No abstract

We investigated the effect of long-term ingestion of dietary medium-chain triacylglycerols (MCT) on body weight and fat in humans. Using a double-blind, controlled protocol, we assessed the potential health benefits of MCT compared with long-chain triacylglycerols (LCT) in 78 healthy men and women [body mass index (BMI) > or = 23 kg/m(2): n = 26 (MCT), n = 30 (LCT); BMI < 23 kg/m(2): n = 15 (MCT), n = 7 (LCT)]. Changes in anthropometric variables, body weight and body fat during the 12-wk MCT treatment period were compared with those in subjects consuming the LCT diet. The subjects were asked to consume 9218 kJ/d and 60 g/d of total fat. The energy, fat, protein and carbohydrate intakes did not differ significantly between the groups. Body weight and body fat in both groups had decreased by wk 4, 8 and 12 of the study. However, in the subjects with BMI > or = 23 kg/m(2), the extent of the decrease in body weight was significantly greater in the MCT group than in the LCT group. In subjects with BMI > or = 23 kg/m(2), the loss of body fat in the MCT group (-3.86 +/- 0.3 kg) was significantly greater than that in the LCT group (-2.75 +/- 0.2 kg) at 8 wk. In addition, in subjects with BMI > or = 23 kg/m(2), the decrease in the area of subcutaneous fat in the MCT group was significantly greater than that in the LCT group at wk 4, 8 and 12. These results suggest that the MCT diet may reduce body weight and fat in individuals (BMI > or = 23 kg/m(2)) more than the LCT diet.

Derivatives of a novel scaffold, C-phenyl 1-thio-D-glucitol, were prepared and evaluated for sodium-dependent glucose cotransporter (SGLT) 2 and SGLT1 inhibition activities. Optimization of substituents on the aromatic rings afforded five compounds with potent and selective SGLT2 inhibition activities. The compounds were evaluated for in vitro human metabolic stability, human serum protein binding (SPB), and Caco-2 permeability. Of them, (1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (3p) exhibited potent SGLT2 inhibition activity (IC(50) = 2.26 nM), with 1650-fold selectivity over SGLT1. Compound 3p showed good metabolic stability toward cryo-preserved human hepatic clearance, lower SPB, and moderate Caco-2 permeability. Since 3p should have acceptable human pharmacokinetics (PK) properties, it could be a clinical candidate for treating type 2 diabetes. We observed that compound 3p exhibits a blood glucose lowering effect, excellent urinary glucose excretion properties, and promising PK profiles in animals. Phase II clinical trials of 3p (TS-071) are currently ongoing.

Sperm-specific phospholipase C-zeta (PLC) causes intracellular Ca2؉ oscillations and thereby egg activation and is accumulated into the formed pronucleus (PN) when expressed in mouse eggs by injection of cRNA encoding PLC, which consists of four EF-hand domains (EF1-EF4) in the N terminus, X and Y catalytic domains, and C-terminal C2 domain. Those in the N terminus of EF1. Ca 2؉ oscillation-inducing activity was lost by the former mutation and was remarkably inhibited by the latter. A short sequence 374 -383 fused with Venus showed active translocation into the nucleus of COS-7 cells, but 296 -309 or 1-19 did not. Despite the presence of these special regions, both activities were deprived by deletion of not only EF1 but also EF2-4 or C2 domain. Thus, PLC is driven into the nucleus primarily by the aid of NLS and putative regulatory sites, but coordinated three-dimensional structure, possibly formed by a folding in the X/Y linker and close EF/C2 contact as in PLC␦1, seems to be required not only for enzymatic activity but also for nuclear translocation ability. PLC2 is a novel isozyme of PLC (the enzyme that hydrolyzes membrane PIP 2 into IP 3 and diacylglycerol) and a strong candidate of the mammalian sperm-derived egg-activating factor (1). PLC is specifically expressed in the sperm (2) and induces repetitive increase in [Ca 2ϩ ] i called Ca 2ϩ oscillations and subsequent early embryonic development when expressed in mouse eggs by injection of RNA encoding PLC (2, 3). In mammalian fertilization, accumulated evidence indicates that a cytosolic sperm factor is driven into the ooplasm upon sperm egg fusion and induces Ca 2ϩ oscillations (4, 5), which are caused by Ca 2ϩ release from the endoplasmic reticulum mainly through type 1 IP 3 receptor (6) and are a pivotal signal for egg activation characterized by resumption of the second meiosis and formation of PN (5). PLC is a strong candidate of the sperm factor, because 1) fertilization-like Ca 2ϩ oscillations are produced by PLC expressed in a mouse egg at an estimated level comparable to the content in single mouse sperm (2, 3). 2) Injection of recombinant PLC into mouse eggs induces Ca 2ϩ oscillations as well (7). 3) Ca 2ϩ oscillation-inducing ability of sperm extract injected into eggs (4, 8) is lost when pretreated with an antibody against PLC (2). 4) PLC content in the mouse sperm and the number of Ca 2ϩ spikes at fertilization are reduced by transgenic RNA interference of PLC (9). 5) PLC has such a high Ca 2ϩ sensitivity of PIP 2 -hydrolyzing activity that the enzyme can be active in the resting cells at ϳ100 nM Ca 2ϩ (7, 10), suitable for the sperm factor as the first stimulus in the egg cytoplasm at fertilization.Another important property of PLC is nuclear translocation ability. PLC expressed by RNA injection is accumulated into the formed PN (3,11,12). This is consistent with earlier observation that sperm-derived Ca 2ϩ oscillation-inducing activity is concentrated into PN formed several hours after fertilization, as examined by transfer of the oopla...

Young age and severe endometriosis appeared to be the factors associated with high recurrence risk. Recurring ovarian endometrimas probably include cysts occurring spontaneously and those recurring from the cyst residues in the lesions where cystectomy has been performed.