The sweet taste receptors present in the taste buds are heterodimers comprised of T1R2 and T1R3. This receptor is also expressed in pancreatic beta-cells. When the expression of receptor subunits is determined in beta-cells by quantitative reverse transcription polymerase chain reaction, the mRNA expression level of T1R2 is extremely low compared to that of T1R3. In fact, the expression of T1R2 is undetectable at the protein level. Furthermore, knockdown of T1R2 does not affect the effect of sweet molecules, whereas knockdown of T1R3 markedly attenuates the effect of sweet molecules. Consequently, a homodimer of T1R3 functions as a receptor sensing sweet molecules in beta-cells, which we designate as sweet taste-sensing receptors (STSRs). Various sweet molecules activate STSR in beta-cells and augment insulin secretion. With regard to intracellular signals, sweet molecules act on STSRs and increase cytoplasmic Ca2+ and/or cyclic AMP (cAMP). Specifically, when an STSR is stimulated by one of four different sweet molecules (sucralose, acesulfame potassium, sodium saccharin, or glycyrrhizin), distinct signaling pathways are activated. Patterns of changes in cytoplasmic Ca2+ and/or cAMP induced by these sweet molecules are all different from each other. Hence, sweet molecules activate STSRs by acting as biased agonists.
Bias (Epidemiology)* ; Calcium ; Cyclic AMP ; Cytoplasm ; Insulin ; Polymerase Chain Reaction ; Potassium ; Reverse Transcription ; RNA, Messenger ; Saccharin ; Sodium ; Taste Buds

Vitamin D (VD) exerts a wide variety of biological actions in addition to its well-known roles in calcium homeostasis. Nutritional VD deficiency induces rachitic abnormalities in growing children and osteomalacia in adults, and it has been proposed to underlie the onset and development of multiple non-communicable chronic diseases. Therefore, the administration of VD or synthetic VD analogues represents a promising therapeutic strategy; indeed, VD and a VD agonist have shown clinical promise in mitigating osteoporosis and symptoms of insufficient calcium intake. However, even though high doses of VD analogues have shown pre-clinical efficacy against several diseases, including cancers, they have not yet had wide-spread clinical success. This difference may be due to limitation of clinical doses in light of the inherent calcemic action of VD. An approach to overcome this problem involves the development of VD analogues with lower calcemic activity, which could be administered in high doses to attenuate the onset and progress of disease. In a similar strategy, selective estrogen receptor modulators have had success as anti-osteoporosis drugs, and they have shown benefit for other estrogen target organs by serving as partial antagonists or agonists of estrogen receptor α. It is thus conceivable to generate synthetic partial antagonists or agonists for the VD receptor (VDR) that would exert beneficial effects on bone and other VD target organs. In this review, we discuss the molecular basis of the development of such synthetic VDR ligands from the viewpoint of roles of VDR in gene regulation.

Purpose: The objective of this study was to investigate whether body fat rate (BFR) and triceps skinfold thickness (TSF) are associated with estimated fentanyl absorption in patients treated with the fentanyl transdermal matrix patch for moderate to severe cancer pain, by measuring the residual content of fentanyl in used matrix patches. Methods: Adult Japanese inpatients experiencing chronic cancer-related pain and receiving treatment for the first time with a transdermal fentanyl matrix patch (Durotep®MT patch) were included in the present study. During the initial application period, BFR was measured using a body fat scale, and TSF was measured by an experienced nurse with an adipometer. One patch was collected from each patient. The residual fentanyl content in used matrix patch was determined by high-performance liquid chromatography. The transdermal fentanyl delivery efficiency was estimated based on the fentanyl content of the used matrix patches. Results: Fifteen adult patients (5 males and 10 females) were included in this study. Nine patches with a release rate of 12.5μg/h and 6 patches with a release rate of 25μg/h were collected. The application site was the chest or upper arm. BFR and TSF both showed a significant positive correlation with delivery efficiency. Conclusion: In malnourished or low-body fat patients receiving DMP, pain intensity should be more carefully monitored, and fentanyl dose adjustment may be required. Additional parameters, such as nutritional status including body fat change, the degree of dry skin, and plasma fentanyl concentration, also require detailed evaluation. Palliat Care Res 2010; 5(2): 206-212