Establishing a whole blood CD4 T cell immunity measurement to predict response to anti-PD-1.

Background: Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62LCD4 T cells (effector T cells; %Teff) and CD4CD25FOXP3 T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method.

A study of the prebiotic effect of lactulose at low dosages in healthy Japanese women.

To investigate the prebiotic effect of lactulose at low dosages, we assessed changes in defaecation frequency following ingestion of 1, 2, or 3 g/day of lactulose for 2 weeks. Each test was carried out after a 2-week washout period. This was an open-label, before-after trial that enrolled 26 healthy Japanese women.

Reducing effect of calcium in combination with magnesium and lactulose on body fat mass in middle-aged Japanese women.

Background: It has been reported that adequate calcium intake decreases body fat and appropriate intakes of magnesium suppress the development of the metabolic syndrome. Furthermore, lactulose increases the absorption of calcium and magnesium. An optimal combination of calcium, magnesium and lactulose may therefore reduce body fat mass.

Inhibitory effect of ramosetron on corticotropin releasing factor- and soybean oil-induced delays in gastric emptying in rats.

Background And Aim: Symptoms of functional dyspepsia (FD) are highly prevalent in patients with irritable bowel syndrome (IBS). However, the effects of therapeutic agents for IBS on the pathophysiology of FD are unclear. In this study, therefore, we examined the effects of ramosetron, a serotonin 5-HT(3) receptor antagonist, on corticotropin releasing factor (CRF)- and soybean oil-induced delays in gastric emptying of rats, in comparison with anti-diarrheal agent and spasmolytics.

In vitro and in vivo characterization of AS2643361, a novel and highly potent inosine 5'-monophosphate dehydrogenase inhibitor.

Inosine 5'-monophosphate (IMP) dehydrogenase is a critical target in solid organ transplantation. To this end, the development of mycophenolate mofetil (MMF) represents a major advance in transplant medicine. Here, we investigated the in vitro and in vivo pharmacological effects of a novel IMP dehydrogenase inhibitor, AS2643361, in several immunological and non-immunological models.

Alleviating effects of AS1892802, a Rho kinase inhibitor, on osteoarthritic disorders in rodents.

The effects of AS1892802, a selective Rho-associated coiled coil kinase (ROCK) inhibitor, on knee cartilage damage and pain behavior were examined in a rat model of osteoarthritis (OA). Monoiodoacetate (MIA) was intraarticularly injected into the right knee joints of rats. ROCK I and II mRNA levels increased in knee joints of MIA-injected rats.

Effect of the inosine 5'-monophosphate dehydrogenase inhibitor BMS-566419 on renal fibrosis in unilateral ureteral obstruction in rats.

Chronic allograft nephropathy (CAN) is a major cause of late allograft loss. One morphological characteristic of CAN is renal interstitial fibrosis. Mycophenolate mofetil (MMF), the inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, has been reported to attenuate the progression of renal interstitial fibrosis.

Effect of the inosine 5'-monophosphate dehydrogenase inhibitor BMS-566419 on rat cardiac allograft rejection.

Inosine 5'-monophosphate dehydrogenase (IMPDH) inhibition is a critical target in solid organ transplantation, and the development of mycophenolate mofetil (MMF) represents a major advance in transplant medicine. In this study, the in vitro and in vivo pharmacological effects of BMS-566419, a novel chemically synthesized IMPDH inhibitor, were compared to those of mycophenolic acid (MPA) and MMF based on results from several immunological experiments. The in vitro inhibitory activity of BMS-566419 on IMPDH type I/II, immune cell proliferation and antibody production from lipopolysaccharide (LPS)-stimulated B cells was similar, albeit slightly less potent than that of MPA.

Efficacy of oral treatment with tacrolimus in the renal transplant model in cynomolgus monkeys.

Many studies have examined the efficacy of tacrolimus in rats and dogs, but few have reported its evaluation in cynomolgus monkeys. The aim of this study was to clarify the efficacy of tacrolimus in a cynomolgus monkey renal transplant model based on the efficacy of various doses. Monkeys that had undergone renal transplant were treated with a vehicle or 0.

Effect of lactulose on calcium and magnesium absorption: a study using stable isotopes in adult men.

To evaluate the effect of lactulose on calcium (Ca) and magnesium (Mg) absorption, we performed a clinical trial with a double-blind, randomized, crossover design in 24 healthy adult male volunteers. The absorptions of Ca and Mg were evaluated by a single-labeling method using stable isotopes. The test foods, containing lactulose at a dose of 0 g (placebo), 2 g (low-dose), or 4 g (high-dose) together with 300 mg of Ca containing 20 mg of 44Ca, and 150 mg of Mg containing 28 mg of 25Mg, were administered orally.

Hyperresponsive TH2 cells with enhanced nuclear factor-kappa B activation induce atopic dermatitis-like skin lesions in Nishiki-nezumi Cinnamon/Nagoya mice.

Background: Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) mice raised in nonair-controlled conventional circumstances spontaneously develop atopic dermatitis-like skin lesions; however, the underlying mechanisms remain unclear.

Objective: We wanted to identify the critical intracellular signaling molecules in T cells that induce atopic dermatitis-like skin legions in NC/Nga mice.

