Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism.

OBJECTIVE: The gastrointestinal tract affects physiological activities and behavior by secreting hormones and generating signals through the activation of nutrient sensors. GPR119, a lipid sensor, is indirectly involved in the secretion of incretins, such as glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, by enteroendocrine cells, while it directly stimulates insulin secretion by pancreatic beta cells. Since GPR119 has the potential to modulate metabolic homeostasis in obesity and diabetes, it has attracted interest as a therapeutic target. However, previous studies have shown that the deletion of Gpr119 in mice does not affect glucose homeostasis and appetite in either basal or high-fat diet-fed conditions. Therefore, the present study aimed to explore the role of GPR119 signaling system in energy metabolism and feeding behavior in mice. METHODS: Gpr119 knockout (KO) mice were generated using CRISPR-Cas9 gene-editing technology, and their feeding behavior and energy metabolism were evaluated and compared with those of wild type (WT) mice. RESULTS: Upon inducing metabolic stress via food deprivation, Gpr119 KO mice exhibited lower blood glucose levels and a higher body weight reduction compared to WT mice. Although food intake in WT and KO mice were similar under free-feeding conditions, Gpr119 KO mice exhibited increased food intake when they were refed after 24 h of food deprivation. Further, food-deprived Gpr119 KO mice presented shorter post-meal intervals and lower satiety for second and later meals during refeeding, resulting in increased food intake. Associated with this meal pattern, levels of oleoylethanolamide (OEA), an endogenous agonist of GPR119, in the luminal contents of the distal gastrointestinal tract were elevated within 2 h after refeeding. The large-intestinal infusion of OEA prolonged post-meal intervals and increased satiety in the first meal, but not the second meal. On the other hand, infusion of oleic acid increased cecal OEA levels at 2 h from the beginning of infusion, while prolonging post-meal intervals and increasing satiety on the meals that occurred approximately 2 h after the infusion. Cecal OEA levels were low in antibiotic-treated mice, suggesting that the gut microbiota partially synthesizes OEA from oleic acid. CONCLUSIONS: Collectively, our results indicate that the activation of gastrointestinal GPR119 by microbiota-produced OEA derived from oleic acid is associated with satiety control and energy homeostasis under energy shortage conditions.

Clinical risk factors for patients with myelodysplastic syndromes undergoing allogeneic hematopoietic stem cell transplantation.

Objectives: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative treatment for myelodysplastic syndromes (MDS), although predicting post-transplant outcomes remains inconclusive. This study evaluated patients who underwent allo-HCT for MDS to identify prognostic factors and develop a clinical risk model.Methods: We evaluated 55 patients between June 2000 and March 2015 to identify prognostic factors and develop a model for three-year overall survival (OS) and event-free survival (EFS). Cox regression analysis was performed on four factors: age ≥55 years; Hematopoietic Cell Transplant-Comorbidity Index >2; intermediate or worse cytogenetic status based on revised International Prognostic Scoring System; and unrelated donor status associated with poor OS in the univariate analysis. A clinical risk model was constructed using the sum of the regression coefficients and evaluated using receiver operating characteristic analysis and five-fold cross-validation.Results: Patient median age was 51 (range: 30-67) years. Median follow-up was 45.8 (range: 1.27-193) months; the three-year OS and EFS rates were 61.8% and 56.4%, respectively. The areas under the curves (AUCs) for OS and EFS were 0.738 and 0.778, respectively, and the average AUC for 50 times five-fold cross-validation were 0.711 and 0.723 for three-year OS and EFS, respectively.Conclusion: A four-clinical-risk-factor model that could effectively predict post-transplantation outcomes and help decision-making in MDS treatment was developed.

Sex differences in serum levels of 5α-androstane-3ß, 17ß-diol, and androstenediol in the young adults: A liquid chromatography-tandem mass spectrometry study.

Animal experiments have consistently shown that estrogen receptor ß (ERß)-selective ligands have antidepressant and anxiolytic effects. In humans, endogenous ligands for ERß include 5α-androstane-3ß, 17ß-diol (3ßAdiol) and androstenediol (Δ5-diol). We determined, for the first time, the exact serum levels of 3ßAdiol and Δ5-diol in young healthy volunteers using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We investigated the effect of the menstrual cycle on the levels of these steroids in women; then, we performed a gender comparison. Blood samples were collected from 48 subjects: 23 women (mean age = 28.4±7.8 years) and 25 men (mean age = 31.4±7.8 years). We collected the blood samples of women at three time-points in the menstrual cycle: the early follicular phase, ovulatory or mid-cycle phase, and mid-luteal phase. A total of 92 blood samples were analyzed using LC-MS/MS. The levels of two well-studied steroids, namely dehydroepiandrosterone (DHEA) and 17ß-estradiol (E2), were simultaneously measured. Depression rating scale (Hamilton Rating Scale for Depression, Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology) scores were also recorded at the time of blood sampling. Significant differences in the levels of 3ßAdiol and E2 and in the depression rating scale scores were observed over the duration of the menstrual cycle of the women. The levels of 3ßAdiol and Δ5-diol were significantly lower in women than in men. E2 levels were higher in women than in men, and DHEA levels did not differ significantly between men and women. Further, women had higher scores than men on the Hamilton Rating Scale for Depression. Sex differences in depressive symptoms can be explained by 3ßAdiol and Δ5-diol levels, and the effect of the menstrual cycle on mood can be explained by 3ßAdiol and E2 levels, not by Δ5-diol level.

