Sweet taste receptor subunit T1R3 regulates casein secretion and phosphorylation of STAT5 in mammary epithelial cells.

During lactation, mammary epithelial cells (MECs) on the apical membrane are in contact with lactose in milk, while MECs on the basolateral membrane are in contact with glucose in blood. Both glucose and lactose are sweeteners that are sensed by a sweet taste receptor. Previously, we have shown that lactose exposure on the basolateral membrane, but not the apical membrane, inhibits casein production and phosphorylation of STAT5 in MECs. However, it remains unclear whether MECs have a sweet taste receptor. In this study, we confirmed that the sweet taste receptor subunit T1R3 existed in both the apical and basolateral membranes of MECs. Subsequently, we investigated the influence of apical and basolateral sucralose as a ligand for the sweet taste receptor using a cell culture model. In this model, upper and lower media were separated by the MEC layer with less-permeable tight junctions. The results showed in the absence of glucose, both apical and basolateral sucralose induced phosphorylation of STAT5, which is a positive transcriptional factor for milk production. In contrast, the T1R3 inhibitor basolateral lactisole reducing phosphorylated STAT5 and secreted caseins in the presence of glucose. Furthermore, exposure of the apical membrane to sucralose in the presence of glucose inhibited the phosphorylation of STAT5. Simultaneously, GLUT1 was partially translocated from the basolateral membrane to the cytoplasm in MECs. These results suggest that T1R3 functions as a sweet receptor and is closely involved in casein production in MECs.

Lactose on the basolateral side of mammary epithelial cells inhibits milk production concomitantly with signal transducer and activator of transcription 5 inactivation.

Mammary epithelial cells (MECs) are the only cells capable of synthesizing lactose. During lactation, alveolar MECs secrete lactose through the apical membrane into the alveolar lumen, whereas alveolar tight junctions (TJs) block the leakage of lactose into the basolateral sides of the MECs. However, lactose leaks from the alveolar lumen into the blood plasma in the mastitis and after weaning. This exposes the basolateral membrane of MECs to lactose. The relationship between lactose in blood plasma and milk production has been suggested. The present study determined whether lactose exposure on the basolateral membrane of mouse MECs adversely affects milk production in vitro. Restricted exposure to lactose on the basolateral side of the MECs was performed using a culture model, in which MECs on the cell culture insert exhibit milk production and less-permeable TJs. The results indicated that lactose exposure on the basolateral side inhibited casein and lipid production in the MECs. Interestingly, lactose exposure on the apical side did not show detectable effects on milk production in the MECs. Basolateral lactose exposure also caused the inactivation of STAT5, a primary transcriptional factor for milk production. Furthermore, p38 and JNK were activated by basolateral lactose exposure. The activation of p38 and JNK following anisomycin treatment reduced phosphorylated STAT5, and inhibitors of p38 blocked the reduction of phosphorylated STAT5 by basolateral lactose exposure. These findings suggest that lactose functions as a partial inhibitor for milk production but only when it directly makes contact with the basolateral membrane of MECs.

Adverse Effects of High Temperature On Mammary Alveolar Development In Vitro.

In the mammary glands during pregnancy, the alveolar buds are first branched from the mammary ducts after which they form the alveolar luminal structure for milk production postparturition. Body temperature could increase for several reasons, such as infectious disease and heat stress. We have previously reported that high temperature adversely effects on the lactation capacity of mouse mammary epithelial cells (MECs). However, it remains unclear how high temperature influences mammary morophogenesis during pregnancy. In this study, we investigated the effects of high temperature on this mammary alveolar development process using two types of culture models including embedded organoids of MECs in Matrigel; these models reproduced mammary alveolar bud induction and alveolar luminal formation. Results showed that a culture temperature of 41 °C repressed alveolar bud induction and inhibited alveolar luminal formation. In addition, the treatment at 41 °C decreased the number of proliferating mammary epithelial cells but did not affect cell migration. Levels of phosphorylated Akt, -ERK1/2, -HSP90, and -HSP27 were increased in organoids cultured at 41 °C. The specific inhibitors of HSP90 and HSP27 exacerbated the disruption of organoids at 41 °C but not at 37 °C. Furthermore, the organoids precultured at 37 and 41 °C in the alveolar luminal formation model showed differences in the expression levels of caseins and tight junction proteins, which express in MECs in lactating mammary glands, after induction of MEC differentiation by prolactin and dexamethasone treatment in vitro. These results suggest that elevated temperature directly hinders mammary alveolar development; however, heat shock proteins may mitigate the adverse effects of high temperatures.

Comparison of the effects of linagliptin and voglibose on endothelial function in patients with type 2 diabetes and coronary artery disease: a prospective, randomized, pilot study (EFFORT).

Endothelial dysfunction contributes to poor cardiovascular prognosis in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). The effect of dipeptidyl peptidase-4 inhibitors on endothelial function remains controversial. We sought to compare the effects of linagliptin and voglibose on endothelial function, as assessed by reactive hyperemia-peripheral arterial tonometry (RH-PAT). Sixteen patients with newly diagnosed T2DM and CAD were randomized 1:1 to linagliptin (5 mg, once-daily) or voglibose (0.9 mg, thrice-daily). The RH-PAT and laboratory parameters, including 75 g oral glucose tolerance test, were measured at baseline and 3 months. Linagliptin increased serum levels of active glucagon-like peptide-1 and high-molecular-weight adiponectin. Age-, sex-, and baseline-adjusted changes in logarithmic RH-PAT index (LnRHI) after 3 months were significant between groups (linagliptin, 0.135 ± 0.097; voglibose, - 0.124 ± 0.091; P = 0.047). In the linagliptin group, change in LnRHI was positively correlated with change in high-density lipoprotein cholesterol and negatively correlated with changes in both urine albumin-to-creatinine ratio and high-sensitivity C-reactive protein. Furthermore, linagliptin treatment for 3 months reduced serum levels of both glucose and insulin at 2 h, relative to voglibose, in the age-, sex-, and baseline-adjusted model. Linagliptin improved endothelial function relative to voglibose, accompanied by amelioration of glycemic, renal, and cardiometabolic parameters, in patients with newly diagnosed T2DM and CAD.Trial registration Unique Trial Number, UMIN 000029169 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000012442 ).

