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Despite the long history of use of steroid ointments for oral mucositis, the analgesic mechanism has not been fully elucidated. In this study, we examined the effects of triamcinolone acetonide (Tmc) on oral ulcerative mucositis-induced pain in conscious rats by our proprietary assay system. Based on evaluations of the physical properties and retention periods in the oral mucosa of human volunteers and rats, we selected TRAFUL® ointment as a long-lasting base. In oral ulcerative mucositis model rats, TRAFUL® with Tmc suppressed cyclooxygenase-dependent inflammatory responses with upregulations of glucocorticoid receptor-induced anti-inflammatory genes and inhibited spontaneous nociceptive behavior. When an ointment with a shorter residual period was used, the effects of Tmc were not elicited or were induced to a lesser extent. Importantly, TRAFUL® with Tmc also improved oral ulcerative mucositis-induced mechanical allodynia, which has been reported to be independent of cyclooxygenase. Ca2+ imaging in dissociated trigeminal ganglion neurons showed that long-term preincubation with Tmc inhibited the hypertonic stimulation-induced Ca2+ response. These results suggest that the representative steroid Tmc suppresses oral ulcerative mucositis-induced pain by general anti-inflammatory actions and inhibits mechanical sensitivity in peripheral nerves. For drug delivery, long-lasting ointments such as TRAFUL® are needed to sufficiently induce the therapeutic effects.

TFEB, a basic helix-loop-helix transcription factor, is a master regulator of autophagy, lysosome biogenesis and lipid catabolism. Compared to posttranslational regulation of TFEB, the regulation of TFEB mRNA stability remains relatively uncharacterized. In this study, we identified the mRNA-binding protein THOC4 as a novel regulator of TFEB. In mammalian cells, siRNA-mediated knockdown of THOC4 decreased the level of TFEB protein to a greater extent than other bHLH transcription factors. THOC4 bound to TFEB mRNA and stabilized it after transcription by maintaining poly(A) tail length. We further found that this mode of regulation was conserved in Caenorhabditiselegans and was essential for TFEB-mediated lipid breakdown, which becomes over-represented during prolonged starvation. Taken together, our findings reveal the presence of an additional layer of TFEB regulation by THOC4 and provide novel insights into the function of TFEB in mediating autophagy and lipid metabolism.

Aims/Introduction: Patients with type 1 diabetes mellitus often show a precipitous postprandial rise in blood glucose that cannot be controlled, even by intensive insulin therapy. The combined use of an α-glucosidase inhibitor with insulin seems to be highly beneficial in such cases. Materials and Methods: We investigated the efficacy and safety of miglitol, an α-glucosidase inhibitor, for 12 weeks in 43 type 1 diabetes patients on intensive insulin therapy. Results: Co-administration of miglitol resulted in only a modest and temporal decrease in HbA1c level. However, it resulted in a significant reduction of plasma glucose level after breakfast (250.7 ± 102.0 mg/dL at 2 h after breakfast before treatment; 212.0 ± 95.8 mg/dL at 2 h after breakfast after treatment for 12 weeks, P = 0.01) and a significant reduction of insulin dosage (41.6 ± 17.1 U/day before treatment; 39.8 ± 17.4 U/day 12 weeks after treatment, P

(-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) is a novel oral hypoglycemic agent possessing a peptide-type bond and a carboxyl group in its structure. Recently, we have shown that nateglinide transport occurs via the ceftibuten/H+ cotransport system, which is distinct from PepT1, and that the fluorescein/H+ cotransport system is involved in the uptake of nateglinide. The aim of this study was to characterize the functional properties of the intestinal nateglinide transporter. In the first part of this study, we demonstrated that the ceftibuten/H+ cotransport system is identical to the fluorescein/H+ cotransport system. We succeeded in purification of the nateglinide transporter from brush-border membranes of the rat small intestine using p-aminobenzoic acid (PABA)-affinity chromatography. We then investigated the functional properties of the nateglinide transporter using proteoliposomes prepared from the PABA-affinity chromatography elute. We demonstrated that nateglinide, ceftibuten, and fluorescein are transported by the same transporter in the intestine.

Nateglinide, a novel oral hypoglycemic agent, rapidly reaches its maximum serum concentration after oral administration, suggesting that it is rapidly absorbed in the intestine. However, nateglinide itself is not transported by MCT1 or PEPT1. The aim of this study was to characterize the transporters on the apical side of the small intestine that are responsible for the rapid absorption of nateglinide. It has been reported that the uptake of fluorescein by Caco-2 cells occurs via an H+-driven transporter and that the intestinal fluorescein transporter is probably not MCT1. We examined the contribution of the fluorescein transporter to the uptake of nateglinide by Caco-2 cells. Fluorescein competitively inhibited H+-dependent nateglinide uptake. All of fluorescein transporter inhibitors examined reduced the uptake of nateglinide. Furthermore, nateglinide inhibited fluorescein uptake. We conclude that the intestinal nateglinide/H+ cotransport system is identical to the intestinal fluorescein/H+ cotransport system.

