AMPK-Dependent Metabolic Regulation by PPAR Agonists

Comprehensive studies support the notion that the peroxisome proliferator-activated receptors, (PPARs), PPARα, PPARβ/δ, and PPARγ, regulate cell growth, morphogenesis, differentiation, and homeostasis. Agonists of each PPAR subtype exert their effects similarly or distinctly in different tissues such as liver, muscle, fat, and vessels. It is noteworthy that PPARα or PPARγ agonists have pharmacological effects by modulating the activity of AMPK, which is a key cellular energy sensor. However, the role of AMPK in the metabolic effects of PPAR agonists has not been thoroughly focused. Moreover, AMPK activation by PPAR agonists seems to be independent of the receptor activation. This intriguing action of PPAR agonists may account in part for the mechanistic basis of the therapeutics in the treatment of metabolic disease. In this paper, the effects of PPAR agonists on metabolic functions were summarized with particular reference to their AMPK activity regulation

A Novel Mechanism of PPARγ Regulation of TGFβ1: Implication in Cancer Biology

Peroxisome proliferator-activated receptor-γ (PPARγ) and retinoic acid X-receptor (RXR) heterodimer, which regulates cell growth and differentiation, represses the TGFβ1 gene that encodes for the protein involved in cancer biology. This review will introduce the novel mechanism associated with the inhibition of the TGFβ1 gene by PPARγ activation, which regulates the dephosphorylation of Zf9 transcription factor. Pharmacological manipulation of TGFβ1 by PPARγ activators can be applied for treating TGFβ1-induced pathophysiologic disorders such as cancer metastasis and fibrosis. In this article, we will discuss the opposing effects of TGFβ on tumor growth and metastasis, and address the signaling pathways regulated by PPARγ for tumor progression and suppression

Proto-Model of an Infrared Wide-Field Off-Axis Telescope

We develop a proto-model of an off-axis reflective telescope for infrared wide-field observations based on the design of Schwarzschild-Chang type telescope. With only two mirrors, this design achieves an entrance pupil diameter of 50 mm and an effective focal length of 100 mm. We can apply this design to a mid-infrared telescope with a field of view of 8 deg X 8 deg. In spite of the substantial advantages of off-axis telescopes in the infrared compared to refractive or on-axis reflective telescopes, it is known to be difficult to align the mirrors in off-axis systems because of their asymmetric structures. Off-axis mirrors of our telescope are manufactured at the Korea Basic Science Institute (KBSI). We analyze the fabricated mirror surfaces by fitting polynomial functions to the measured data. We accomplish alignment of this two-mirror off-axis system using a ray tracing method. A simple imaging test is performed to compare a pinhole image with a simulated prediction.Comment: 14 pages, 16 figure

Role of G{alpha}12 and G{alpha}13 as Novel Switches for the Activity of Nrf2, a Key Antioxidative Transcription Factor

G{alpha}12 and G{alpha}13 function as molecular regulators responding to extracellular stimuli. NF-E2-related factor 2 (Nrf2) is involved in a protective adaptive response to oxidative stress. This study investigated the regulation of Nrf2 by G{alpha}12 and G{alpha}13. A deficiency of G{alpha}12, but not of G{alpha}13, enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, G{alpha}12 knockout activated Nrf2 and thereby facilitated heme catabolism to bilirubin and its glucuronosyl conjugations. An oligonucleotide microarray demonstrated the transactivation of Nrf2 target genes by G{alpha}12 gene knockout. G{alpha}12 deficiency reduced Jun N-terminal protein kinase (JNK)-dependent Nrf2 ubiquitination required for proteasomal degradation, and so did G{alpha}13 deficiency. The absence of G{alpha}12, but not of G{alpha}13, increased protein kinase C {delta} (PKC {delta}) activation and the PKC {delta}-mediated serine phosphorylation of Nrf2. G{alpha}13 gene knockout or knockdown abrogated the Nrf2 phosphorylation induced by G{alpha}12 deficiency, suggesting that relief from G{alpha}12 repression leads to the G{alpha}13-mediated activation of Nrf2. Constitutive activation of G{alpha}13 promoted Nrf2 activity and target gene induction via Rho-mediated PKC {delta} activation, corroborating positive regulation by G{alpha}13. In summary, G{alpha}12 and G{alpha}13 transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas G{alpha}13 regulates Rho-PKC {delta}-mediated Nrf2 phosphorylation, which is negatively balanced by G{alpha}12

