BubR1 Is Essential for Thio-Dimethylarsinic Acid-Induced Spindle Assembly Checkpoint and Mitotic Cell Death for Preventing the Accumulation of Abnormal Cells.

Thio-dimethylarsinic acid (thio-DMA) was detected in human urine after exposure to inorganic arsenic and arsenosugars consumed by marine algae. Our previous studies have shown that thio-DMA disturbed the cell cycle progression and arrested cells in mitosis, though the biological significance or the mechanism by which thio-DMA-induced mitotic phase accumulation occurs is yet to be understood. In this study, we showed that thio-DMA promotes the phosphorylation of BubR1 protein, which is one of the constituents of the spindle assembly checkpoint (SAC) complex and accumulates in the cell in mitotic phase.

TAS-203, an oral phosphodiesterase 4 inhibitor, exerts anti-inflammatory activities in a rat airway inflammation model.

Cyclic adenosine monophosphate (cAMP) is a key intracellular second messenger, which is degraded by phosphodiesterase 4 (PDE4). PDE4 suppresses cAMP levels, and thus stimulates the activity of inflammatory cells. Therefore, PDE4 has been considered as a therapeutic target for airway inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD).

Insulin-like growth factor 1 promotes cochlear synapse regeneration after excitotoxic trauma in vitro.

In the context of acquired sensorineural hearing loss (SNHL), cochlear hair cells have long been thought to be among the most vulnerable elements in mammalian cochleae. However, recent studies have indicated that the synaptic connection between inner hair cells (IHC) and spiral ganglion neurons (SGN) can be an important target for the treatment of SNHL. Our previous studies in patients with sudden SNHL demonstrated delayed and gradual hearing recovery following topical application of insulin-like growth factor 1 (IGF-1), suggesting that not only protective but also regenerative mechanisms may account for hearing recovery after treatment with IGF-1.

Effects of the new benzimidazole derivative TAS-203, an orally active phosphodiesterase 4 inhibitor, on airway inflammation in rats and emetic responses in ferrets.

TAS-203 (2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-5-(1H-1,2,4-triazol-1-yl)-1H-benzimidazole, CAS 223909-92-0) is a novel phosphodiesterase 4 (PDE4) inhibitor that has been found to have good anti-inflammatory effects and low emetogenic activity in vivo. In the present studies, the anti-inflammatory profile of TAS-203 was examined and compared with that of cilomilast (CAS 153259-65-5), the most advanced PDE4 inhibitor. TAS-203 inhibited the activity of purified human PDE4 with an IC50 value of 88 nM and also the recombinant PDE4 subtypes (4A, 4B, 4C and 4D) with respective IC50 values of 47, 35, 227 and 43 nM.

Effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on tissue carnitine and lipid levels in rats.

MET-88, 3-(2,2,2-trimethylhydrazinium) propionate, suppresses carnitine synthesis by inhibiting (gamma-butyrobetaine hydroxylase. The purpose of this study was to clarify the effects of suppression of carnitine synthesis on carnitine and lipid contents in tissues. MET-88 (50, 100, 200 or 400 mg/kg/d) was administered orally to male SD rats for 10, 30 or 60 d.

Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction.

Myocardial ischemia can cause myocardial infarction and as a consequence, heart failure. 3-(2,2,2-trimethylhydrazinium) propionate (MET-88) inhibits gamma-butyrobetaine hydroxylase and has cardioprotective effects on the ischemic heart. We now examined the effects of MET-88 in rats with congestive heart failure following myocardial infarction.

Beneficial effects of MET-88 on left ventricular dysfunction and hypertrophy with volume overload in rats.

We examined the effects of MET-88 on haemodynamics and cardiac hypertrophy in rats with an aortocaval shunt (A-V shunt). On the day of surgery, an A-V shunt was produced by using an 18-gauge needle in Wistar rats as described by Garcia and Diebold. MET-88 and captopril were orally administered to rats 1 week after surgery, and the administration was continued for 3 weeks.

Cardioprotective profile of MET-88, an inhibitor of carnitine synthesis, and insulin during hypoxia in isolated perfused rat hearts.

3-(2,2,2-trimethylhydrazinium) propionate (MET-88) is an inhibitor of carnitine synthesis. This study was carried out to investigate whether or not reduction of carnitine content could attenuate hypoxic damage in isolated perfused rat hearts. Rats were divided into four groups: 1) vehicle control; 2) pretreatment with MET-88 (MET-88); 3) application of insulin (500 muU/mL) in the perfusate (insulin); and 4) pretreatment with MET-88 and application of insulin (MET-88 + insulin).

Secondary abnormality of carnitine biosynthesis results from carnitine reabsorptional system defect in juvenile visceral steatosis mice.

We characterized the L-carnitine transport system which is defective in the kidney of juvenile visceral steatosis (JVS) mice by using kidney slices and carnitine-related compounds, and evaluated the influence of the transport defect on the biosynthetic pathway of carnitine. The JVS mouse transport system defect, calculated as the difference in the transport activity between control and JVS mice, was simulated in control by gamma-butyrobetaine (gamma-BB) and acetyl L-carnitine. gamma-BB hydroxylase activity in the liver of JVS mice was double that of control mice, but the hepatic level of gamma-BB in JVS mice was lower than in control mice, suggesting that the conversion of gamma-BB to carnitine is not activated in the liver of JVS mice.

Beneficial effect of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on energy metabolism in ischemic dog hearts.

The effect of MET-88 [3-(2, 2, 2-trimethylhydrazinium) propionate], a gamma-butyrobetaine hydroxylase inhibitor, on the ischemic changes of energy metabolism was studied in the anesthetized dog. In the dog pretreated orally with MET-88 (50, 100 or 200 mg/kg/day) or placebo for 10 days, the left anterior descending coronary artery was occluded for 60 min, and the myocardium was taken from the left anterior descending coronary area (ischemic area) and left circumflex area (nonischemic area) for metabolic analysis. In the ischemic area, occlusion of the left anterior descending coronary artery decreased the tissue levels of adenosine triphosphate, adenosine diphosphate and creatine phosphate, increased the tissue levels of adenosine monophosphate and lactate, and decreased the value of the energy charge potential.

[A simultaneous determination of honokiol and mangolol in Oriental pharmaceutical decoctions containing magnolia bark by ion-pair high-performance liquid chromatography. II].

A simple method using ion-pair high-performance liquid chromatography was established for the rapid and precise determination of honokiol(3',5-di-2-propenyl-1,1'-biphenyl-2,4'-diol) and magnolol(5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol) in eighteen species of oriental pharmaceutical decoctions containing Magnolia bark. An ODS column and a mixed solvent system of water involving 10 mM tetra-n-amyl-ammonium bromide (TAA) and acetonitrile (4:6) as a mobile phase were used for the separation. Honokiol and magnolol were eluted without interference of other coexisting components within 12 min.

Microwave dielectric study on hydration of moist collagen.

Two dielectric relaxation peaks were found in moist collagen by the time domain reflectometry. The low-frequency peak around 100 MHz moves little as the water content is varied. Its relaxation strength depends on the content and vanishes for completely dried collagen.