Aim: JTP‐426467 was identified as a result of screening in search of selective antagonist for peroxisome proliferator‐activated receptor γ (PPARγ). We examined whether JTP‐426467 functioned as a ...PPARγ antagonist in vitro and in vivo and investigated physiological effects of JTP‐426467.
Methods: The effect of JTP‐426467 as a PPARγ antagonist was studied in a cell‐based reporter assay and an adipocyte differentiation assay. Target mRNA expression levels were determined by branched DNA (bDNA) assay. To examine the effects as a PPARγ antagonist in vivo, a competitive study between JTP‐426467 and BRL49653 (rosiglitazone), a PPARγ agonist, was performed using KK‐Ay mice. The effects of JTP‐426467 alone after administration to KK‐Ay mice were also explored.
Results: JTP‐426467 antagonized PPARγ activity in a reporter assay system, but not PPARα. JTP‐426467 inhibited the expression of hormone‐sensitive lipase (HSL) mRNA, an adipocyte‐abundant gene, but not PPARγ itself or cyclophilin mRNA (as constitutive mRNA), and also suppressed triglyceride accumulation in differentiated stromal vascular fraction cells (SVFs). JTP‐426467 antagonized PPARγ agonistic action by BRL49653 in KK‐Ay mice on high‐fat diet, in terms of plasma glucose, body weight gain and interscapular brown adipose tissue (IBAT) weight. JTP‐426467 alone inhibited body weight gain and decreased plasma leptin level in KK‐Ay mice.
Conclusions: JTP‐426467 acted as a pure and potent PPARγ antagonist in vitro. Interestingly, JTP‐426467 completely antagonized the effects of PPARγ agonist BRL49653 in an obese diabetic model. JTP‐426467 may be a useful tool for the study of PPARγ in biological and physiological function.
We have measured proton and neutron energy spectra by means of time-of-flight (TOF) from
4He(
K
stopped
−
,
p
/
n
) reactions (KEK PS E471 experiment). In the proton spectrum, a clear mono-energetic ...peak was observed under semi-inclusive condition, which was assigned to the formation of a strange tribaryon S
0(3115) with isospin
T
=
1
. The mass and width of the state were deduced to be
3117.7
−2.0
+3.8
(
syst
.
)
±
0.9
(
stat
.
)
MeV
/
c
2
and
<
21.6
MeV
/
c
2
, respectively, and its main decay mode was
Σ
N
N
. In the neutron spectrum, a mono-energetic peak was found as the result of a detailed analysis, which was assigned to the formation of another kind of strange tribaryon S
+(3140). The mass and width of the state were deduced to be
3140.5
−0.8
+3.0
(
syst
.
)
±
2.3
(
stat
.
)
MeV
/
c
2
and
<
21.6
MeV
/
c
2
, respectively, and its main decay mode was
Σ
±
N
N
. The isospin of the state is assigned to be 0. The results are compared with recent theoretical calculations.
Purpose.
To study the anatomy of the pubic ramus and adjacent structures in 160 Japanese to establish a safer pubic screw fixation technique.
Methods.
80 male and 80 female Japanese aged 16 to 89 ...(mean, 50) years (10 persons in each decade of age) underwent 3-dimensional computed tomographic scanning of their pelvises. The angle at which the screw should be targeted, the appropriate length of the screw, the size of the canal for screw insertion, and the proximity to the bladder, iliac artery, and iliac vein were determined. Correlations between the canal diameters (of the acetabular, base, and parasymphyseal areas) and body features (age, height, and weight) were analysed.
Results.
In men and women respectively, the appropriate mean screw length was 124.6 and 123.8 mm; the guide wire should be targeted at a mean of 66° and 67° cephalad and 54.1° and 55.9° laterally for insertion of a retrograde pubic screw; the minimum distances from the pubis to the bladder/iliac artery/iliac vein were 0 and 0 mm/4.9 and 4.6 mm/0.8 and 0.2 mm. In both men and women, the canal diameters at the base were positively correlated to weight. In women, the canal diameters at the parasymphyseal area were correlated to height and weight. Canal diameters at the acetabulum were not correlated to height and weight.
Conclusion.
Pubic screw fixation may be potentially disastrous (owing to joint penetration and iliac vein injury) and should be performed with caution. When the canal diameter at the acetabulum is extremely narrow, plate fixation, computer-assisted surgery, or changing to a smaller-diameter screw is recommended.
A proportion of chronic hepatitis C patients who were treated with interferon have a sustained normalization of transaminase levels after interferon therapy without hepatitis C virus (HCV)-RNA ...clearance. We determined their clinical characteristics and long-term outcome in relation to progression to liver cirrhosis (LC) and the development of hepatocellular carcinoma (HCC). A total of 250 patients with chronic hepatitis C who were treated with interferon were studied for 8 to 11 years' posttherapy. Sixty-seven patients (27%) were complete responders with clearance of HCV RNA. Twenty-six (10%) were biochemical responders who had sustained normal alanine transaminase (ALT) levels without viral clearance. The remaining patients were short-term responders (n = 70) and nonresponders (n = 87). Biochemical responders were older, had higher levels of pretreatment HCV RNA in serum than complete responders, and had less advanced liver histology than nonresponders. Histologic grading scores decreased significantly at the end of therapy, while the staging scores did not change significantly. The annual incidence of cirrhosis was 0% in biochemical and complete responders, which was significantly lower than nonresponders and the controls (P = .0001). The annual incidence of HCC was 0.37% in complete responders and 0.50% in biochemical responders, which was significantly lower than nonresponders (P = .0001 for both). Our findings suggest that biochemical responders had high pretreatment viral levels with less advanced liver histology, and their long-term outcome appeared to be good irrespective of the persistence of the virus. (HEPATOLOGY 2001;33:1299-1302.)
Diacylglycerol kinase (DGK) and protein kinase C (PKC) are two different enzyme families that interact with diacylglycerol. Both enzymes contain cysteine-rich C1 domains with a zinc finger-like ...structure. Most of the C1 domains of PKCs show strong phorbol-12,13-dibutyrate (PDBu) binding with nanomolar dissociation constants (Kd's). However, there has been no experimental evidence that phorbol esters bind to the C1 domains of DGKs. We focused on DGKγ because its C1A domain has a high degree of sequence homology to those of PKCs, and because DGKγ translocates from the cytoplasm to the plasma membrane following 12-O-tetradecanoylphorbol-13-acetate treatment similar to PKCs. Two C1 domains of DGKγ (DGKγ-C1A and DGKγ-C1B) were synthesized and tested for their PDBu binding along with whole DGKγ (Flag-DGKγ) expressed in COS-7 cells. DGKγ-C1A and Flag-DGKγ showed strong PDBu binding affinity, while DGKγ-C1B was completely inactive. Scatchard analysis of DGKγ-C1A and Flag-DGKγ gave Kd's of 3.1 and 4.4 nM, respectively, indicating that the major PDBu binding site of DGKγ is C1A. This is the first evidence that DGKγ is a specific receptor of tumor-promoting phorbol esters.
A novel tandem 2 + 2 cycloaddition−Dieckmann condensation via ynolate anions is described. Ynolate anions are useful for the formation of reactive β-lactone enolates via a pathway not involving the ...enolization of the corresponding β-lactones. The 2 + 2 cycloaddition of ynolate anions with δ- or γ-keto esters, followed by Dieckmann condensation, gives bicyclic β-lactones, which are easily decarboxylated to produce synthetically useful 2,3-disubstituted cyclopentenones and cyclohexenones in one pot. This tandem reaction was applied to a novel, one-pot synthesis of highly substituted naphthalenes.
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