The aim of this study was to assess the clinical significance of ankle brachial pressure index (ABI) and carotid intima-media thickness (IMT) in Japanese patients with type 2 diabetes. ABI and ultrasonographic carotid IMT measurements were made in 1311 patients and the relationships between ABI, IMT, and cardiovascular diseases were examined. Patients were assigned to one of three groups depending on their ABI index: (i) ABIor = 1.0; (ii) ABI fromor = 0.9 to1.0; and (iii) ABI0.9. The odds ratios (ORs) for groups (ii) and (iii) compared with (i) for the prevalence of coronary heart disease (CHD), cerebrovascular disorder (CVD), and carotid atherosclerosis (mean carotid IMTor = 1.1mm) demonstrated that these conditions were inversely related to ABI. As the combined ABI/carotid IMT score increased, each OR for the prevalence of CHD and CVD increased significantly. This suggests that a lower ABI is associated with generalized atherosclerosis. Measurements of the ABI and carotid IMT might provide a good prognostic indicator, and both should be assessed during screening for atherosclerosis in Japanese patients with type 2 diabetes.

(-)-N-(trans-4-Isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) is a novel oral hypoglycemic agent possessing a carboxyl group and a peptide-type bond in its structure. Although nateglinide quickly reaches the maximal serum concentration after oral administration, nateglinide itself is not transported by PepT1 or MCT1. The aim of this study was to characterize the transporters on the apical side of the small intestine that are responsible for the rapid absorption of nateglinide. The uptake of nateglinide by rat intestinal brush-border membrane vesicles is associated with a proton-coupled transport system. Ceftibuten competitively inhibited H(+)-dependent nateglinide uptake. Glycylsarcosine (Gly-Sar), cephradine, and cephalexin did not significantly inhibit the uptake of nateglinide. The combination of Gly-Sar and nateglinide greatly reduced the uptake of ceftibuten. The effect of the combined treatment was significantly greater than that of Gly-Sar alone. Furthermore, nateglinide competitively inhibited H(+)-driven ceftibuten transporter-mediated ceftibuten uptake. Ceftibuten transport occurs via at least two H(+)-dependent transport systems: one is PepT1, and the other is the ceftibuten/H(+) cotransport system. On the other hand, we demonstrated that nateglinide transport occurs via a single system that is H(+) dependent but is distinct from PepT1 and may be identical to the ceftibuten/H(+) cotransport system.

OBJECTIVE—To investigate the association between carotid atherosclerosis, measured as intima-media thickness (IMT), and cardiovascular morbidity in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—We investigated the relationship between IMT and coronary artery disease (CAD) in 40 type 2 diabetic patients and 40 control subjects. Diabetic patients with CAD determined by coronary angiography were consecutively recruited, whereas the control subjects were recruited from among diabetic outpatients without CAD at the same institution. IMT was measured in both carotid arteries using B-mode ultrasonography. RESULTS—Carotid IMT was significantly greater in the diabetic patients than in the control subjects (1.27 ± 0.07 vs. 1.03 ± 0.04 mm, P < 0.05). IMT was associated with CAD by logistic regression analysis using all independent variables (P = 0.062). When the 40 patients with CAD were divided into a group of 20 patients with coronary artery bypass grafting (CABG) and another 20 patients without CABG, the IMT was significantly greater in the CABG group than in the non-CABG group (1.47 ± 0.11 vs. 1.07 ± 0.07 mm, P < 0.05). CONCLUSIONS—These results indicate that the presence of carotid atherosclerosis implies a high probability of coronary involvement in Japanese nonobese subjects with type 2 diabetes.

Summary Physical flexibility, such as joint range of motion and muscle extension, may influence muscle blood volume. Women have been shown to have a greater degree of flexibility than men. We examined whether there is a gender difference in the relationship between fascicle length and muscle blood volume or oxygenation in untrained men and women. In 16 untrained men and thirteen untrained women, we measured the total-[haemoglobin (Hb) + myoglobin (Mb)] (total-[Hb + Mb]) and relative oxy-[Hb + Mb] after calibrating baseline and arterial occlusion deoxygenation levels with near-infrared spectroscopy. Also, fascicle length was measured with B-mode ultrasonography at the tibialis anterior muscle during passive plantarflexion. Increases in fascicle length from baseline (ankle joint angle 120°, composed from the caput fibulae, the malleolus (pivot), and the distal epiphysis of the fifth metatarsal bone) were greater in women than in men during plantarflexion of 140° and 160° and the maximal angle without pain. However, the decreases in total-[Hb + Mb] and relative oxy-[Hb + Mb] from baseline were not different between women and men at any degree of plantarflexion. Moreover, fascicle length and total-[Hb + Mb]/muscle thickness (men > women) showed a similar relationship, with muscle thickness increasing capillary compression. These findings indicate the possibility of a mechanical function underlying muscle blood volume during muscle stretching, which is greater in women than in men.

