U 18666A

U 18666A is an inhibitor of cholesterol transport and synthesis [1] [2].

Cholesterol is a sterol that biosynthesized by all animal cells and is an essential component of all animal cell membranes that is required to maintain membrane fluidity and structural integrity.

U 18666A is an inhibitor of cholesterol transport and synthesis. In rat brain, U 18666A inhibited sterols production in a concentration-dependent way [1]. In cultured Chinese hamster ovary (CHO) cells, U18666A inhibited cholesterol esterification stimulated by low density lipoprotein (LDL)-derived cholesterol and also inhibited LDL receptor activities and 3-hydroxy-3-methylglutaryl-coenzyme A reductase. U18666A caused the accumulation of LDL-derived cholesterol in the lysosomes, suggesting the inhibition of LDL-derived cholesterol transport [2]. In cultured baby hamster kidney cells and human skin fibroblasts (HSF), U18666A reversibly and rapidly inhibited acyl-CoA cholesterol acyl transferase (ACAT) activated by sphingomyelinase in a dose dependent way. In sphingomyelinase-treated HSF cells, U18666A significantly and reversibly reduced the translocation of plasma membrane cholesterol. In mouse Leydig tumor cells, U18666A inhibited steroid hormones secretion stimulated by cyclic AMP in a dose dependent way [3]. In primary cortical neurons, U18666A caused cellular injury and caspase-3 activation. U18666A also caused the accumulation of cholesterol [4].

References:
[1].  Cenedella RJ. Concentration-dependent effects of AY-9944 and U18666A on sterol synthesis in brain. Variable sensitivities of metabolic steps. Biochem Pharmacol, 1980, 29(20): 2751-2754.
[2].  Liscum L, Faust JR. The intracellular transport of low density lipoprotein-derived cholesterol is inhibited in Chinese hamster ovary cells cultured with 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one. J Biol Chem, 1989, 264(20): 11796-11806.
[3].  Härmälä AS, Pörn MI, Mattjus P, Slotte JP. Cholesterol transport from plasma membranes to intracellular membranes is inhibited by 3 beta-[2-(diethylamino)ethoxy]androst-5-en-17-one. Biochim Biophys Acta, 1994, 1211(3): 317-325.
[4].  Cheung NS, Koh CH, Bay BH, et al. Chronic exposure to U18666A induces apoptosis in cultured murine cortical neurons. Biochem Biophys Res Commun, 2004, 315(2): 408-417.

Living with the Choice: A Grounded Theory of Iraqi Refugee Resettlement to the U.S.[Pubmed:28379737]

Issues Ment Health Nurs. 2017 Apr;38(4):352-360.

Though the United States has become a place of increasing resettlement for refugees, particularly Iraqi refugees who have been forced to flee their homeland due to violence, persecution and civil unrest, little is known about Iraqi refugee resettlement in the United States, or the way in which resettlement impacts health and adjustment. A grounded theory study was conducted to develop a substantive theory of Iraqi refugee resettlement. Participants in the qualitative study included 29 Iraqi refugees and 2 community partners who participated in face-to face interviews. Data analysis and interpretation revealed fundamental concepts related to Iraqi refugee resettlement. Results of analysis showed that for Iraqis choosing to resettle here, the outcome is dichotomous: satisfaction or regret. The outcome is influenced by contextual factors as well as facilitating and hindering intervening conditions during the basic social process of resettlement transition. Each refugee's story is unique, yet all share common threads. This study allowed Iraqi refugees the opportunity to voice their personal experiences of resettling in America, and revealed life stories that inspire and illuminate a process that can guide health care delivery as they cope with the stresses of their journey. As a result, an in-depth storyline was established to explain the process of resettlement for Iraqi refugees. The development of this resettlement theory, grounded in Iraqi refugee experience, has the potential to guide nursing education, enhance the efficacy of practice, inform policy development and form the basis for research.

Metformin use and survival after non-small cell lung cancer: A cohort study in the US Military health system.[Pubmed:28380674]

Int J Cancer. 2017 Jul 15;141(2):254-263.

Research suggests that metformin may be associated with improved survival in cancer patients with type II diabetes. This study assessed whether metformin use after non-small cell lung cancer (NSCLC) diagnosis is associated with overall survival among type II diabetic patients with NSCLC in the U.S. military health system (MHS). The study included 636 diabetic patients with histologically confirmed NSCLC diagnosed between 2002 and 2007, identified from the linked database from the Department of Defense's Central Cancer Registry (CCR) and the Military Health System Data Repository (MDR). Time-dependent multivariate Cox proportional hazards models were used to assess the association between metformin use and overall survival during follow-up. Among the 636 patients, 411 died during the follow-up. The median follow-up time was 14.6 months. Increased post-diagnosis cumulative use (per 1 year of use) conferred a significant reduction in mortality (adjusted hazard ratio (HR) = 0.76; 95% CI = 0.65-0.88). Further analysis by duration of use revealed that compared to non-users, the lowest risk reduction occurred among patients with the longest duration of use (i.e. use for more than 2 years) (HR = 0.19; 95% CI = 0.09-0.40). Finally, the reduced mortality was particularly observed only among patients who also used metformin before lung cancer diagnosis and among patients at early stage of diagnosis. Prolonged duration of metformin use in the study population was associated with improved survival, especially among early stage patients. Future research with a larger number of patients is warranted.

