Periodontal tissue susceptibility to glycaemic control in type 2 diabetes.

Aim: To assess the direct effect of intensive glycaemic control on periodontal tissues in patients with diabetes mellitus.

Materials And Methods: Twenty-nine patients with type 2 diabetes were enrolled and hospitalized to receive a 2-week intensive glycaemic control regimen. We observed and analysed the systemic and oral disease indicators before and after treatment and clarified the indicators related to periodontal inflammation.

Evaluation of changes in glycemic control and diabetic complications over time and factors associated with the progression of diabetic complications in Japanese patients with juvenile-onset type 1 diabetes mellitus.

Background: This study aimed to evaluate the changes in glycemic control and diabetic complications over time in Japanese patients with juvenile-onset type 1 diabetes mellitus and to clarify the factors associated with the progression of diabetic complications.

Methods: We tracked 129 patients with type 1 diabetes mellitus (21.8 ± 4.

Discovery of a novel series of medium-sized cyclic enteropeptidase inhibitors.

Enteropeptidase is located in the duodenum that involved in intestinal protein digestion. We have reported enteropeptidase inhibitors with low systemic exposure. The aim of this study was to discover novel enteropeptidase inhibitors showing more potent in vivo efficacy while retaining low systemic exposure.

Salivary metabolic signatures of carotid atherosclerosis in patients with type 2 diabetes hospitalized for treatment.

Atherosclerosis is a life-threatening disease associated with morbidity and mortality in patients with type 2 diabetes (T2D). This study aimed to characterize a salivary signature of atherosclerosis based on evaluation of carotid intima-media thickness (IMT) to develop a non-invasive predictive tool for diagnosis and disease follow-up. Metabolites in saliva and plasma samples collected at admission and after treatment from 25 T2D patients hospitalized for 2 weeks to undergo medical treatment for diabetes were comprehensively profiled using metabolomic profiling with gas chromatography-mass spectrometry.

Change in fatty acid composition of plasma triglyceride caused by a 2 week comprehensive risk management for diabetes: A prospective observational study of type 2 diabetes patients with supercritical fluid chromatography/mass spectrometry-based semi-target lipidomic analysis.

Aims/introduction: Hypertriglyceridemia is common in patients with diabetes. Although the fatty acid (FA) composition of triglycerides (TGs) is suggested to be related to the pathology of diabetes and its complications, changes in the fatty acid composition caused by diabetes treatment remain unclear. This study aimed to identify short-term changes in the fatty acid composition of plasma triglycerides after diabetes treatment.

Comparison of continuous subcutaneous insulin infusion treatment and multiple daily injection treatment on the progression of diabetic complications in Japanese patients with juvenile-onset type 1 diabetes mellitus.

To evaluate whether continuous subcutaneous insulin infusion attenuates the progression of diabetic complications, we retrospectively extracted data from 35 individuals who had developed type 1 diabetes mellitus aged ≤20 years and whose treatment had been changed from multiple daily injections to continuous subcutaneous insulin infusion. The annual changes in estimated glomerular filtration rate, urinary albumin excretion rate, carotid intima-media thickness and brachial-ankle pulse wave velocity during each treatment period were calculated. Although mean glycated hemoglobin under the continuous subcutaneous insulin infusion treatment was lower than that under the multiple daily injection treatment, there were no significant differences in annual changes in diabetic nephropathy and atherosclerosis between the two treatment periods.

Saliva and Plasma Reflect Metabolism Altered by Diabetes and Periodontitis.

Periodontitis is an inflammatory disorder caused by disintegration of the balance between the periodontal microbiome and host response. While growing evidence suggests links between periodontitis and various metabolic disorders including type 2 diabetes (T2D), non-alcoholic liver disease, and cardiovascular disease (CVD), which often coexist in individuals with abdominal obesity, factors linking periodontal inflammation to common metabolic alterations remain to be fully elucidated. More detailed characterization of metabolomic profiles associated with multiple oral and cardiometabolic traits may provide better understanding of the complexity of oral-systemic crosstalk and its underlying mechanism.

