Takeuchi C.S.,Exelixis |
Kim B.G.,Exelixis |
Kim B.G.,Asan Institute of Life Science |
Blazey C.M.,Exelixis |
And 27 more authors.
Journal of Medicinal Chemistry | Year: 2013
A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity. © 2013 American Chemical Society.
Inceoglu B.,University of California at Davis |
Zolkowska D.,University of California at Davis |
Yoo H.J.,Asan Institute of Life Science |
Wagner K.M.,University of California at Davis |
And 7 more authors.
PLoS ONE | Year: 2013
In the brain, seizures lead to release of large amounts of polyunsaturated fatty acids including arachidonic acid (ARA). ARA is a substrate for three major enzymatic routes of metabolism by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes. These enzymes convert ARA to potent lipid mediators including prostanoids, leukotrienes and epoxyeicosatrienoic acids (EETs). The prostanoids and leukotrienes are largely pro-inflammatory molecules that sensitize neurons whereas EETs are anti-inflammatory and reduce the excitability of neurons. Recent evidence suggests a GABA-related mode of action potentially mediated by neurosteroids. Here we tested this hypothesis using models of chemically induced seizures. The level of EETs in the brain was modulated by inhibiting the soluble epoxide hydrolase (sEH), the major enzyme that metabolizes EETs to inactive molecules, by genetic deletion of sEH and by direct administration of EETs into the brain. All three approaches delayed onset of seizures instigated by GABA antagonists but not seizures through other mechanisms. Inhibition of neurosteroid synthesis by finasteride partially blocked the anticonvulsant effects of sEH inhibitors while the efficacy of an inactive dose of neurosteroid allopregnanolone was enhanced by sEH inhibition. Consistent with earlier findings, levels of prostanoids in the brain were elevated. In contrast, levels of bioactive EpFAs were decreased following seizures. Overall these results demonstrate that EETs are natural molecules which suppress the tonic component of seizure related excitability through modulating the GABA activity and that exploration of the EET mediated signaling in the brain could yield alternative approaches to treat convulsive disorders.
Kwon H.-S.,University of Ulsan |
Kim T.-B.,University of Ulsan |
Lee Y.S.,University of Ulsan |
Jeong S.-H.,University of Ulsan |
And 5 more authors.
Annals of Allergy, Asthma and Immunology | Year: 2014
Background Oxidative stress is thought to play a role in the pathogenesis of asthma. Clusterin is a sensitive cellular biosensor of oxidative stress and has antioxidant properties. The function and expression of clusterin in patients with asthma have not been fully investigated. Objective To investigate whether the expression of clusterin in patients with asthma is regulated by increased oxidative burden and whether clusterin expression could be used to assess the response to inhaled corticosteroids. Methods Clusterin levels in serum, induced sputum, and peripheral blood mononuclear cells of patients with asthma were measured by enzyme-linked immunosorbent assay and western blotting and compared with pulmonary function and levels of expression of hyperoxidized peroxiredoxins. Serum concentrations of clusterin in treatment-naive patients were compared before and after inhaled corticosteroid use. Results Serum clusterin concentration was significantly elevated in patients with severe asthma and was inversely correlated with pulmonary function. The expression of hyperoxidized peroxiredoxins was greatly increased in peripheral blood mononuclear cells of patients with asthma and was strongly correlated with clusterin expression. Serum clusterin concentrations in treatment-naive patients with asthma were decreased significantly after initial treatment with inhaled corticosteroids. Conclusion Clusterin may be a biomarker of asthma severity and the burden of oxidative stress in patients with asthma. Moreover, clusterin may be useful for the prompt assessment of airway inflammation. © 2014 American College of Allergy, Asthma & Immunology.
Kim G.B.,Asan Institute of Life Science |
Ha H.,Pohang University of Science and Technology |
Kweon J.,Asan Institute of Life Science |
Lee S.J.,Pohang University of Science and Technology |
And 3 more authors.
Magnetic Resonance Imaging | Year: 2016
Purpose: To investigate the details of the flow structure of a plug-like jet that had a vortex ring in pulsatile stenotic phantoms using 4D flow MRI. Method: Pulsatile Newtonian flows in two stenotic phantoms with 50% and 75% reductions in area were scanned by 4D flow MRI. Blood analog working fluid was circulated via the stenotic phantom using a pulsatile pump at a constant pulsating frequency of 1 Hz. The velocity and vorticity fields of the plug-like jet with a vortex ring were quantitatively analyzed in the spatial and temporal domains. Results: Pulsatile stenotic flow showed a plug-like jet at the specific stenotic degree of 50% in our pulsatile waveform design. This plug-like jet was found at the decelerating period in the post-stenotic region of 26.4 mm (1.2 D). It revealed a vortex ring structure with vorticity strength in the range of ±100 s-1. Conclusion: We observed a plug-like jet with a vortex ring in pulsatile stenotic flow by in vitro visualization using 4D flow MRI. In this plug-like jet, the local fastest flow region occurred at the post-systole phase in the post-stenotic region, which was distinguishable from a typical stenotic jet flow at systole phase. © 2015 Elsevier Inc.
Rhee D.Y.,University of Ulsan |
Cho H.I.,Asan Institute of Life Science |
Park G.-H.,Hallym University |
Moon H.-R.,University of Ulsan |
And 9 more authors.
Journal of Cosmetic and Laser Therapy | Year: 2016
Background: Nonablative lasers have been widely used to improve photodamaged skin, although the mechanism underlying dermal collagen remodeling remains unclear. Objective: To investigate the effects and the molecular mechanisms of long-pulse neodymium-doped yttrium aluminum garnet (Nd:YAG) laser irradiation on dermal collagen remodeling in association with different pulse durations. Material and methods: Five hairless mice were pretreated with ultraviolet B irradiation for 8 weeks. The dorsal quadrant of each mouse was then irradiated twice at 1-week intervals at a pulse duration of 1 ms, 12 ms, or 50 ms, and a constant fluence of 20 J/cm2. The levels of dermal collagen, mRNAs of procollagens, matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), and various growth factors were analyzed after 4 weeks. Results: Long-pulse Nd:YAG treatment increased the dermal collagen level. A substantial increase in the level of procollagens, MMPs, TIMPs, and various growth factors was also observed irrespective of pulse duration, with a trend toward maximal increase at a pulse duration of 12 ms. Conclusion: Long-pulse 1,064-nm Nd:YAG laser irradiation promotes wound-healing process, which is characterized by the induction of growth factor expression and subsequent increase in MMPs and TIMPs, followed by matrix remodeling as confirmed by new procollagen production. © 2016 Taylor & Francis Group, LLC.