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Lipophilic Molecule (lipophilic + molecule)
Selected AbstractsRetinoic acid, a regeneration-inducing moleculeDEVELOPMENTAL DYNAMICS, Issue 2 2003Malcolm Maden Abstract Retinoic acid (RA) is the biologically active metabolite of vitamin A. It is a low molecular weight, lipophilic molecule that acts on the nucleus to induce gene transcription. In amphibians and mammals, it induces the regeneration of several tissues and organs and these examples are reviewed here. RA induces the "super-regeneration" of organs that can already regenerate such as the urodele amphibian limb by respecifying positional information in the limb. In organs that cannot normally regenerate such as the adult mammalian lung, RA induces the complete regeneration of alveoli that have been destroyed by various noxious treatments. In the mammalian central nervous system (CNS), which is another tissue that cannot regenerate, RA does not induce neurite outgrowth as it does in the embryonic CNS, because one of the retinoic acid receptors, RAR,2, is not up-regulated. When RAR,2 is transfected into the adult spinal cord in vitro, then neurite outgrowth is stimulated. In all these cases, RA is required for the development of the organ, in the first place suggesting that the same gene pathways are likely to be used for both development and regeneration. This suggestion, therefore, might serve as a strategy for identifying potential tissue or organ targets that have the capacity to be stimulated to regenerate. Developmental Dynamics 226:237,244, 2003.© 2003 Wiley-Liss, Inc. [source] Doublecortin-expressing cells in the ischemic penumbra of a small-vessel strokeJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2008Rui Hua Abstract A cortical lesion was induced by disrupting the medium-size pial vessels, which led to a cone-shaped cortical lesion and turned into a fluid-filled cavity surrounded by a glial acidic fibrillary protein-positive (GFAP+) glia limitans 21 days after injury. Therefore, it mimics conditions of lacunar infarctions, one of the most frequent human stroke pathologies. Doublecortin (DCX)-positive cells were present in the neocortex and corpus callosum at the base of the lesion. The number of DCX-positive cells in the corpus callosum was significantly increased from day 5 to day 14 compared with the control group. In contrast, there were no DCX-positive cells in neocortex of control animals; the DCX-positive cells appeared in the neocortex after lesioning and were maintained until 14 days postlesioning. Some of the DCX-positive cells were also immunoreactive for ,III-tubulin, another marker of immature neurons. They did not stain positively for markers of glia cells. The presence of these DCX-positive cells near the lesion might indicate a migratory pathway for developing neuroblasts from the subventricular zone (SVZ) through the corpus callosum to the lesion. SVZ cells were labeled with a lipophilic molecule, 5- (and 6-) carboxyfluorescein diacetate succinimidyl ester (CFSE) stereotaxical injections. Although rostral migratory stream and olfactory bulb were intensely labeled, no CFSE-containing cells were found in the cortex beneath the lesion. These results do not support the idea that the DCX-positive cells were originating from neural precursors of the SVZ, but they might be generated from local progenitor cells. © 2007 Wiley-Liss, Inc. [source] Melatonin suppresses tumor angiogenesis by inhibiting HIF-1, stabilization under hypoxiaJOURNAL OF PINEAL RESEARCH, Issue 2 2010Shi-Young Park Abstract:, Angiogenesis is an important mediator of tumor progression. As tumors expand, diffusion distances from the existing vascular supply increases, resulting in hypoxia in the cancer cells. Sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and nutrients. The key regulator of hypoxia-induced angiogenesis is the transcription factor known as hypoxia-inducible factor (HIF)-1. HIF-1, is stabilized by hypoxia-induced reactive oxygen species (ROS) and enhances the expression of several types of hypoxic genes, including that of the angiogenic activator known as vascular endothelial cell growth factor (VEGF). In this study, we found that melatonin, a small lipophilic molecule secreted primarily by the pineal gland, destabilizes hypoxia-induced HIF-1, protein levels in the HCT116 human colon cancer cell line. This destabilization of HIF-1, resulted from the antioxidant activity of melatonin against ROS induced by hypoxia. Moreover, under hypoxia, melatonin suppressed HIF-1 transcriptional activity, leading to a decrease in VEGF expression. Melatonin also blocked in vitro tube formation and invasion and migration of human umbilical vein endothelial cells induced by hypoxia-stimulated conditioned media of HCT116 cells. These findings suggest that melatonin could play a pivotal role in tumor suppression via inhibition of HIF-1-mediated angiogenesis. [source] The Effects of 5-Aminolevulinic Acid Esters on Protoporphyrin IX Production in Human Adenocarcinoma Cell Lines,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2001H. Brunner ABSTRACT Photodynamic diagnosis (PDD) and photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA),induced protoporphyrin IX (PPIX) is an interesting approach to detect and treat dysplasia and early cancers in the gastrointestinal tract. Because of low lipophilicity resulting in poor penetration across cell membranes, high doses of ALA should be administered in order to reach clinically relevant levels of PPIX. One way of increasing PPIX accumulation is derivatization of ALA into a more lipophilic molecule. In our in vitro study, different esterifications of ALA were investigated to analyze the effects on PPIX accumulation in human adenocarcinoma cell lines. For systematic analysis of cell type,specific PPIX accumulation, three human adenocarcinoma cell lines (SW480, HT29 and CaCo2) and a fibroblast cell line (CCD18) were tested. 