Evaluation of change in metabolome caused by comprehensive diabetes treatment: A prospective observational study of diabetes inpatients with gas chromatography/mass spectrometry-based non-target metabolomic analysis.

Aims/introduction: Diabetes patients develop a variety of metabolic abnormalities in addition to hyperglycemia. However, details regarding change in various metabolites after comprehensive diabetes treatment remain unknown. This study aimed to identify the short-term change in metabolome in inpatients who were subject to comprehensive diabetes treatment, using gas chromatography/mass spectrometry-based non-target metabolomics techniques.

Associations of continuous glucose monitoring-assessed glucose variability with intima-media thickness and ultrasonic tissue characteristics of the carotid arteries: a cross-sectional analysis in patients with type 2 diabetes.

Background: The association between glucose variability and the progression of atherosclerosis is not completely understood. We aimed to evaluate the associations of glucose variability with the progression of atherosclerosis in the early stages.

Methods: We conducted a cross-sectional analysis to investigate the associations of glucose variability, assessed by continuous glucose monitoring, with intima-media thickness (IMT) and gray-scale median (GSM) of the carotid arteries, which are different indicators for the progression of atherosclerosis.

Plasma xanthine oxidoreductase activity in Japanese patients with type 2 diabetes across hospitalized treatment.

Aims/introduction: Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine and xanthine to xanthine and uric acid, respectively. Plasma XOR activity has recently been measured in humans. However, limited information is known about plasma XOR activity in patients with type 2 diabetes mellitus, and its changes after short-term glycemic control treatment.

Plasma metabolites associated with arterial stiffness in patients with type 2 diabetes.

Background: Although an increased arterial stiffness has been associated with traditional coronary risk factors, the risk factors and pathology of arterial stiffness remain unclear. In this study, we aimed to identify the plasma metabolites associated with arterial stiffness in patients with type 2 diabetes mellitus.

Methods: We used the metabolomic data of 209 patients with type 2 diabetes as the first dataset for screening.

Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor γt (RORγt) Agonist Structure-Based Functionality Switching Approach from In House RORγt Inverse Agonist to RORγt Agonist.

Retinoic acid receptor-related orphan receptor γt (RORγt) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation of Th17 cells and Tc17 cells. Herein, we describe a novel structure-based functionality switching approach from in house well-optimized RORγt inverse agonists to potent RORγt agonists. We succeeded in the identification of potent RORγt agonist 5 without major chemical structure change.

Reductive Formation of a Vanadium(IV/V) Oxide Cluster Complex [VO(4,4'- Bubpy)] Having a C-Symmetric Propeller-Shaped Nonionic VO Core.

A novel C-symmetric propeller-shaped vanadium(IV/V) oxide cluster complex, [VO(4,4'- Bubpy)] (V'), has been synthesized from the reaction of the windmill-shaped vanadium(V) oxide cluster complex [VO(4,4'- Bubpy)] (V) with PPh under N, whereas refluxing V in methanol or ethanol under N provides tetranuclear oxido(alkoxido)vanadium(IV/V) complexes [VO(OR)(4,4'- Bubpy)] [R = Me (V'-Me) and Et (V'-Et)]. The mixed-valent vanadium(IV/V) clusters V' and V' are converted back to V under O. Interconversions of V' and the oxido(alkoxido)vanadium(V) complexes [VO(OMe)(4,4'- Bubpy)] (V) and [VO(OEt)(4,4'- Bubpy)] (V-Et) are also presented.

Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile.

We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity.

Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist.

A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log  D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile.

Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives.

A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile.

Design and synthesis of a novel series of orally active, selective somatostatin receptor 2 agonists for the treatment of type 2 diabetes.

The discovery of a novel series of β-methyltryptophan (β MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A, β-MeTrp derivative with highly potent and selective SSTR2 agonistic activity IC (SSTR2/SSTR5)=0.3/>100 (nM), was identified asa drug candidate for treatment of Type 2 diabetes which lowers significantly plasma glucose level in Wistar fatty rats in its oral administrations.