Task complexity interacts with state-space uncertainty in the arbitration between model-based and model-free learning

It has previously been shown that the relative reliability of model-based and model-free reinforcement-learning (RL) systems plays a role in the allocation of behavioral control between them. However, the role of task complexity in the arbitration between these two strategies remains largely unknown. Here, using a combination of novel task design, computational modelling, and model-based fMRI analysis, we examined the role of task complexity alongside state-space uncertainty in the arbitration process. Participants tended to increase model-based RL control in response to increasing task complexity. However, they resorted to model-free RL when both uncertainty and task complexity were high, suggesting that these two variables interact during the arbitration process. Computational fMRI revealed that task complexity interacts with neural representations of the reliability of the two systems in the inferior prefrontal cortex

GADOLINIUM CHLORIDE INHIBITION OF RAT HEPATIC MICROSOMAL EPOXIDE HYDROLASE AND GLUTATHIONE S-TRANSFERASE GENE EXPRESSION

ABSTRACT: The effects of gadolinium chloride, a Kupffer cell toxicant, on the constitutive and inducible expression of hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) genes were examined in rats. Northern blot analysis showed that treatment of rats with GdCl 3 caused suppression of mEH and GST gene expression. mEH mRNA levels were decreased in a time-dependent manner after a single injected dose of GdCl 3 (10 mg/kg, iv), resulting in 95, 55, 17, 36, and 69% of the levels in untreated animals at 6, 12, 18, 24, and 48 hr after treatment, respectively. A maximal reduction in GST Ya, Yb1/2, and Yc1 mRNA levels was also noted at 18 hr after treatment with GdCl 3 , followed by a gradual return to levels in untreated rats at later time points. Whereas treatment of rats with thiazole, allyl disulfide, propyl sulfide, oltipraz, or clotrimazole caused 2-13-fold increases in mEH mRNA levels at 18 hr after treatment, concomitant GdCl 3 treatment caused 30-70% reductions in the increases in mEH mRNA levels. The chemical-inducible mRNA levels for GST Ya, Yb1/2, and Yc1 were also significantly inhibited by GdCl 3 at 18 hr after treatment. Rats treated with GdCl 3 (10 mg/kg/day, iv) for 3-5 consecutive days exhibited 40-90% decreases in mEH, GST Ya, and GST Yb1/2 mRNA levels, relative to control, whereas the Yc1 mRNA level was suppressed at early times and returned to levels in untreated animals at day 5 after treatment. The mRNA levels for mEH and GST Ya in rats treated daily with both allyl disulfide (25 mg/kg, po) and GdCl 3 for 3 consecutive days were 20-30% of those in rats treated with allyl disulfide alone. Western immunoblotting showed that mEH and GST Ya protein expression was decreased at 1-3 days after consecutive daily treatment with GdCl 3 . Whereas treatment of rats with GdCl 3 at a dose of 1 mg/kg suppressed constitutive hepatic mEH gene expression by 85% at 18 hr, rats treated with CaCl 2 (10 mg/kg, iv) in combination with GdCl 3 (1 mg/kg, iv) showed 45% suppression of the mEH mRNA level, compared with untreated animals. GdCl 3 -induced suppression was also significantly reversed for GST Ya mRNA by excessive CaCl 2 administration. These results demonstrate that GdCl 3 effectively inhibits constitutive and inducible mEH and GST expression, with decreases in their mRNA levels. GdCl 3 suppression of detoxifying enzyme expression may be associated with its blocking of intracellular Ca 2؉ influx, which affects signaling pathways for the expression of the genes