3-(4,5-Dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) assays were performed to ensure that the ALA esters showed no cellular dark toxicity. Different concentrations (ranging from 0.012 to 0.6 mmol/L, 3 h) and incubation times (5, 10, 30, 180 min; 0.12 mmol/L) were examined. PPIX accumulation was measured using flow cytometry. ALA esters, especially ALA-hexylester and ALA-benzylester, induced significant higher PPIX levels in adenocarcinoma cell lines when compared with ALA and may be promising candidates for PDT and PDD. [source] The effect of stationary phase on lipophilicity determination of , -blockers using reverse-phase chromatographic systemsBIOMEDICAL CHROMATOGRAPHY, Issue 10 2005Tomasz Welerowicz Abstract Evaluation of lipophilicity parameters for basic compounds using different chromatographic stationary phases is presented. An HPLC method for determination of lipophilic molecule,stationary phase interactions was based on gradient analysis. Differences in correlation between the lipophilicity of compounds and experimental chromatographic results obtained in pseudo-membrane systems showed a strong influence of stationary phase structure and physico-chemical properties. , -Blocker drugs with varying lipophilicity and bio-activity were chosen as test compounds. The stationary phases used for the study were monolithic rod-structure C18 and silica gel octadecyl phase SG-C18 as reference material. The second group was silica gel-based polar-embedded alkylamide and cholesterolic phases. The mobile phase was composed of acetonitrile or methanol with ammonium acetate, and a linear gradient of methanol and acetonitrile in mobile phase was performed. A linear correlation of plots of log kg = f(log P) was observed, especially for polar-embedded phases, and this allowed log PHPLC to be calculated. The behavior of stationary phases in methanol and acetonitrile buffer showed differences between obtained log PHPLC values. Copyright © 2005 John Wiley & Sons, Ltd. [source] Differential expression of nitric oxide synthases in human scalp epidermal and hair follicle pigmentary units: implications for regulation of melanogenesisBRITISH JOURNAL OF DERMATOLOGY, Issue 2 2005H.M. Sowden Summary Background, Nitric oxide (NO) is a ubiquitous gaseous lipophilic molecule generated from the conversion of l -arginine to l -citrulline by the NO synthases (NOSs). Ultraviolet radiation (UVR)-induced NO production appears to stimulate epidermal melanogenesis. However, given their relative protection from UVR, it is unclear whether NO plays a similar role in hair bulb melanocytes. Objectives, We aimed to identify the expression profiles of the NOS isoforms endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS) and of phosphorylated eNOS and nitrotyrosine within the epidermal and follicular melanin units of normal human haired scalp during the hair growth cycle. Methods, This study employed single and double immunohistochemical and immunofluorescence staining techniques using haired scalp from 10 healthy individuals (six women and four men). Results, Melanocytes in the basal layer of the epidermis expressed eNOS, nNOS and nitrotyrosine. By contrast, melanogenically active melanocytes of the anagen hair bulb were wholly negative for these markers. However, other follicular melanocytes not actively involved in pigment production, including undifferentiated melanocytes located in the outer root sheath and melanocytes surviving the apoptosis-driven hair follicle (HF) regression during catagen/telogen, expressed eNOS, nNOS and nitrotyrosine. While iNOS was only weakly expressed in the basal layer of the human epidermis, it was highly expressed in keratinocytes of the inner root sheath (IRS), where it colocalized with trichohyalin, a differentiation-associated protein of the IRS that requires enzyme-catalysed conversion of arginine to citrulline. Conclusions, The NOS isoforms and nitrotyrosine are differentially expressed in different cutaneous melanocyte subpopulations. Results of this study suggest a possible role for eNOS, nNOS, iNOS and nitrotyrosine in melanocyte biology, particularly with respect to melanogenesis and melanocyte survival during HF regression. Another example of possible NO involvement in HF biology is the postsynthetic modification of trichohyalin in differentiating keratinocytes of the IRS. These results suggest that NO may influence several aspects of HF biology. [source] Atomic Interactions and Profile of Small Molecules Disrupting Protein,Protein Interfaces: the TIMBAL DatabaseCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2009Alícia P. Higueruelo Growing evidence of the possibility of modulating protein,protein interactions with small molecules is opening the door to new approaches and concepts in drug discovery. In this paper, we describe the creation of TIMBAL, a hand-curated database holding an up to date collection of small molecules inhibiting multi-protein complexes. This database has been analysed and profiled in terms of molecular properties. Protein,protein modulators tend to be large lipophilic molecules with few hydrogen bond features. An analysis of TIMBAL's intersection with other structural databases, including CREDO (protein,small molecule from the PDB) and PICCOLO (protein,protein from the PDB) reveals that TIMBAL molecules tend to form mainly hydrophobic interactions with only a few hydrogen bonding contacts. With respect to potency, TIMBAL molecules are slightly less efficient than an average medicinal chemistry hit or lead. The database provides a resource that will allow further insights into the types of molecules favoured by protein interfaces and provide a background to continuing work in this area. Access at http://www-cryst.bioc.cam.ac.uk/timbal [source] | ||||||||||