Prolonged Inflation Technique Using a Scoring Balloon for Severe Calcified Lesion.

Percutaneous coronary intervention for the treatment of a severe calcified lesion is still one of the most technically challenging areas of interventional cardiology. Calcified lesions are a cause of stent underexpansion, which significantly increases the subsequent risks of in-stent restenosis and thrombosis, even when drug-eluting stents are used. In this report, we describe the usefulness of prolonged inflations using a scoring balloon catheter (Scoreflex) for severe calcified lesions. Prolonged inflation using a scoring balloon enables an adequate dilation for treatment of a severe calcified plaque that was unresponsive to conventional technique with or without rotational atherectomy.

A left atrial appendage thrombus that developed during prophylactic low-dose dabigatran treatment resolved after switching to apixaban.

We describe a case of atrial fibrillation in which an intracardiac thrombus that could not be prevented with "low-dose" dabigatran treatment was resolved by switching to apixaban treatment. Thrombolysis using direct oral anticoagulants (DOACs) could be a therapeutic option for patients with intracardiac thrombi, although the efficacies of different DOACs seem to differ and need further examination.

Black hole restenosis after drug-eluting stent implantation for in-stent restenosis: potential mechanism and optimal strategy.

In-stent restenosis (ISR) has long remained as the major limitation of coronary stenting. The use of drug-eluting stent (DES) reduces the risk of repeat revascularization without an increase of death and myocardial infarction, compared to the standard bare metal stents. DES has also demonstrated markedly to reduce ISR for complex lesions. However, ISR after DES implantation still occurs and optimal treatment for ISR after DES has not been established. Herein, we report 3 cases with black hole restenosis confirmed by intravascular ultrasound at the site of overlapped DES and discuss potential mechanism and optimal strategy for this phenomenon.

Wear performance of bovine tooth enamel against translucent tetragonal zirconia polycrystals after different surface treatments.

The wear performances of bovine tooth enamel (BTE) against translucent tetragonal zirconia polycrystals (TZP) compared to that of feldspar porcelain and the influence of surface treatments of translucent TZP were investigated by the two-body wear test. Translucent TZP and feldspar porcelain were used as hemisphere abrader specimens with a radius of curvature of 5 mm; flat BTE surfaces were used as substrate specimens. The cross-sectional area of the worn surfaces of the substrates and the wear volume of the antagonist abraders were measured. Surface roughness, hardness and coefficient of friction as well as SEM observations and EPMA analyses were also performed to investigate the underlying mechanism of wear. The results suggested that BTE is less susceptible to wear when translucent TZP is used as the antagonist in contrast to the use of feldspar porcelain, and that surface treatment of the TZP abraders significantly influenced the wear of BTE substrates.

Cyclic fatigue resistance of yttria-stabilized tetragonal zirconia polycrystals with hot isostatic press processing.

This study investigated the influence of surface roughness and cyclic loading on fatigue resistance in Y-TZP subjected to hot isostatic pressing (HIP). Fifty Y-TZP cylinders 3.0 mm in diameter were divided into Group A (polished by centerless method; TZP-CP) or Group B (blasted and acid-etched: TZP-SB150E). Twenty five cp-titanium cylinders (Ti-SB150E) were used as a control. Static and cyclic tests were carried out according to ISO 14801. The cyclic fatigue test was performed in distilled water at 37°C. Surface morphology and roughness as well as crystal phase on the surfaces were also evaluated. Fracture force under the static test was 1,765N (TZP-CP), 1,220N (TZP-SB150E), and 850 N (yield force, Ti-SB150E). Fracture values under the cyclic test decreased to approximately 70% of those under the static tests. These results indicate that HIPed Y-TZP with a 3.0-mm diameter has sufficient durability for application to dental implants.

High prevalence of early repolarization in short QT syndrome.

BACKGROUND: Short QT syndrome (SQTS) is characterized by an abnormally short QT interval and sudden death. Due to the limited number of cases, the characteristics of SQTS are not well understood. It has been reported recently that early repolarization is associated with idiopathic ventricular fibrillation and the QT interval is short in patients with early repolarization. OBJECTIVE: The purpose of this study was to study the association between early repolarization and arrhythmic events in SQTS. METHODS: The study consisted of three cohorts: SQTS cohort (N = 37), control cohort with short QT interval and no arrhythmic events (N = 44), and control cohort with normal QT interval (N = 185). ECG parameters were compared among the study cohorts. RESULTS: Heart rate, PR interval, and QRS duration were similar among the three study cohorts. Early repolarization was more common in the SQTS cohort (65%) than in the short QT control cohort (30%) and the normal QT control cohort (10%). Duration from T-wave peak to T-wave end was longer in the SQTS cohort than in the short QT control cohort, although QT and corrected QT intervals were similar. In the SQTS cohort, there were more males among patients with arrhythmic events than in those with a family history but without arrhythmic events. In multivariate models, early repolarization was associated with arrhythmic events in the SQTS cohort. ECG parameters including QT and QTc intervals were not associated with arrhythmic events in the SQTS cohort. CONCLUSION: There is a high prevalence of early repolarization in patients with SQTS. Early repolarization may be useful in identifying risk of cardiac events in SQTS.