In clinical, patients usually take many kinds of drugs at the same time. Thus, drug-drug interactions involving transporters can often directly affect the therapeutic safety and efficacy of many drugs. However, there have been few studies on food-drug interactions involving transporters. Dietary polyphenols have been widely assumed to be beneficial to human health. Polyphenols are commercially prepared and used as functional foods. We report here for the first time that ferulic acid, which is widely used as a functional food, affects the transport of clinical agents. It is important to be aware of the potential of food-drug interactions and to act in order to prevent undesirable and harmful clinical consequences.

The aim of this study was to investigate the effect of cilostazol, a cAMP phosphodiesterase inhibitor, on carotid artery intima-media thickness (IMT) and on the incidence of cardiovascular events in Japanese subjects with type 2 diabetes. A total of 62 type 2 diabetic subjects were allocated equally to the cilostazol treatment group (n = 31) and the control group (n = 31). Carotid IMT was evaluated before and after treatment using B-mode ultrasonography. After the study period (mean +/- SD: 2.6 +/- 0.17 years), carotid IMT showed a significantly greater increase in the control group than in the cilostazol group (0.12 +/- 0.14 mm vs. 0.04 +/- 0.02 mm, p < 0.05). In the control group, 1 out of 31 patients suffered from symptomatic cerebral infarction and 1 had angina pectoris during the observation period. On the other hand, no subject in the cilostazol group developed cardiovascular events during the study period. At baseline, the diabetic patients given cilostazol had a significantly lower HbA1c level than the control subjects, but the other atherosclerotic risk factors (BMI, blood pressure, and serum lipids) and the duration of diabetes did not differ between the two groups. These results indicate that cilostazol therapy can attenuate the increase of carotid artery IMT in Japanese subjects with type 2 diabetes.

As a part of our studies on the metabolism of natural compounds, gallic acid was orally administered to rats. The urinary metabolites were analyzed by high-performance liquid chromatography, and their structures were determined to be pyrogallol (M1), pyrogallol-1-O-beta-D-glucuronide (M2), 4-O-methylgallic acid-3-O-sulfate (M3), 2-O-methylpyrogallol-1-O-beta-D-glucuronide (M4), 2-O-methylpyrogallol (M5), 4-O-methylgallic acid (M6), and unchanged gallic acid on the basis of chemical and spectral data. The radical scavenging effects of gallic acid and its urinary metabolites were evaluated using 1,1-diphenyl-2-picrylhydrazyl radical.

Recently a new automatic device that measures brachial-ankle pulse wave velocity using an oscillometric method has been developed. However, the practical significance of brachial-ankle pulse wave velocity measurement remains uncertain. The purpose of this study was to examine the association between brachial-ankle pulse wave velocity and symptomatic cerebral infarction in patients with type 2 diabetes. One thousand sixty six patients with type 2 diabetes were studied cross-sectionally. Measurements of brachial-ankle pulse wave velocity were made using the automatic device. Logistic regression analysis was used to calculate the odds ratio for cerebral infarction. The presence of symptomatic cerebral infarction was confirmed in 86 patients. In these patients brachial-ankle pulse wave velocity was found to be significantly higher than in patients without cerebral infarction (18.94 ± 4.95 versus 16.46 ± 3.62 m/s, p < 0.01). The association between brachial-ankle pulse wave velocity and cerebral infarction remained significant after adjustment for traditional risk factors. There was an increasing odds ratio for each tertile of brachial-ankle pulse wave velocity, from the second tertile (odds ratio, 2.28; 95% confidence interval, 1.05 to 4.94), to the third (odds ratio, 2.53; 95% confidence interval, 1.09 to 5.86). Overall, we conclude that an increase in brachial-ankle pulse wave velocity is associated with symptomatic cerebral infarction in patients with type 2 diabetes.

Thyrotoxicosis with diffuse thyroid disease can be caused by Graves' disease (GD) or destructive thyroiditis (DT). Optimal treatment of the underlying condition requires a prompt and accurate method for the diagnosis of thyrotoxicosis. This study evaluated measurement of the mean peak systolic velocity of the superior thyroid artery (STA-PSV) by ultrasonography in detecting thyrotoxicosis in Japanese patients. We recruited 44 patients with untreated GD, 13 with DT, 55 with treated GD, and 49 subjects without thyroid disease. Blood samples were taken to analyze thyroid function and STA-PSV was measured by ultrasonography. The mean STA-PSV was the highest in the untreated GD group, followed by treated GD patients and then those with DT. Receiver operating characteristic curves of the STA-PSV values demonstrated that the area under the curve required discriminating untreated GD from DT was 0.941. The optimal sensitivity and specificity were 83.7% and 92.3%, respectively, using 45 cm/sec as the cutoff value. In conclusion measurement of STA-PSV by ultrasonography is useful for the diagnosis of thyrotoxicosis in Japanese patients.