Passenger lymphocyte syndrome after ABO-incompatible allogeneic hematopoietic stem cell transplantation; dynamics of ABO allo-antibody and blood type conversion.

Passenger lymphocyte syndrome (PLS) is a specific subtype of graft versus host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) characterized by an immune-mediated hemolysis caused by donor-derived B cells. However, precise nature of PLS has not been well characterized due to its rarity. We herein report two cases of PLS following ABO-incompatible HSCT whose clinical course and dynamics of anti-ABO allo-antibody and blood type conversion were closely examined. Both cases demonstrated acute hemolysis upon engraftment, and the presence of high titer allo-antibody against recipients' red blood cells (RBCs) helped us to reach the diagnosis of PLS. Hemolysis in both cases showed spontaneous improvement with prednisolone and supportive therapy including transfusion and fluid support. In one case with blood type O, the patient recursively developed PLS in the second and the third HSCT from ABO-mismatch donors, leading to a hypothesis that original blood type O may serve as a background for acute elevation of serum anti-ABO antibody and therefore a risk for developing PLS in multiple ABO-incompatible HSCTs. When hemolysis is noted following ABO-incompatible HSCTs, PLS should be considered and measurement of anti-ABO antibodies is warranted.

Chiral Recognition of Pharmaceuticals Having a Xanthine Skeleton by (-)-Epigallocatechin-3-O-gallate in Water.

A mixture of pharmaceuticals having a xanthine skeleton, theophylline, proxyphylline, diprophylline and (-)-epigallocatechin-3-O-gallate (EGCg) in water created a sticky precipitates, which were thought to be 2 : 2 complexes of the pharmaceuticals and EGCg. The molecular capture ability of the pharmaceuticals having a xanthine skeleton by EGCg was estimated by the amount of the pharmaceuticals included in the precipitates of the complexes, and measured by the integrated value of proton signals in the quantitative 1H-NMR spectra. Based on changes in chemical shifts of proton signals of the pharmaceuticals with a xanthine skeleton in 1H-NMR spectra by adding standard amounts of EGCg, the xanthine skeleton of the pharmaceuticals was considered to exist in the hydrophobic space formed by the three aromatic A, B, B' rings of EGCg, and a part of the proxyphylline and diprophylline side chains existed out of the hydrophobic space. In the 1H-NMR spectra of the mixture of (R)- and (S)-proxyphylline, (R)- and (S)-diprophylline and an equimolecular amount of EGCg, the N3-CH3 signal of (R)- and (S)-proxyphylline, and (R)- and (S)-diprophylline was clearly observed as two singlets. This suggested that EGCg recognized the chirality of proxyphylline and diprophylline in water.

Chiral Recognition of Diketopiperazine Cyclo(Pro-Gly) and Propranolol Using (-)-Epigallocatechin-3-O-gallate.

In the (1)H-NMR spectrum of a solution containing an equimolecular amount of cyclo(L-Pro-Gly), cyclo(D-Pro-Gly) and (-)-epigallocatechin-3-O-gallate (EGCg) in a D2O, a difference in the chemical shift of (1)H-NMR signal for H7α, H7ß,8α of the Pro residue was observed. Judging from the crystal structures of the 2 : 2 complexes of EGCg and cyclo(L-Pro-Gly), cyclo(D-Pro-Gly), the difference in the chemical shift resulted mainly from a magnetic anisotropic shielding effect by the ring current from the B ring of EGCg. Therefore, it was considered that chirality of cyclo(Pro-Gly) was recognized by EGCg in the D2O solution. Furthermore, in the (1)H-NMR spectrum of a solution containing an equimolecular amount of racemic propranolol ((R)- and (S)-propranolols) and EGCg in D2O, the (1)H-NMR signal for H2 of the naphthalene group was observed as two doublets, suggesting that the racemic propranolol formed diastereomers of complexes with EGCg; as a result, chirality of propranolol was recognized by EGCg in the D2O solution.