Methods: We examined the levels of signal transduction and cytokine production in T cells, particularly those in atopic dermatitis-like lesions induced by the topical injection of mite antigens in NC/Nga mice under specific pathogen-free conditions.

Anti-inflammatory activity of non-nucleoside adenosine deaminase inhibitor FR234938.

Adenosine has anti-inflammatory activity. Adenosine deaminase (EC 3.5.

Structural basis of compound recognition by adenosine deaminase.

Structural snapshots corresponding to various states enable elucidation of the molecular recognition mechanism of enzymes. Adenosine deaminase has two distinct conformations, an open form and a closed form, although it has so far been unclear what factors influence adaptation of the alternative conformations. Herein, we have determined the first nonligated structure as an initial state, which was the open form, and have thereby rationally deduced the molecular recognition mechanism.

Characterization of a transglutaminase from scallop hemocyte and identification of its intracellular substrates.

Scallop hemocytes contain a transglutaminase (TGase) that is electrophoretically different from the TGase in the adductor muscle. The optimum temperature of the hemocyte TGase was lower (about 15 degrees C), compared with the muscle TGase (35-40 degrees C). Other properties, such as the high sodium chloride (NaCl) and CaCl2 concentrations required for activation, instability in salt solutions, and the Km values against monodansylcadaverine (MDC) and succinylated casein, were similar for both enzymes.

Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors.

We disclose herein optimization efforts around the novel, highly potent non-nucleoside adenosine deaminase (ADA) inhibitor, 1-[(R)-1-hydroxy-4-(6-(3-(1-methylbenzimidazol-2-yl)propionylamino)indol-1-yl)-2-butyl]imidazole-4-carboxamide 1 (K(i)= 7.7 nM), which we recently reported. Structure-based drug design (SBDD) utilizing the crystal structure of the 1/ADA complex was performed in order to obtain structure-activity relationships (SAR) for this type of compound rationally and effectively.

Structure-based design and synthesis of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors.

We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K(i) = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K(i) = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we discovered two inhibitors with improved oral bioavailability [6 (K(i) = 13 nM, BA = 44%) and 7 (K(i) = 9.

Transformation of lactulose trihydrate into anhydrous lactulose by fluidized bed drying and its characterization.

Stable anhydrous lactulose was produced from lactulose trihydrate by stepwise heating on a fluidized bed. The processes were performed on stable powder forms. The anhydrous lactulose was characterized by an opaque white appearance, a coarse surface structure with random cracks and indentations, a high degree of crystallization, stability under humid conditions, and by X-ray powder diffraction, differential thermal analysis, and differential thermogravimetry.

CD28 costimulation controls histone hyperacetylation of the interleukin 5 gene locus in developing th2 cells.

Interleukin 5 (IL-5) plays a unique role in allergic inflammatory responses, and the understanding of molecular mechanisms underlying the generation of IL-5-producing cells is crucial for the regulation of allergic disorders. Differentiation of naive CD4 T cells into type-2 helper (Th2) cells is accompanied by chromatin remodeling including hyperacetylation of histones H3 and H4 in the nucleosomes associated with the IL-4, IL-13, and IL-5 genes. Histone hyperacetylation of the IL-5 gene displayed a delayed kinetics compared with that of the IL-4 and IL-13 genes, suggesting a distinct remodeling mechanism for the IL-5-gene locus.

Aspolin, a novel extremely aspartic acid-rich protein in fish muscle, promotes iron-mediated demethylation of trimethylamine-N-oxide.

Trimethylamine-N-oxide (TMAO) is abundant in marine fish. Formaldehyde synthesis by TMAO demethylation during storage markedly deteriorates fish meat. In the present work, we cloned the extremely aspartic acid-rich proteins from skeletal muscle of a commercially important species, walleye pollack, in the course of molecular identification of trimethylamine-N-oxide demethylase (TMAOase).

Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis.

It has been shown that osteopontin (OPN) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). However, the molecular mechanism of OPN action is yet to be elucidated. Splenic monocytes obtained from arthritic mice exhibited a significant capacity for cell migration toward thrombin-cleaved OPN but not toward full-length OPN.

FR252921, a novel immunosuppressive agent isolated from Pseudomonas fluorescens no. 408813 II. In vitro property and mode of action.

A novel immunosuppressive agent, FR252921 was isolated from the cultured broth of a species of Pseudomonas fluorescens. We have shown that FR252921 inhibited splenic proliferation stimulated with LPS, insensitive to calcinuerin inhibitor. In this study, FR252921 was found to inhibit IL-2 and IL-12 production as well as proliferaion of splenocyte.

Structure-based de novo design of non-nucleoside adenosine deaminase inhibitors.

We searched for non-nucleoside inhibitors of adenosine deaminase by rational structure-based de novo design and succeeded in the discovery of 1-(1-hydroxy-4-phenyl-2-butyl)imidazole-4-carboxamide (FR221647: K(i)=5.9 microM to human ADA) as a novel inhibitor with moderate activity and good pharmacokinetics compared with the known inhibitors pentostatin and EHNA.

Quinoline-3-carbothioamides and related compounds as novel immunomodulating agents.

A series of quinoline-3-carbothioamides and their analogues was prepared via four synthetic routes and evaluated for their antinephritic and immunomodulating activities. The optimal compound 9g strongly inhibited the T-cell independent antibody production in mice immunized with TNP-LPS and was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.