD341 cells in NSG mice to create a reproducible mouse model to study stem cell engraftment,
differentiation, and systemic repopulation after IUHCT
A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components
Screening constant by unit nuclear charge calculations for (n s2)1Se, (np2)1De and (N s n p)1Pâ excited states of He-like systems
Characterization of LY2775240, a selective phosphodiesteraseâ4 inhibitor, in nonclinical models and in healthy subjects
Abstract LY2775240 is a highly selective, potent and orallyâadministered inhibitor of phosphodiesterase 4 (PDE4), and is being investigated as a treatment option for inflammatory disorders, such as psoriasis. LY2775240 was investigated in rodent and rhesus monkey nonclinical models. Treatment with LY2775240 led to significant reductions in TNFα production, a marker of PDE4 engagement upon immune activation, in both nonclinical models. In the first part of a 2âpart firstâinâhuman randomized study, a wide dose range of LY2775240 was safely evaluated and found to be wellâtolerated with common adverse events (AEs) of nausea, diarrhea, and headache. No serious AEs were reported. The pharmacokinetic profile of LY2775240 was wellâcharacterized, with a halfâlife that can support onceâaâday dosing. An ex vivo pharmacodynamic (PD) assay demonstrated doseâdependent PDE4 target engagement as assessed by reduction in TNFα production. A 20 mg dose of LY2775240 led to nearâmaximal TNFα inhibition in this PD assay in the first part of the study and was selected for comparison with the clinical dose of apremilast (30 mg) in the crossover, second part of this study. The 20 mg dose of LY2775240 demonstrated sustained maximal (50%â80%) inhibition of TNFα over all timepoints over the 24âh duration. The comparator apremilast achieved peak inhibition of ~ 50% at only 4 h postdose with a return to about 10% inhibition within 12 h of dosing. In summary, the nonclinical data and safety, tolerability, and PK/PD data in healthy subjects supports further investigation of LY2775240 in inflammatory indications. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Phosphodiesterase 4 (PDE4) inhibitors, such as apremilast, are currently approved to treat autoimmune disorders, such as psoriasis. LY2775240 is an oral PDE4 inhibitor being developed for treatment of a variety of inflammatory disorders. The degree of enzymatic inhibition achieved by PDE4 inhibitors clinically is poorly understood. WHAT QUESTION DID THIS STUDY ADDRESS? This study investigated single ascending doses of LY2775240, a highly selective oral PDE4 inhibitor, in healthy subjects. LY2775240 was wellâtolerated over the dose range evaluated, and pharmacokinetic/pharmacodynamic (PD) profiles were wellâcharacterized. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study evaluated different doses of LY2775240 and subsequently compared a selected LY2775240 dose with the clinical dose of apremilast with an ex vivo assay. This information builds a connection between target engagement and clinical efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This is the first report of an ex vivo PD assay that has been systematically implemented in a PDE4 inhibitor Phase 1 study. Early investigation of exposureâresponse relationships versus a comparator can support evaluation of clinically meaningful doses of investigational agents
Novel Synthesis of 2-Arylbenzothiazoles Mediated by Ceric Ammonium Nitrate (CAN): A Rebuttal
CostâUtility Analysis of Mindfulness-Based Cognitive Therapy Versus Antidepressant Pharmacotherapy for Prevention of Depressive Relapse in a Canadian Context: Analyse coĂ»t-utilitĂ© de la thĂ©rapie cognitive basĂ©e sur la pleine conscience contre la pharmacothĂ©rapie antidĂ©pressive pour prĂ©venir la rechute de la dĂ©pression en contexte canadien
Revisiting Hughesâ dynamic continuum model for pedestrian flow and the development of an efficient solution algorithm
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