Itch is a major indicator of psoriasis, but the underlying mechanisms behind this symptom are largely unknown. To investigate the neuronal mechanisms of psoriatic itch, we tested whether mice subjected to the imiquimod-induced psoriasis model exhibit itch-associated behaviors. Mice received daily topical applications of imiquimod to the rostral back skin for seven days. Imiquimod-treated mice exhibited a significant increase in spontaneous scratching behavior directed to the treated area as well as touch-evoked scratching (alloknesis). To characterize this model, we measured the mRNA expression levels of pruritogens and itch-relevant receptors/channels using real-time RT-PCR. The mRNA expression of MrgprA3, MrgprC11, and MrgprD decreased gradually over time in the dorsal root ganglion (DRG) cells. There was no significant change in the mRNA expression of TRPV1 or TRPA1 in DRG cells. TRPV4 mRNA expression was transiently increased in the DRG cells, while TRPM8 mRNA was significantly decreased. The mRNA expression levels of histidine decarboxylase and tryptophan hydroxylase 1, as well as the intensity of histamine and serotonin immunoreactivity, were transiently increased in the skin on day 2, returning to baseline by day 7. Histamine H1 receptor (H1R) antagonists, chlorpheniramine and olopatadine, significantly inhibited spontaneous scratching on day 2, but not day 7. Neither chlorpheniramine nor olopatadine affected alloknesis on day 2 or day 7. These results may reflect the limited antipruritic effects of H1R antagonists on human psoriasis. The imiquimod-induced psoriasis model appears to be useful for the investigation of itch and its sensitization in psoriasis.

Objective-Pyripyropene A (PPPA) of fungal origin is the first compound that has been found to strongly and selectively inhibit acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) isozyme activity in vitro. The purpose of the present study was to investigate in vivo efficacy of the ACAT2-selective inhibitor in atherosclerosis. Methods and Results-PPPA treatment (10 to 100 mg/kg) caused 30.5Ϯ4.7% to 55.8Ϯ3.3% inhibition of the cholesterol absorption from the mouse intestine. When PPPA (10 to 50 mg/kg per day) was orally administered to apolipoprotein E-knockout mice for 12 weeks, the levels of plasma cholesterol, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) and hepatic cholesterol content were lowered. Furthermore, the ratio of cholesteryl oleate (exclusively synthesized in hepatic ACAT2) to cholesteryl linoleate in VLDL-and LDL-derived cholesteryl ester decreased, indicating that hepatic ACAT2 activity was inhibited by PPPA. PPPA-treated mice had reduced atherogenic lesion areas that were lowered by 26.2Ϯ3.7% to 46Ϯ3.8% in the aortae and by 18.9Ϯ3.6% to 37.6Ϯ6.0% in the hearts. Conclusion-Our findings indicate that ACAT2-selective inhibition in the intestine and the liver can be effective against atherosclerosis and that PPPA appears to be a potential antiatherogenic lead compound. This study is the first demonstration of the in vivo efficacy of PPPA, an ACAT2-selective inhibitor, in atherosclerosis. PPPA-treated atherogenic mice showed a decrease in intestinal cholesterol absorption and cholesterol and cholesteryl oleate levels in both LDL and VLDL, resulting in protection of atherosclerosis development. Key Words: atherosclerosis Ⅲ hypercholesterolemia Ⅲ inhibitors C ardiovascular diseases are a group of disorders of the heart and blood vessels. They represent the leading cause of death globally, with more individuals dying each year from cardiovascular diseases than from any other cause. Statins, which are inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A reductase, reduce the risk of complications and death from cardiovascular events by approximately 30%. 1 Consequently, the quest for novel pharmacological agents that target specific steps of atherogenesis has intensified significantly in recent years. The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT), which catalyzes the synthesis of cholesteryl ester (CE) from free cholesterol and long-chain fatty acyl-coenzyme A, has been considered a promising therapeutic target. 2 Although a number of synthetic ACAT inhibitors have been developed, they have failed to reduce cardiovascular events in clinical trials.Two ACAT isozymes have been identified in mammals: ACAT1 and ACAT2. [3][4][5][6] Each isozyme has a distinct pattern of expression among tissues. Although ACAT1 is ubiquitously expressed at a high level in sebaceous glands, steroidogenic tissues, and macrophages, ACAT2 is expressed predominantly in the liver and intestine. 7 ACAT1-selective inhibition may cause detrimental effects, 8 -10 whereas ACAT2-selective inhibitio...