Synthesis and Interconversion of V4, V7, and V8 Oxide Clusters: Unexpected Formation of Neutral Heptanuclear Oxido(alkoxido)vanadium(V) Clusters [V7O17(OR)(4,4'-(t)Bubpy)3] (R = Et, MeOC2H4).

The octanuclear oxidovanadium(V) complex [V8O20(4,4'-(t)Bubpy)4] (1; 4,4'-(t)Bubpy = 4,4'-di-tert-butyl-2,2'-bipyridine) was synthesized in multigram-scale quantities by the reaction of VOSO4 with 4,4'-(t)Bubpy in the presence of sodium benzoate under O2. The reaction of 1 with MeOH under air afforded the tetranuclear oxidovanadium(V) complex [V4O8(OMe)4(4,4'-(t)Bubpy)2] (2) selectively. In contrast, treatment of 1 with EtOH or MeOC2H4OH under air gave the heptanuclear oxidovanadium(V) complexes [V7O17(OR)(4,4'-(t)Bubpy)3] (R = Et (3a), MeOC2H4 (3b)) having an unprecedented neutral V7O17(OR) core.

Discovery of novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives as γ-secretase modulators (Part 2).

γ-Secretase modulators (GSMs), which lower pathogenic amyloid beta (Aβ) without affecting the production of total Aβ or Notch signal, have emerged as a potential therapeutic agent for Alzheimer's disease (AD). A novel series of 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives was discovered and characterized as GSMs. Optimization of substituents at the 8-position of the core scaffold using ligand-lipophilicity efficiency (LLE) as a drug-likeness guideline led to identification of various types of high-LLE GSMs.

A novel octanuclear vanadium(V) oxide cluster complex having an unprecedented neutral V8O20 core functionalized with 4,4'-di-tert-butyl-2,2'-bipyridine.

A novel octanuclear vanadium(V) oxide cluster complex, [V8O20(4,4'-(t)Bubpy)4] (1), was synthesized and characterized by single-crystal X-ray structure analysis to reveal that 1 has an unprecedented neutral V8O20 core. An unexpected interconversion between 1 and the methoxo(oxo)vanadium(V) cluster complex, [V4O8(OMe)4(4,4'-(t)Bubpy)2] (2), was observed upon changes in the solvent systems.

Design and synthesis of potent inhibitor of apoptosis (IAP) proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic.

To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC(50): 1.

Synthesis and characterization of hydrophobic zeolite for the treatment of hydrocarbon contaminated ground water.

Hydrophobic zeolite was synthesized, modified and characterized for its suitability as a permeable reactive barrier (PRB) material for treatment of hydrocarbons in groundwater. Batch sorption tests were performed along with a number of standard characterization techniques. High and low ionic strength and pH tests were also conducted to determine their impact on hydrocarbon uptake.

Highly enantioselective reformatsky reaction of ketones: chelation-assisted enantioface discrimination.

[reaction: see text] Highly enantioselective Reformatsky reaction of ketones was accomplished using cinchona alkaloids as chiral ligands. Chelation with the sp(2)-nitrogen adjacent to the reactive carbonyl center contributed the enantioface discrimination for the high enantioselectivities.

Fas-mediated apoptosis of peripheral blood mononuclear cells in patients with hepatitis C.

In the present study, we demonstrated that a close relationship exists between hepatitis C virus (HCV) infection of peripheral blood mononuclear cells (PBMCs) and cell-surface Fas expression in patients with hepatitis C, and showed the possibility of PBMCs apoptosis via a Fas-mediated system. The expression of Fas on PBMCs was found by flowcytometric analysis to be significantly increased in these patients. In addition, the treatment of patients' PBMCs with anti-Fas antibody induced cell death, with nuclear condensation and fragmentation and cellular DNA fragmentation.