Double Glomus Tumors Originating in the Submandibular and Parotid Regions

Glomus tumors are rare neoplasms that originate from the glomus bodies, an arteriovenous anastomosis with a specialized vascular structure. The most common site for these tumors is the subungal region of the fingers. Occasionally, glomus tumors are found in the middle ear, trachea, nasal cavities, stomach, and lungs. The occurrence in the parotid regions is very rare. While multiple glomus tumors in the whole body are thought to represent only 10% of all cases, instances of multiple tumors in the neck have not yet been reported in the literature. We report a case of double glomus tumors in the submandibular and parotid regions

The Ministry of Education, and Human Resources Development

ABSTRACT Peroxisome proliferator-activated receptor (PPAR)-␥ and retinoic acid X receptor (RXR) heterodimer regulates cell growth and differentiation. Zinc finger transcription factor-9 (Zf9), whose phosphorylation promotes target genes, is a transcription factor essential for transactivation of the transforming growth factor (TGF)-␤1 gene. This study investigated whether activation of PPAR␥-RXR heterodimer inhibits TGF␤1 gene transcription and Zf9 phosphorylation and, if so, what signaling pathway regulates it. Either 15-deoxy-␦(12,14)-prostaglandin J 2 (PGJ 2 ) or 9-cis-retinoic acid (RA) treatment decreased the TGF␤1 mRNA level in L929 fibroblasts. PGJ 2 ϩ RA, compared with individual treatment alone, synergistically inhibited the TGF␤1 gene expression, which was abrogated by PPAR␥ antagonists. Likewise, PGJ 2 ϩ RA decreased luciferase expression from the TGF␤1 gene promoter. Promoter deletion analysis of the TGF␤1 gene revealed that pGL3-323 making up to Ϫ323-base pair region, but lacking PPAR-responsive elements, responded to PGJ 2 ϩ RA. PGJ 2 ϩ RA treatment inhibited the activity of p70 ribosomal S6 kinase-1 (S6K1), abolishing Zf9 phosphorylation at serine as did rapamycin [a mammalian target of rapamycin (mTOR) inhibitor]. Zf9 dephosphorylation by PGJ 2 ϩ RA was reversed by transfection of cells with the plasmid encoding constitutively active S6K1 (CA-S6K1). Transfection with dominant negative S6K1 inhibited the TGF␤1 gene. TGF␤1 gene repression by PGJ 2 ϩ RA was consistently antagonized by CA-S6K1. Ectopic expression of PPAR␥1 and RXR␣ repressed pGL3-323 transactivation with S6K1 inhibition, which was abrogated by CA-S6K1 transfection. PGJ 2 ϩ RA induced phosphatase and tensin homolog deleted on chromosome 10 (PTEN), whose overexpression repressed the TGF␤1 gene through S6K1 inhibition, decreasing extracellular signal-regulated kinase 1/2-90-kDa ribosomal S6 kinase 1 and Akt-mTOR phosphorylations. Data indicate that activation of PPAR␥-RXR heterodimer represses the TGF␤1 gene and induces Zf9 dephosphorylation via PTEN-mediated S6K1 inhibition, providing insight into pharmacological manipulation of the TGF␤1 gene regulation. The human transforming growth factor-␤ isoforms constitute extracellular signaling molecules that have antiproliferative effects on mammalian cells, promoting the expression of cell adhesion molecules and extracellular matrix proteins. In particular, transforming growth factor (TGF)-␤1 serves as a key fibrogenic mediator that can enhance extracellular matrix deposition and inhibit collagenase activity during fibrogenesis The peroxisome proliferator-activated receptors (PPARs) are transcription factors that are members of the nuclear This work was supported b