Itch consists of both sensory and affective components. For chronic itch patients, the affective component of itch affects both quality of life (leading to psychological comorbidities) and disease prognosis (by promoting scratching of itchy skin). We found that acute itch stimuli, such as histamine, induced anxiety-like behavior and increased activity (c-Fos expression) in the amygdala in adult male C57BL/6 mice. Itch stimuli also increased activity in projection areas to the amygdala, suggesting that these regions form a circuit for affective itch processing. Electrophysiological characterization of histamine-responsive amygdala neurons showed that this population was active on a behaviorally relevant timescale and partially overlapped with pain signaling. Selective optogenetic activation of histamine-responsive amygdala neurons in adult male and female Fos:CreER T2 ;R26 Ai14 mice using the Targeted Recombination in Active Populations system enhanced both scratching and anxiety-like behavior. These results highlight the importance of itch-responsive amygdala neurons in modulating itch-related affect and behavior.The sensation of itch includes an affective component that leads to stress and anxiety in chronic itch patients. We investigated the neuronal basis of affective itch in mice, with a focus on the amygdala, the key brain region for the generation of anxiety. A subpopulation of amygdala neurons responded to itch stimuli such as histamine. Optogenetic activation of histamine-responsive amygdala neurons affected both scratching and anxiety-like behavior. Therefore, this population appears to be important for mediating the affective component of itch.

Atherosclerotic cardiovascular diseases are the leading cause of mortality in industrialized countries, despite advances in the management of coronary risk factors. Heart attacks arise from the thrombotic occlusion of coronary arteries following the rupture of plaques. Characteristic of these rupture-prone plaques is their lipid-rich nature due to the presence of cholesteryl ester (CE)-laden macrophage foam cells ( 1 ).The hydrolysis of intracellular CE, the initial step of reverse cholesterol transport, is catalyzed by multiple enzymes: neutral cholesterol ester hydrolase 1 (NCEH1) ( 2 ), also known as KIAA1363 or arylacetamide deacetylase-like 1 (AADACL1) ( 3 ), hormone-sensitive lipase (LIPE) ( 4 ), and possibly carboxylesterase 1 (CES1) ( 5, 6 ). NCEH1 is a microsomal protein tethered to the endoplasmic reticulum (ER) membrane by its N terminus with the rest of the protein containing the catalytic domain residing in the ER Abbreviations: acLDL, acetyl-LDL; Bip, immunoglobulin heavy chain-binding protein; CE, cholesteryl ester; CHOP, CCAAT/enhancer-binding protein-homologous protein; ER, endoplasmic reticulum; 25-HC, 25-hydroxycholesterol; 27-HC, 27-hydroxycholesterol; Hmgcs1 , 3-hydroxy-3-methylglutaryl-CoA synthase 1; 7-KC, 7-ketocholesterol; LD, lipid droplet; LIPE, hormone-sensitive lipase; LPDS, lipoprotein defi cient serum; LXR, liver X receptor; NCEH1, neutral cholesterol ester hydrolase 1; PPPA, pyripyropene A; Srebp, sterol regulatory element binding protein; TEM, transmission electron microscopy; TGEM, thioglycollate-elicited peritoneal macrophage; TUNEL, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; Xbp-1, X-box-binding protein 1 . This work was supported by a grant-in-aid from Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists, a grant-in-aid for Scientifi c Research from the Ministry of Education and Science, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) and JKA through its promotion funds from KEIRIN RACE, and MEXT-Supported Program for the Strategic Research

Disturbance of circadian rhythms underlies various metabolic diseases. Constant light exposure (LL) is known to disrupt both central and peripheral circadian rhythms. Here, we attempted to determine whether the effects of LL are different between various peripheral tissues and whether time-restricted feeding restores the circadian rhythms especially in white adipose tissue (WAT). Six-week-old mice were subjected to three feeding regimes: ad libitum feeding under light/dark phase (LD), ad libitum feeding under LL cycle, and restricted feeding at night-time under LL cycle with a normal chow. After 3 weeks, we compared body weight, food intake, plasma levels of lipids and glucose, and the expression patterns of the clock genes and the genes involved in lipid metabolism in the liver and WAT. The mice kept under LL with or without time-restricted feeding were 5.2% heavier (p<0.001, n = 16) than the mice kept under LD even though the food intakes of the two groups were the same. Food intake occurred mostly in the dark phase. LL disrupted this pattern, causing disruptions in circadian rhythms of plasma levels of triglycerides (TG) and glucose. Time-restricted feeding partially restored the rhythms. LL eliminated the circadian rhythms of the expression of the clock genes as well as most of the genes involved in lipid metabolism in both liver and WAT. More notably, LL markedly decreased not only the amplitude but also the average levels of the expression of the genes in the liver, but not in the WAT, suggesting that transcription in the liver is sensitive to constant light exposure. Time-restricted feeding restored the circadian rhythms of most of the genes to various degrees in both liver and WAT. In conclusion, LL disrupted the peripheral circadian