How Many U.S. High School Students Have a Foreign Language Reading "Disability"? Reading Without Meaning and the Simple View.[Pubmed:28380307]

J Learn Disabil. 2018 Mar/Apr;51(2):194-208.

Conventional wisdom suggests that students classified as learning disabled will exhibit difficulties with foreign language (FL) learning, but evidence has not supported a relationship between FL learning problems and learning disabilities. The simple view of reading model posits that reading comprehension is the product of word decoding and language comprehension and that there are good readers and 3 types of poor readers-dyslexic, hyperlexic, and garden variety-who exhibit different profiles of strengths and/or deficits in word decoding and language comprehension. In this study, a random sample of U.S. high school students completing first-, second-, and third-year Spanish courses were administered standardized measures of Spanish word decoding and reading comprehension, compared with monolingual Spanish readers from first to eleventh grades, and classified into reader types according to the simple view of reading. The majority of students fit the hyperlexic profile, and no participants fit the good reader profile until they were compared with first- and second-grade monolingual Spanish readers. Findings call into question the practice of diagnosing an FL "disability" before a student engages in FL study.

Cyclopamine inhibition of Sonic hedgehog signal transduction is not mediated through effects on cholesterol transport.[Pubmed:10926779]

Dev Biol. 2000 Aug 15;224(2):440-52.

Cyclopamine is a teratogenic steroidal alkaloid that causes cyclopia by blocking Sonic hedgehog (Shh) signal transduction. We have tested whether this activity of cyclopamine is related to disruption of cellular cholesterol transport and putative secondary effects on the Shh receptor, Patched (Ptc). First, we report that the potent antagonism of Shh signaling by cyclopamine is not a general property of steroidal alkaloids with similar structure. The structural features of steroidal alkaloids previously associated with the induction of holoprosencephaly in whole animals are also associated with inhibition of Shh signaling in vitro. Second, by comparing the effects of cyclopamine on Shh signaling with those of compounds known to block cholesterol transport, we show that the action of cyclopamine cannot be explained by inhibition of intracellular cholesterol transport. However, compounds that block cholesterol transport by affecting the vesicular trafficking of the Niemann-Pick C1 protein (NPC1), which is structurally similar to Ptc, are weak Shh antagonists. Rather than supporting a direct link between cholesterol homeostasis and Shh signaling, our findings suggest that the functions of both NPC1 and Ptc involve a common vesicular transport pathway. Consistent with this model, we find that Ptc and NPC1 colocalize extensively in a vesicular compartment in cotransfected cells.

The intracellular transport of low density lipoprotein-derived cholesterol is inhibited in Chinese hamster ovary cells cultured with 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one.[Pubmed:2745416]

J Biol Chem. 1989 Jul 15;264(20):11796-806.

In mammalian cells, low density lipoprotein (LDL) is bound, internalized, and delivered to lysosomes where LDL-cholesteryl esters are hydrolyzed to unesterified cholesterol. The mechanisms of intracellular transport of LDL-cholesterol from lysosomes to other cellular sites and LDL-mediated regulation of cellular cholesterol metabolism are unknown. We have identified a pharmacological agent, U18666A (3-beta-[2-diethyl-amino)ethoxy]androst-5-en-17-one), which impairs the intracellular transport of LDL-derived cholesterol in cultured Chinese hamster ovary (CHO) cells. U18666A blocks the ability of LDL-derived cholesterol to stimulate cholesterol esterification, and to suppress 3-hydroxy-3-methylglutaryl-coenzyme A reductase and LDL receptor activities. However, U18666A does not impair 25-hydroxycholesterol-mediated regulation of these processes. In addition, U18666A impedes the ability of LDL-derived cholesterol to support the growth of CHO cells. However, U18666A has only moderate effects on growth supported by non-lipoprotein cholesterol. LDL binding, internalization, and lysosomal hydrolysis of LDL-cholesteryl esters are not affected by the presence of U18666A. Analysis of intracellular cholesterol transport reveals that LDL-derived cholesterol accumulates in the lysosomes of U18666A-treated CHO cells which results in impaired movement of LDL-derived cholesterol to other cell membranes.